|Year : 2022 | Volume
| Issue : 2 | Page : 125-132
Molecular profiling of large B-Cell lymphomas : A retrospective observational pilot study
Amrit Kaur Kaler1, Shaila1, R Ashwini2, R Veena1, Sachin Jadav3, Baby Dharman2, Ramesh Patil4, Gautam Balaram2, Prassana Kumari2, Mithua Ghosh2, Shruthi Sudarshan2, BS Ajai Kumar5
1 Department of Pathology, HCG Cancer Care Hospital, Bangaluru, Karnataka, India
2 Department of Molecular and Clinical Genomics, HCG Cancer Care Hospital, Bangaluru, Karnataka, India
3 Department of Hematology, HCG Cancer Care Hospital, Bangaluru, Karnataka, India
4 Department of Statistics, HCG Cancer Care Hospital, Bangaluru, Karnataka, India
5 Department of Radiation Oncology, HCG Cancer Care Hospital, Bangaluru, Karnataka, India
|Date of Submission||17-Oct-2022|
|Date of Decision||11-Nov-2022|
|Date of Acceptance||23-Nov-2022|
|Date of Web Publication||06-Feb-2023|
Dr. Amrit Kaur Kaler
Molecular Pathology and Genomics, Department of Laboratory Medicine, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Large B-cell non-Hodgkin's lymphoma (NHL) comprises of a heterogeneous group of lymphomas with a high-grade morphology and aggressive nature. The diagnosis has gradually evolved from morphological characterization to classification of this group based on ancillary techniques such as immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and molecular studies. Diffuse large B-cell lymphomas (DLBCL), not otherwise specified (NOS) is the most common B-cell NHL reported and a new diagnostic entity termed high-grade B-cell lymphoma harboring an MYC rearrangement with a BCL2 and/or BCL6 have been introduced by the WHO in 2017. MYC and BCL2/BCL6 proteins expression on IHC due to mutations leading to nuclear factor kappa B pathway activation is considered as double-expressor lymphoma (DEL).
Materials and Methods: Sixty-two patients diagnosed with DLBCL, NOS on histopathology were subjected to IHC markers such as (CD20, CD79a, PAX5, CD10, Bcl6, Bcl2, MUM1, TDT, and Myc) and classified into activated B-cell and germinal center B-cell based on Hans' Algorithm. The samples were consequently subjected to tissue FISH for the detection of MYC, BCL2, and BCL6 gene translocations and classified as double-hit lymphoma (DHL)/triple-hit lymphoma (THL). The FISH results were subsequently compared for IHC expression of c-myc, Bcl2, and Bcl6. The staging, international prognostic index (IPI) scoring and lactate dehydrogenase levels were compared with progression-free survival (PFS) of 15 months among DHL/THL and DEL/TEL.
Results: The median age of presentation among DLBCL-NOS patients is 58 years, while males (66.7%) were affected more commonly than females (33.3%). The majority of the patients presented with nodal involvement (71%) while extranodal involvement was seen in 29% cases. Hans' algorithm showed a significant P value with the IHC expression of BCL2, BCL6 and C-MYC. IHC and FISH correlation for BCL2 and BCL6 showed 100% sensitivity and 100% negative predictive value. IHC and FISH for c-MYC showed concordant results with a significant P < 0.03. The clinicopathological results of S/D/THL showed association with higher stage disease, higher IPI scoring, and high Ki-67 index with inferior PFS.
Conclusions: IHC MYC is a sensitive screening modality for MYC translocation and can be used for the identification of rearrangement in lower socioeconomic areas. Based on clinicopathological studies, all patients with DLBCL must undergo MYC FISH testing as these patients behave as high-grade lymphomas. Hence, a new entity DLBCL with MYC rearrangement without BCL-2/6 rearrangements maybe considered as a novel entity and to be studied in future cohorts.
Keywords: Cell of origin, expressors, hits, international prognostic index scoring, large B-cell lymphomas, survival
|How to cite this article:|
Kaler AK, Shaila, Ashwini R, Veena R, Jadav S, Dharman B, Patil R, Balaram G, Kumari P, Ghosh M, Sudarshan S, Ajai Kumar B S. Molecular profiling of large B-Cell lymphomas : A retrospective observational pilot study. J Precis Oncol 2022;2:125-32
|How to cite this URL:|
Kaler AK, Shaila, Ashwini R, Veena R, Jadav S, Dharman B, Patil R, Balaram G, Kumari P, Ghosh M, Sudarshan S, Ajai Kumar B S. Molecular profiling of large B-Cell lymphomas : A retrospective observational pilot study. J Precis Oncol [serial online] 2022 [cited 2023 Mar 28];2:125-32. Available from: https://www.jprecisiononcology.com//text.asp?2022/2/2/125/369213
| Introduction|| |
WHO 2017 hematolymphoid classification has proposed a provisional classification of large B-cell lymphoma to encompass four categories, i.e., diffuse large B-cell lymphomas (DLBCL), not otherwise specified (NOS); other lymphomas of large B cells; high grade B-cell lymphomas (HGBLs), and B-cell lymphomas unclassifiable. The categorization has shifted significantly over the decades, from a purely morphologic diagnosis to the usage of sophisticated ancillary studies like immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and molecular analysis, in addition to clinical presentation. DLBCL is the most common subtype, accounts for 30%–40% of cases with the frequent development of resistance and/or relapse after treatment with standard chemotherapy. The patients usually present with rapidly enlarging single or multiple nodal involvement with 40% cases confined to extranodal sites.
DLBCL shows apparent heterogeneity in clinical outcome and has been divided into two broad subgroups based on cell of origin (COO) by Hans' IHC algorithm into activated B cell (ABC), and germinal center B-cell (GCB) subtypes. Apparently, GCB and ABC arise from B cell, at different stages of differentiation in germinal center and postgerminal center and they utilize different oncogenic pathways in tumorogenesis with varied impact on survival. GCB like tumors show a translocation at t (14;18)(q32;q21.3) which usually involves bcl2 genes and t (8;14)(q24;q32) involves myc genes while ABC like tumors shows activation of the nuclear factor kappa B pathway secondary to mutations.
DLBCL that shows the expression for both MYC and BCL2 by immunohistochemical (IHC) analysis is commonly known as double expressors which constitutes approximately 20%–30% of DLBCL. While the patients harboring an MYC rearrangement along with a BCL2 and/or BCL6 have been given a new diagnostic entity termed as HGBL, also commonly called as double-hit lymphoma (DHL) or triple-hit lymphoma (THL), respectively. The clinical outcome and prognosis of these translocations are usually poor when treated with rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, oncovin prednisone (R-CHOP) regimen.
The aim of this study is to understand the incidence of different types of large B-cell lymphomas, understand the molecular characterization by Hans Algorithm; correlate FISH and IHC of BCL2, BCL6 and c-MYC, comprehend the clinical presentation with double-expressor lymphoma (DEL) and dihydrotestosterone and to calculate the progression free survival (PFS) in these lymphomas.
| Materials and Methods|| |
An observational retrospective pilot study was carried out on a total of 62 retrospective cases diagnosed histopathologically proven as large B-cell lymphomas in a Tertiary Comprehensive Hospital, HealthCare Global Enterprises, Bengaluru India from 2018 to 2021. The provisional classification large B-cell lymphomas was referred from WHO 2017 classification of hematolymphoid systems.
The clinical data of all the patients were collected retrospectively from medical records which included proper history, primary site, age, biochemical parameters (e.g., lactate dehydrogenase [LDH]), bone marrow biopsy findings, and central nervous system (CNS) metastasis of Large B cell lymphoma (LBCL) was recorded. The prognosis was measured based on an arbor staging and international prognostic index (IPI) scoring which incorporates age, LDH, stage, Eastern Cooperative Oncology Group performance status (ECOG PS), and number of extranodal sites to calculate IPI score. IPI scoring was calculated using lymphoma IPI score calculator developed by MD App.
IHC studies were performed using formalin-fixed, paraffin-embedded tissue sections using an automated immunostainer (Benchmark XT) and a streptavidin-biotin peroxidase detection system. Monoclonal antibodies against CD3, CD20, CD79A, CD10, PAX 5, TdT, BCL6, MUM1, BCL2, C-MYC, and Ki-67 from Biocare were used. Heat retrieval was used for all antibodies, and tonsillar tissue was used as a positive control. Further processing for staining is done with autostainer Intelipath from Biocare. The results were reviewed and a standardized system of reporting was developed for percent of tumor cell positivity and nuclear intensity on the stained IHC slides. The cutoff scores for positive antibody staining were: 30% for CD10, MUM1, and BCL6, 50% for BCL2, 40% for CMYC. The Ki-67 of >70% was considered as high and was calculated using nuclear positivity of the number of cells. Double expressors were diagnosed based on the percentage of tumors cell showing >40% nuclear positivity for Myc (>40%); >50% cytoplasmic positivity for Bcl2 with/without >30% cytoplasmic positivity for Bcl6. The slides were reviewed blindly by 2 histopathologist for scoring the IHC percentage. The Hans Alogarithm is used to classify DLBCL into COO based on three markers (CD10, BCL6, MUM1) to distinguish between GCB and ABC type. The cases which could not be classified in either of the types were named as unclassifiable.
Fluorescence in situ hybridization protocol
FISH is a molecular cytogenetic method that detects fluorescently-labeled DNA/RNA or oligonucleotide probes hybridized to interphase/metaphase cells and then allows the visualization of specific target sequences in a cellular preparation. FISH detection is performed using 3 μm formalin-fixed, paraffin-embedded tissue sections with Metasystems probes. The sections are immersed in Xylene solution and dehydrated in 100% ethanol at room temperature. The slides are then subjected to pretreatment with proteinase K treatment with an ascending sequential ethanol series (70%, 95% and 100%). The probes are added to the slides, coverslipped and sealed with rubber cement and subjected to overnight hybridization using a prewarmed humidified hybridization chamber and incubate slides 37°C (14–18 h). The slides are subsequently washed next day in posthybridization buffers and subsequently counterstained with 4′,6-diamidino-2-phenylindole (DAPI), mounted and cover slipped and stored in dark room. Fluorescent signals are detected visually with a fluorescence microscope. In general, 200 interphase cells are analyzed per probe by two readers (100 cells/reader).
For detection of BCL2 gene translocation at t (14;18)(q32; q21.3) the Metasystems Dual Color XL BCL2 BA probe is designed as a break apart probe and consists of an orange-labeled probe hybridizing proximal to the BCL2 gene region at 18q21.3 and a green-labeled probe hybridizing distal to the BCL2 gene region at 18q21.3. The aberrant cell signals as one fusion signal and one break apart positive signal (1 green + one orange) indicates a chromosome break in BCL2 locus [Figure 1].
|Figure 1: (a) High power (×40) Section of DLBCL shows nuclear and cytoplasmic staining of BCL2 positive cells (>90%), (b). FISH analysis shows 2 fusion (yellow) signals and 1 green and 1 red signal. DLBCL: Diffuse large B cell Lymphomas. FISH: Fluorescence in situ hybridization|
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Similarly, for BCL6, metasystems XL BCL6 BA consists of a green-labeled probe hybridizing proximal to the BCL6 gene region at 3q27 and an orange-labeled probe hybridizing distal to the BCL6 gene region at 3q27-28. The signal interpretation is similar to BCL2 probe [Figure 2].
|Figure 2: (a) Low power (×10) section of DLBCL shows nuclear staining of c-MYC positive cells (>40%) (b) FISH analysis shows 1 green and 1 red and 2 fusion (yellow) signals. DLBCL: Diffuse large B cell Lymphomas. FISH: Fluorescence in situ hybridization|
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For c-myc gene translocation, metasystems XL t(8;14) MYC/IGH dual fusion probe, consists of an orange-labeled probe hybridizing to the MYC gene region at 8q24.21 and a green-labeled probe hybridizing to the IGH gene region at 14q32.3. The aberrant signal pattern consists of one green (1G), one orange (1O), and two fusion signals (2GO) resulting from a reciprocal translocation between the relevant loci [Figure 3].
|Figure 3: (a) High power (×40) section of DLBCL shows nuclear staining of BCL6 positive cells (>30%), (b) FISH analysis shows 1 green and 1 red and 1 fusion (yellow) signals. DLBCL: Diffuse large B cell Lymphomas. FISH: Fluorescence in situ hybridization|
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| Results|| |
The present study showed that majority of large B-cell lymphomas were composed of DLBCL, NOS (84%); 9% cases of other large B-cell Lymphomas, 4% cases of HBCL and B-cell lymphomas unclassifiable as 3% [Figure 4]. DLBCL with MYC rearrangements were included in DLBCL, NOS category. The median age of presentation among DLBCL-NOS patients (62 cases) is 58 years, while males (66.7%) were affected more commonly than females (33.3%).
The majority of the patients presented with nodal involvement (71%) while extranodal involvement was seen in 29% of cases. The extranodal sites include the following in descending order stomach, tonsils, thyroid, mediastinum, lung, adrenals, testicles, kidney, bladder, paravertebral soft tissue, and bone.
The COO determined on IHC based on Hans' algorithm showed a concordance with IHC positivity (BCL2, BCL6, and c-MYC) with molecular subtyping-COO (Hans Algorithm) with a significant P < 0.001. However, there was no significant P value associated with COO and BCL2, BCL6, and C-MYC translocation by FISH. However, GCB phenotype is noted in 48.4%, ABC in 43.5%, and ulcerative colitis in 6.4% of DLBCL cases [Figure 5] [Table 1], [Table 2] and [Table 3].
|Figure 5: Hans algorithm to classification B-cell lymphomas on the basis of cell of origin (molecular subtypes)|
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|Table 2: Correlation of cell of origin with immunohistochemistry percentage|
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The correlation between IHC results and FISH was done, which showed only 20.6% of cases positivity rate with maximum positive cases in IHC cut off percentage of >90% [Table 4]. Similarly, positive correlation in BCL6 and MYC was found in 12.1% and 23.5% of cases, respectively. However, the sensitivity and negative predictive value is found to be 100% in all three markers [Table 5] and [Table 6]. This proves that IHC can be an ideal screening modality for identifying a translocation. However, a definite cutoff criteria could not be established in BCL2 and BCL6 due to higher number of false-positive cases. A significant P (<0.03) could be established in c-Myc IHC of >40% as a good diagnostic cutoff criteria in locating FISH translocation.
|Table 4: B-cell lymphoma 2 immunohistochemistry and fluorescence in situ hybridization correlation showed 100% sensitivity, 17.2% specificity, 14.3% positive predictive value, and 100% negative predictive value|
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|Table 5: B-cell lymphoma 6 immunohistochemistry and fluorescence in situ hybridization correlation showed 100% sensitivity, 17.2% specificity, 14.3% positive predictive value and 100% negative predictive value|
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|Table 6: c-MYC immunohistochemistry and fluorescence in situ hybridization correlation showed 100% sensitivity, 45.8% specificity, 23.5% positive predictive value and 100% negative predictive value|
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The incidence of BCl2 translocation in our study is 23.9% and BCL6 is 14.6% and MYC is 18.9% of cases. Only 5.7% of with MYC-positive DLBCL cases showed an additional rearrangement in BCL2 and BCL6, also known as DHL/THL, which showed advanced disease, Ann Arbor staging, higher Ki-67% presentation, high IPI score and were put on additional therapy. Double/triple expression was seen in 27.4% of DLBCL cases. The clinicopathological parameters of double and triple hit and double expressors and triple expressors are tabulated in [Table 7] and [Figure 6].
|Table 7: Clinicopathological correlation of double/triple/hit/expressor lymphomas|
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Survival analysis demonstrated poorers PFS in double hit (n = 10 months) and double expression (n = 12 months) in our cohort as compared to DLBCL without any genomic alterations (n = 14 months) with no significant P value (P = 0.14 and P = 0.80, respectively) [Figure 7].
| Discussion|| |
DLBCL, NOS is the most common subtype of nonHodgkin lymphoma (NHL) and approximately 40% of patients will relapse after an initial response, and the majority of patients with relapsed DLBCL succumb to the disease. In an Indian study, Nair et al. stated that developing countries such as India have a varied difference in the presentation in DLBCL which include: A decade younger age (median age of 54 years), higher male-to-female ratio, higher proportion of patients with B-symptoms (40–60 vs. 20%–30%), poor ECOG PS (≥2) at diagnosis (50 vs. 20%–30%), higher frequency of DLBCL (60–70 vs. <40%), lower frequency of follicular NHL (<20 vs. 30%–40%).,, The present study showed DLBCL, NOS as the most common entity, with a median age of 58 years, affecting males more commonly than women, presented at a higher Stage (III-IV) with a higher IPI score, high LDH values and relapse within 15 months. The relapse is usually associated with poor outcomes regardless of molecular subtype in DLBCL.
The extranodal lymphomas were seen in 29% of cases in the present study with maximum number of cases in the gastrointestinal tract (GIT) followed by tonsil and thyroid (head and neck). Devi et al. in their study showed that head and neck was the most common site for extranodal lymphomas, whereas a study conducted by Pai et al. reported extranodal lymphomas constituted 22% of the total NHLs.,, Gross et al. in their study on 728 cases found GIT as the most common site with an incidence of NHL as 28%.
The molecular subtyping of DLBCL, NOS into GCB, ABC, based on gene expression profiling by IHC has been studied widely. Hans' algorithms provide the most concise classification based on markers CD10, Bcl6 and MUM1 as provided in [Table 2]. The relative frequencies of the GCB subtype and the ABC subtype have been studied on geographical location, median age of the patient population, and methodology used but are typically about 60% and 40%, respectively. The frequency of the GCB subtype is lower in East Asian countries such as China and Korea., The present Indian study showed an almost equal distribution of GCB (48%) and ABC (45%) subtypes.
The use of IHC as a screening modality for the detection of translocation involving MYC, BCL2, and BCL6 genes has been studied by different authors., For a BCL2 translocation, Oliveira et al. proposed a cutoff percentage of >50% and >70% cells and demonstrated significance at these cut-offs (P < 0.005). Significant findings were observed by Green et al. when using a cut-off of MYC >40% and BCL2 more than 70% on IHC. The present study focused on MYC cutoff percentage of >40%. A significant P (<0.03) was observed in c-Myc IHC suggesting MYC IHC >40% is a suitable diagnostic cut off criteria on IHC evaluation for identifying the myc translocation. Various cutoff criteria (>90%, >70% and >50%) were applied for BCL2, utilization of a higher cutoff value provided high sensitivity but excluded approximately half of the BCL-2 positive cases. BCl6 >30% demonstrated excellent negative predictive value but was associated with a high rate of false positives.
Double expressors lymphomas which overexpress MYC and BCL2 protein are aggressive DLBCLs and are also associated with advanced-stage disease, intermediate/high-risk to high-risk IPI scores, a higher Ki-67 proliferative index and an inferior complete response rate to R-CHOP hemotherapy. The present study had majority cases presented with multiple extranodal sites of disease with many cases showing extranodal origin. The treatment protocol of R-CHOP was started in <60 years with Regimen Bortezomib Rituximab in patients above 60 years. Two patients showed relapse and one patient died of complications of pneumonia and acute respiratory distress syndrome.
DHL is associated with extranodal involvement at presentation, have increased propensity to involve bone marrow (BM) and CNS in comparison to other subtypes, and associated with poor outcomes with standard chemoimmunotherapy., Petrich et al. described in their study that 67% of the patients were males, 81% demonstrated advanced-stage disease, and 76% were noted to have elevated LDH levels. The present study showed that 63.6% cases presented with advanced stage disease (Stage III-IV) and multiorgan involvement, IPI score >2, high LDH values (>500 IU/L) and males were involved in 75% cases. Two patients showed cutaneous metastasis at relapse and another one showed CNS involvement. These patients were upgraded to etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH) chemotherapy and PFS was measured at 15 months.
Herrera et al. described that PFS in patients with DEL was inferior to that of patients without MYC/BCL2 co-expression. The present study had similar findings (PFS 10 vs. 12 months) but was not statistically significant. Ott et al. reported that 58% to 83% MYC translocated DLBCL with concurrent dual or triple translocation with BCL2 and/or BCL6 (less likely) show an inferior outcome with overall survival of 12 months when treated with R-CHOP. They also studied 50 Patients with DHL which had poor OS, with a median survival of 13 versus 95 months for patients without DHL. The present study with single hit, double hit or triple hit lymphomas (SHL/DHL/THL) showed had inferior PFS of 8 months as compared to DLBCL without mutations.
We observed that DLBCL with FISH MYC positivity demonstrated clinical picture suggestive of HGBLs. The authors put forth an opinion that an additional entity may be considered as DLBCL with MYC rearrangement without BCL2 an BCL6 rearrangements and included under other large B-cell lymphomas. Moreover, this entity might show traslocations of DHL/THL on further follow-up. Studies on larger cohort may be necessary to validate this observation better.
| Conclusions|| |
The current study assesses the IHC profile and FISH translocations and revealed Hans Algorithm was useful in identifying the COO. FISH correlation of BCL2 and BCL6 with IHC did not provide a significant data. IHC MYC expression >40% is the only parameter which demonstrated statistical significance to FISH MYC reporting and can be considered as a significant marker for screening. DHL/THL showed an aggressive clinical presentation. High-grade disease was also observed in patients with only MYC rearrangements, and the entity of DLBCL with MYC rearrangements without BCL-2/6 rearrangements maybe considered as a novel separate entity and studied in future cohorts.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]