|Year : 2015 | Volume
| Issue : 2 | Page : 90-98
Immunoglobulin heavy-chain gene rearrangement in B-cell non-Hodgkin lymphoma using the fluorescence in-situ hybridization technique
Mohamed A. M. Mekawy1, Manal M Ismail1, Mahira I El Mogy1, Ahmed M. M. Mostafa1, Saad S Eissa2, Samy A Abu Sikkien3, Ghada M ElGohary MD 4
1 Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Histopathology, Egyptian National Cancer Institute, Cairo, Egypt
3 Department of Anatomy, Faculty of Medicine, Ain Shams University, Cairo, Egypt
4 Department of Internal Medicine/Adult Hematology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||09-May-2015|
|Date of Acceptance||15-May-2015|
|Date of Web Publication||22-Jul-2015|
Ghada M ElGohary
17 Ahmed Shafick Street 1121, Cairo
Source of Support: None, Conflict of Interest: None
Objectives Non-Hodgkin lymphoma (NHL) comprises an extremely heterogeneous group of clonal lymphoproliferative disorders that might be derived from either B-cell or T/NK-cell lineages. The molecular pathogenesis of NHL represents a complex process involving the accumulation of multiple genetic lesions, which include the activation of proto-oncogens such as BCL-1, BCL2, BCL6, and c-MYC by chromosomal translocation, as well as inactivation of tumor-suppressor genes such as TP53 by chromosomal deletion or mutation.
Aim of the study The present study aimed to detect immunoglobulin heavy-chain (IgH) gene rearrangement by the fluorescent in-situ hybridization (FISH) technique in paraffin-embedded bone marrow trephine and lymph node biopsies, and to correlate the presence of IgH chain gene rearrangement to the standard prognostic factors of NHL.
Participants and methods The present study was carried out on 50 newly diagnosed adults with NHL. The study included 26 diffuse large B-cell lymphoma patients, 21 follicular lymphoma (FL) patients, and three mantle cell lymphoma patients. FISH was performed using LSI 14q break-apart rearrangement probes.
Results The IgH gene rearrangement was detected by the FISH technique in lymph node sections of 36 out of 50 patients (72%) and only in six patients (12%) by trephine biopsy; also, it was found that 14q+ve patients were significantly associated with advanced stage of disease as well as low hemoglobin level, high total leukocytic count, low platelet count, high peripheral blood lymphocyte percentage, high lactate dehydrogenase level, and a high International Prognostic Index score. For diffuse large B-cell lymphoma, IgH gene rearrangement was detected in lymph node sections of 17/26 (65.4%) patients and in two patients by trephine biopsy, indicating a highly significant difference. In FL patients, IgH gene rearrangement was detected by the FISH technique in lymph node sections in 16/21 (76%) patients and in one patient (5%) by trephine biopsy, with a high statistical significance. For mantle cell lymphoma, IgH gene rearrangement was detected in all patients 3/3 (100%) both by lymph node and by trephine biopsies.
Conclusion This study shows the increasing importance of detailed cytogenetic analysis of NHL cases and focuses on the necessity of use of the FISH technique on lymph node as it identifies early cytogenetic aberrations that are not detected in a bone marrow trephine biopsy, except in stage IV lymphoma.
Keywords: fluorescent in-situ hybridization, immunoglobulin heavy chain, non-Hodgkin lymphoma
|How to cite this article:|
Mekawy MA, Ismail MM, El Mogy MI, Mostafa AM, Eissa SS, Abu Sikkien SA, ElGohary GM. Immunoglobulin heavy-chain gene rearrangement in B-cell non-Hodgkin lymphoma using the fluorescence in-situ hybridization technique. Egypt J Haematol 2015;40:90-8
|How to cite this URL:|
Mekawy MA, Ismail MM, El Mogy MI, Mostafa AM, Eissa SS, Abu Sikkien SA, ElGohary GM. Immunoglobulin heavy-chain gene rearrangement in B-cell non-Hodgkin lymphoma using the fluorescence in-situ hybridization technique. Egypt J Haematol [serial online] 2015 [cited 2020 Feb 20];40:90-8. Available from: http://www.ehj.eg.net/text.asp?2015/40/2/90/161295
| Introduction|| |
It is well known that certain recurrent cytogenetic abnormalities are the hallmark of neoplastic disease, including some subtypes of mature B-cell lymphomas. The presence of a particular abnormality may have diagnostic significance, such as t(14; 18) (q32;q21) in follicular lymphoma (FL), or prognostic/diagnostic significance such as t(11;14)(q13;q32) in mantle cell lymphoma (MCL)  .
The ability to detect such chromosomal translocations is thus very important in the evaluation of patients. The cytogenetic methods that are utilized to determine the presence of chromosomal abnormalities include conventional cytogenetic studies and fluorescence in-situ hybridization (FISH)  .
As conventional cytogenetic and FISH techniques require fresh, unfixed specimens, touch preparations, or air-dried smears, and analysis is limited by the availability of these tissue types, the ability to assess the genetic aberrations on fixed, paraffin-embedded specimens has great potential in the diagnosis of lymphoma  .
A successful method was described  to extract nuclei from fixed tissues and perform FISH on isolated, intact interphase nuclei. This method is straightforward and efficient. However, the nuclei extraction procedure requires preparation time, which may be unavailable in small laboratories.
The detection of genetic abnormalities (e.g. translocations, amplifications) in paraffin-embedded samples by the FISH technique could be performed on whole sections of formalin-fixed, paraffin-embedded tissues and be generalized for use in the testing of routine specimens. These routine specimens could be used for specific translocations that can be of diagnostic utility or may be prognostically significant in non-Hodgkin lymphomas (NHL)  .
The aim of this work was to detect immunoglobulin heavy-chain (IgH) gene rearrangement by the FISH technique in paraffin-embedded bone marrow (BM) trephine and lymph node (LN) biopsies. Moreover, the presence of IgH chain gene rearrangement was correlated to the standard prognostic factors of NHL.
| Participants and methods|| |
This study was carried out on 50 diagnosed adult NHL patients attending the Hematology/Oncology Unit of Ain Shams University Hospitals and the National Cancer Institute of Cairo University. The patients were diagnosed and selected as diffuse large B-cell lymphoma (DLBCL), FL, and MCL according to histopathologic examination, immunohistochemical analysis, and clinical findings.
All patients were subjected to the following:
- Full assessment of history and thorough clinical examination, with a focus on the presence of fever, weight loss, lymphadenopathy, hepatomegaly, and splenomegaly.
- Chest radiography, abdominal ultrasound, and/or computed tomography scan.
- Histopathological evaluation of LN biopsy.
- Complete blood count using Cell Dyne 1800 (Abbott Inc. USA).
- Lactate dehydrogenase (LDH) level assay using an automated analyzer (Synchron Cx9, (Beckman Coulter, Hileah, CA, USA)).
- Examination of Leishman-stained peripheral blood (PB) film for differential leukocytic count and assessment of lymphocyte number and morphology.
- BM aspiration with examination of Leishman-stained smears, with a focus on the BM cellularity and percentage of lymphocytes and their morphology.
- Histopathological evaluation of paraffin-embedded LN/BM trephine biopsy for further assessment of infiltration, followed by immunohistochemical analysis using CD markers for diagnosis.
- FISH technique using specific probes.
- One milliliter BM aspirate was collected on K-ethylene diamine tetraacetic acid (K 2 -EDTA) for Leishman-stained smears for morphological examination.
- Two milliliters of PB was collected on (K 2 -EDTA) and used for complete blood count, Leishman-stained smears.
- Two milliliters of clotted PB samples were obtained for the estimation of LDH.
- BM trephine biopsy was performed for all patients. A trephine core of about 1 cm was drawn and dispensed into a 2 ml preservative solution for histopathological evaluation of paraffin-embedded core biopsy and FISH.
- The LN biopsy histopathological results were obtained from the patients' files and LN biopsy paraffin-embedded slides were obtained for all patients for FISH to detect IgH chain gene 14q32.
Interpretation of results
At least 100 fixed cells were scanned in every case under the fluorescence microscope for the detection of 14q break-apart rearrangements. Negative cells showed two yellow signals (juxtaposed red and green or fused). Cells were considered positive for the rearrangements of 14q if more than 6% showed one yellow fusion signal, one red, and one green split signal  .
FISH was performed using fluorophore-labeled locus-specific identifier (LSI) 14q rearrangement.
Principle: The target DNA sequence in the chromosome to be analyzed is denaturated and hybridized to a single-stranded fluorophore-labeled complementary nucleic acid sequence (probe) that is detected using fluorescence microscopy  . Probe LSI 14q break-apart rearrangement is applied on LN and BM biopsy samples for the detection of 14q gene rearrangement.
Statistical analysis was carried out using the SPSS software, version 15 (SPSS Inc., Chicago, Illinois, USA). Data are expressed as mean ± SD, range or as number, percentage of cases. Comparison of proportions and means between both groups was carried out using the χ2 -test and independent t-test, respectively. Nonparametric data were analyzed using the Mann-Whitney test. The level P less than 0.05 was considered the cut-off value for significance.
| Results|| |
The results of this study are summarized in Tables 1-6 and Photos 1 and 2. This study was carried out on 50 newly diagnosed adults with NHL. Their ages ranged from 40 to 69 years, mean ± SD (53.02 ± 7.47 years). Overall, 37 were men and 13 were women, with a male to female ratio of 2.8 : 1.
Comparative studies on all patients showed that 36 out of 50 patients (72%) were 14q+ by LN biopsy, whereas only six (12%) were 14q+ by trephine biopsy, with a highly statistically significant difference (P < 0.001) ([Table 1]).
|Table 1 Comparative study between LN and trephine biopsies among all patient groups |
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14 q +ve patients were significantly associated with advanced stage of disease (18 were stage III and IV vs. one patient was stage III among 14q −ve patients) (P = 0.02) ([Table 2]).
|Table 2 Statistical comparison between 14q +ve and 14q −ve by FISH on LN biopsy of all studied patients |
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In addition, 14q +ve patients were associated with a low hemoglobin (Hb) level, high total leukocytic count (TLC), low platelet count, high PB lymphocytes percentage, high LDH, and a high International Prognostic Index (IPI) score revealing a highly significant relation (P < 0.001, 0.01, <0.01, <0.001, <0.001, and <0.001, respectively) ([Table 2]).
DLBCL patient group
This group included 26 DLBCL patients; 21 (80.8%) were men and five (19.2%) were women, with a male to female ratio of 4.2 : 1. Their ages ranged from 41 to 69 years, mean ± SD (52.88 ± 8.05 years). Comparative studies showed that 17/26 patients (65.4%) were 14q +ve by LN biopsy, whereas only 2 (7.7%) were positive by trephine biopsy, with a highly significant difference (P < 0.001) ([Table 3]).
|Table 3 Comparative study between LN and trephine biopsies among the DLBCL patient group |
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Comparison of 14q +ve and −ve patients in terms of all studied data showed that 14q +ve patients were associated with a lower Hb level, higher TLC, lower platelet count, higher PB lymphocytes percentage and a higher LDH level, and a high IPI score than 14q −ve patients, with a highly statistically significant difference (P < 0.001, <0.001, <0.01, <0.001, <0.001, and <0.001, respectively), whereas all other parameters showed no statistically significant difference (P>0.05) ([Table 4]).
|Table 4 Comparison between 14q −ve and 14q +ve among DLBCL patients on LN biopsy |
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FL patient group
This group included 21 FL patients; 13/21 (61.9%) were men and 8/21 (38.1%) were women, with a male to female ratio of 1.6 : 1. Their ages ranged from 40 to 67 years, mean ± SD (52.76 ± 7.35). Comparative studies showed that 16/21 patients (76%) were 14q+ve by LN biopsy, whereas only one patient (5%) was positive by trephine, with a highly statistically significant difference (P < 0.001) ([Table 5]).
|Table 5 Comparative study between LN and trephine biopsies among the FL patient group |
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Comparison between 14q −ve and +ve patients showed that 14q +ve patients were associated with lower Hb level, higher LDH, level, and a higher IPI score than 14q −ve patients, with a statistically significant difference (P < 0.01, <0.05, and <0.001, respectively), whereas all other parameters showed no significant statistical difference (P > 0.05) ([Table 6]).
|Table 6 Statistical comparison between 14q −ve and 14q +ve among FL patients on LN biopsy |
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MCL patient group
This group included three MCL patients; all were men. Their ages ranged from 54 to 57 years, with a mean ± SD of 56 ± 1.73. FISH on LN biopsy and BM trephine samples showed that 14q gene rearrangement was detected in all three patients in the MCL group (100%). They all were men with hepatomegaly, splenomegaly, and score IV of IPI.
| Discussion|| |
The discovery that nonrandom recurring genetic aberrations are involved in the pathogenesis of NHL has provided new insights into the understanding of these diseases, improved their classification as well as revolutionized their diagnosis, prognosis, and therapy monitoring  .
The wide clinicopathologic heterogeneity of NHL reflects differences in the genetic aberrations underlying the pathogenesis, which involves inactivation of tumor-suppressor genes including TP53 (17p13), p16, and Rb genes  as well as activation of protooncogenes including c-Myc, BCL-1, BCL2, and BCL6 genes  .
Rearrangements involving the IgH gene have been identified in about 50% of NHL and correlated to clinical relevant subgroups. However, the detection rate varied markedly with the technique used  .
To diagnose these rearrangements, conventional cytogenetics requires fresh tissue samples and yields a relatively low success rate, making its use difficult under routine conditions. To overcome this limitation, FISH, performed on nuclei extracted from fresh or frozen samples, has been proposed as a reliable alternative to a conventional cytogenetic study  .
The aim of this study was to detect IgH gene rearrangement by the FISH technique in paraffin-embedded BM trephine and LN biopsies. Moreover, the presence of IgH chain gene rearrangement was correlated to the standard prognostic factors of NHL.
To highlight the role of IgH chain gene rearrangement in NHL using the FISH technique, this study aimed to analyze IgH chain gene rearrangement in 50 adults with NHL (26 DLBCL, 21 FL, and three MCL), evaluating its impact on the prognosis of these patients.
14q +ve gene rearrangement in LN biopsy was detected in 36 out of 50 patients (72%), whereas only 6 (12%) were 14q +ve by trephine, with a highly statistically significant relation. 14q +ve patients were found be associated with advanced stage of disease (18 were stage III and IV versus one stage III patient among 14q −ve patients, with a statistically significant difference.
In addition, 14q +ve patients were associated with low Hb level, high TLC, low platelet count, high PB lymphocyte percentage, high LDH level, and a high IPI score; similar results were obtained by Parry-Jones et al.  . These findings are in agreement with the predictive model for aggressive lymphomas, which considers tumor stage and LDH as markers of prognosis, and do not fit with age which was not significant in our study , .
In agreement with these results, Montoto et al.  reported nonsignificant differences between BCL2/IgH-positive and BCL2/IgH-negative subgroups in terms of sex and staging. However, they observed that patients harboring this molecular event were younger than BCL2-negative cases. This was further confirmed by Paszkiewicz-Kozik et al.  , who reported a higher frequency of BCL2 rearrangements in younger age groups, with no significant association among BCL2-positive patients with respect to their Hb level, platelet count, and LDH.
In the present study, IgH gene rearrangement was detected by FISH in LN sections of FL patients in 16/21 (76%) and in one patient (5%) by trephine biopsy, showing a highly significant relation. This was in agreement with Deghiedy et al.  , who detected these genetic aberrations in 14/18 (77.8%) patients using the FISH technique on LN samples.
Among FL patients, 14q +ve was associated with lower Hb level, higher LDH level, and a higher IPI score than 14q −ve, with a statistically significant relation.
The most common translocation encountered in FL is t(14;18), which involves the BCL2 gene. This gene is located in the 18q21 band, coding for an integral inner mitochondrial membrane protein, whose function is to inhibit apoptosis  .
This is in agreement with Sekiguchi et al.  , who found that FL that transformed into aggressive LBCL with a poor prognosis had a high frequency of t(14; 18).
In FL, t(14;18) is associated with a poor prognosis ,, . Matsumoto et al.  reported that the presence of t(14;18) was associated with a poor response to therapy and poor disease-free survival. Similarly, Goodlad et al.  reported that in patients with nodal or extranodal FL, those with t(14;18)-positive disease had a poor overall survival than those with t(14;18)-negative disease. In addition, t(14,18) was associated with poor survival in patients with DLBCL , .
Furthermore, the transformation from FL into DLBCL reportedly occurs more frequently in t(14;18)-positive patients than in t(14;18)-negative patients , .
T(14;18) is considered an initial event in the development of FL, resulting in the overexpression of BCL2 protein, which confers a growth advantage to the affected B-cell through inhibition of apoptosis  .
It was reported that 63.6 and 67% of FL patients were BCL2 positive using FISH and PCR techniques, respectively , .
It was found that 80-90% of FLs contain the t(14;18)(q32;q21), the most common chromosomal translocation in human lymphoid malignancy. On the derivative 14 chromosome resulting from this translocation, the gene BCL2 (B-cell leukemia and lymphoma 2), normally located on chromosome 18, is introduced into the IgH locus on chromosome 14  .
BCL2 protein is a member of a large family of proteins involved in the regulation of programmed cell death by their ability to modulate mitochondrial function; following its release in the cytosol, cytochrome C interacts with ApaF1 and activates caspase 9, which activates caspase 3, leading to the cleavage of target protein and DNA fragmentation  .
BCL2 functions are served through protein-protein interactions with a number of BCL2 homologues, including the death-promoting protein BAX. BAX can heterodimerize with BCL2 and homodimerize with itself. When it is overexpressed in cells, BAX homodimerizes and accelerates apoptotic cell death; when BCL2 is overexpressed, it heterodimerizes with BAX and inhibits cell death. Thus, the ratio of BCL2 to BAX is critical in determining the susceptibility to apoptosis  .
Regulation of BCL2 is through other BCL2 family members such as BAK (BCL2 homologous antagonist/killer), which can interact with BCL2 in a manner functionally similar to BAX, thus opposing the death-repressor activity of BCL2, BAD protein (BCL-X-associated death promoter), which negatively regulates BCL2 by displacing BAX from BCL2/BAX heterodimers in a concentration-dependent manner  .
Also, BAG-1 protein is not significantly homologous to the BCL2 family members, but can interact with BCL2 and enhances its death-repressor activity  .
Patients whose lymphoma contains the t(14;18) as a solitary abnormality usually have an indolent course compared with those whose tumors have additional karyotypic abnormalities; for example, additional structural breaks in chromosome 17 that affect the p53 gene locus at 17p13 have been shown to be a predictor of poor outcome and associated with histologic transformation of FL  . In addition to its well-defined role as an antagonist in apoptosis, BCL2 may act as an intercellular suppressor of cell motility and adhesion under certain conditions  .
In the present study, the low percentage of positivity of IgH gene rearrangement on trephine biopsy may be attributed to the low number of patients on stage IV.
Deghiedy et al.  proved that FISH is the method of choice for the detection of specific chromosomal aberrations. A similar observation was reported previously by Dey  , who suggested that this could be because of the use of FISH probes that span long regions of DNA according to the targeted sequences. Therefore, it enables the detection of chromosomal breakpoints that are widely dispersed.
In this study, among DLBCL patients, IgH gene rearrangement was detected by FISH in LN sections of 17/26 (65.4%) patients and in two patients (7.7%) by trephine biopsy. 14q +ve patients were associated with a lower Hb level, higher TLC, lower platelet count, higher PB lymphocyte percentage, a higher LDH level, and a higher IPI score than 14q −ve patients, with a highly significant statistical relation. Pasqualucci et al.  reported that the most common chromosomal translocations that occur at the IgH breakpoint in DLBCL are BCL6, whereas BCL2 occurs in ~25% of patients.
Akyurek et al.  found a lower frequency (31%) of BCL6-positive expression using Southern blot analysis in DLBCL patients. Also, Pervez et al.  observed an almost similar incidence (38%) by immunhistochemical studies. However, a lower frequency (25%) was reported by Barrans et al.  in DLBCL by FISH.
The high incidence of BCL6 rearrangements (20-40%) in DLBCL at diagnosis was discussed previously by Jardin and Sahota  . They reported that the most common translocation encountered in DLBCL is t(3;14) involving BCL6, which is a proto-oncogene located in the 3q27 region, coding for a zinc finger transcriptional repressor that is necessary for germinal center formation and the T-cell-dependent antibody response. Translocations involving band 3q27 result in the juxtaposition of the BCL6 coding region to heterologous promoters that lead to deregulated BCL6 gene expression. The dysregulated activity of BCL6 will have a marked effect on B-cell survival and function, with a potential to promote lymphomagenesis  .
These results confirmed those of the previous study of Vega et al.  , who reported that the BCL6 gene is translocated with a variety of partner chromosome loci in DLBCL and the most common karyotypic pattern of BCL6 positivity is t(3;14), where the IgH gene locus is most commonly involved in 40-50% of cases. The variety of partner chromosomes may indicate that the genetic mechanisms involved are not uniform among patients with BCL6 gene rearrangements.
The prognostic relevance of BCL6 rearrangements in DLBCL was addressed by several investigators and controversial results were reported without consistent data to allow a definite conclusion at present. Jardin et al.  attributed this controversy to cryptic rearrangements and/or the lack of a correlation between translocation and BCL6 expression as reported previously by Barrans et al.  , who suggested that rearrangement of the BCL6 gene does not directly lead to BCL6 protein expression in every case. This variation may be a reflection of the number of potential translocation partners. As a result of Ig/BCL6 translocation, overexpression of normal BCL6 protein occurs, which may favor apoptosis in these tumors if BCL2 is downregulated, and this would explain the favorable survival in this group of patients.
Among MCL patients, IgH gene rearrangement was detected by FISH in all patients (100%) both by LN and by trephine biopsies. This is in agreement with the results of Caraway et al.  and Parry-Jones et al.  . The reason for this positivity in all cases is the fact that all cases of MCL express t(11; 14) (q13; q32), which results in the juxtaposition of the cyclin D1 proto-oncogene to the enhancer sequence of the IgH gene, with the resultant overexpression of cyclin D1  .
Cyclin D1 plays a key role in cell cycle regulation during the G1/S transition by cooperating with cyclin-dependent kinases (CDK) 4 and 6. The complexes between these kinases, particularly CDK4 and cyclin D1 phosphorylate retinoblastoma, release the transcription factor E2 F from the influence of histone deacetylase, enabling active transcription and allowing the cell to proceed from the G1 phase to the S phase of the cell cycle. Cyclin D1 overexpression drives cell proliferation , . Further evidence suggests that cyclin D1 can function as an oncogene, the overexpression of which may lead to a growth advantage for tumor cells by way of cell cycle progression , .
| Conclusion|| |
This study shows the increasing importance of detailed cytogenetic analysis of NHL on LN biopsy as well as trephine biopsy. However, in early stages, cytogenetics performed on LN biopsy are recommended as it shows cytogenetic aberrations that are not detected in a BM trephine biopsy, except in stage IV lymphoma. Moreover, the 14q +ve gene rearrangement was found to be associated with poor prognostic factors.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]