Lymphomas morphologically, immunohistochemically, and ISH compatible with BL: A single-center experience

Neha Singh; Manoj Panigrahi; Payal Malhotra; Arvind Kumar; Namrata Kaul; Abhimanyu Sharma; Anurag Mehta

doi:10.4103/IJPM.IJPM_715_20

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LETTER TO EDITOR

Year : 2021 | Volume : 64 | Issue : 4 | Page : 870-872

Lymphomas morphologically, immunohistochemically, and ISH compatible with BL: A single-center experience

Neha Singh, Manoj Panigrahi, Payal Malhotra, Arvind Kumar, Namrata Kaul, Abhimanyu Sharma, Anurag Mehta
Department of Pathology and Lab Services, Rajiv Gandhi Cancer Institute and Research Center, New Delhi, India

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Date of Submission	01-Jul-2020
Date of Decision	15-Aug-2020
Date of Acceptance	23-Sep-2020
Date of Web Publication	20-Oct-2021

How to cite this article:
Singh N, Panigrahi M, Malhotra P, Kumar A, Kaul N, Sharma A, Mehta A. Lymphomas morphologically, immunohistochemically, and ISH compatible with BL: A single-center experience. Indian J Pathol Microbiol 2021;64:870-2

How to cite this URL:
Singh N, Panigrahi M, Malhotra P, Kumar A, Kaul N, Sharma A, Mehta A. Lymphomas morphologically, immunohistochemically, and ISH compatible with BL: A single-center experience. Indian J Pathol Microbiol [serial online] 2021 [cited 2023 Mar 31];64:870-2. Available from: https://www.ijpmonline.org/text.asp?2021/64/4/870/328574

Dear Editor,

Burkitt Lymphoma (BL) is a mature B-cell NHL with distinct morphology, consistent immunophenotype, and classic translocations between the immunoglobulin heavy chain and MYC genes. The revised WHO classification of lymphoid neoplasms introduced a new provisional entity “Burkitt Like Lymphoma with 11q Aberrations (BL-11q)” with gene expression and pathological characteristics of Burkitt Lymphoma (BL) and absence of MYC translocation, carrying 11q proximal gains and telomeric losses. The minimal region of gain (MGR) and loss (MLR) has been defined at 11q23.3 and 11q24.1-q25 respectively based on the studies by Ferreiro et al. (2015) and Salaverria et al. (2014).^[1],[2],[3] Compared to BL, these lymphomas have more complex karyotypes, lower levels of C-MYC expression, a certain degree of cytological pleomorphism, and frequently a nodal presentation. The clinical course seems to be similar to BL but the number of cases reported is still limited. The study by Farre et al. documented 11 cases of BL-11q based on CN analysis. They suggested that BL-11q is genetically similar to DLBCL rather than BL as they lacked the typical BL mutations in ID3, TCF3, or CCND3 genes.^[4] In addition, they showed that BL-11q differed clinically, morphologically, and phenotypically from conventional BL and instead showed features more similar to high-grade B-cell lymphomas (HGBCL) or DLBCL such as higher incidence in younger patients <40 years, propensity for localized lymphadenopathy, and favorable treatment outcome, although treatment needs to be validated.^[5],[6]

The primary aim of this retrospective and prospective study was to find out the frequency of BL-11q aberrations in Indian settings and define the clinico-pathologic characteristics and prognostic outcome of the “lymphomas morphologically, immunohistochemically and ISH compatible with BL” in accordance with the revised WHO classification of lymphoid neoplasms 2017. Initially, a review of approximately three hundred and sixty Non-Hodgkin Lymphoma cases newly diagnosed in the department of Histopathology during the period of 2012–2018 was done to select the final cohort of thirty-six (~10%) lymphomas morphologically, immunohistochemically and ISH compatible with BL. It mainly comprised of intermediate-sized atypical lymphoid cells with prominent nucleoli, scant cytoplasm and brisk mitosis, negligible background T cells, starry sky pattern, and immunohistochemistry showing CD10+/CD20+/BCL-6+/BCL-2 negative/MUM-1 negative/EBER-ISH±/Ki-67 of 95–100% [Figure 1]. Both c-MYC positive (cut –off of >40% was considered positive) and c-MYC negative cases were included for further testing Relapsed/refractory patients were excluded from the study. The study was approved by the Institutional Review Board and informed consent was taken from all patients in accordance with the Declaration of Helsinki. FISH studies were performed on paraffin blocks according to the manufacturer's protocol. Zytolight SPEC MYC Dual Color Break Apart Probe was used for detecting translocations involving the chromosomal region 8q24.21 harboring the MYC gene [Figure 2]. Zytolight SPEC 11q gain/loss Triple Color Probe was used for detecting the 11q aberrations [Figure 3].

Figure 1: High power view of (a) H and E of Classical BL, (b) IHC for CD20, (c) Ki-67, (d) CD10, (e) BCL-6, and (f) C-MYC

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Figure 2: 100× view: In an interphase nucleus lacking a translocation involving the 8q24.21 band, two orange/green fusion signals are expected representing two normal (non-rearranged) 8q24.21 loci. A signal pattern consisting of one orange/green fusion signal, one orange signal, and a separate green signal indicates one normal 8q24.21 locus and one 8q24.21 locus affected by an 8q24.21 translocation. Alternating breakpoints observed in variant MYC translocations t(8;22) and t(2;8) might result in different signal patterns

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Figure 3: 100× view: The SPEC 11q gain/loss Triple Color probe is a mixture of a green fluorochrome direct labeled probe hybridizing in the MGR at 11q23.3, an orange fluorochrome direct labeled probe hybridizing in the MLR at 11q24.3, and a blue fluorochrome direct labeled CEN 11 probe specific for the alpha satellite centromeric region of chromosome 11. In a normal interphase nucleus, two green, two orange, and two blue signals are expected. In a cell with amplification at 11q23.3 and deletion at 11q24.3, multiple copies of the green signals and a reduced number of orange signals will be observed

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Of the thirty-six lymphomas morphologically, immunohistochemically and ISH compatible with BL, MYC rearrangement was found in 22/36 patients (61.1%). IHC for c-MYC protein was positive in 31/36 (86.1%) patients. Around 25% of patients showed discordance between c-MYC expression by IHC and MYC rearrangement. All 36 patients were negative for 11q aberrations by FISH studies. The remaining 14/36 (38.8%) dual negative patients (by FISH) were re-classified as High-Grade B Cell Lymphoma-NOS.

Patients <18 years were staged as per Murphy's classification and received risk-stratified based treatment as per LMB 96 protocol. The treatment consisted of an initial cytoreductive phase - COP (cyclophosphamide, vincristine, prednisolone), followed by two induction courses-COPAD-M (cyclophosphamide, vincristine, prednisolone, adriamycin, methotrexate). An interim assessment with a PET scan was done for all patients after a single course of consolidation-CYM (Cytarabine, Methotrexate) and CYVE (Cytarabine, Etoposide) for group A, B, and group C patients respectively. In case of CR (complete remission), another course of consolidation was given and the patient received maintenance COPADM. However, if there was PR or No CR, patient's treatment group was upgraded. Patients >18 years were staged as per Ann arbors staging criterion. Patients were risk-stratified as low risk (completely resectable abdominal disease with normal LDH and mass <10 cm) or high-risk disease. Low-risk patients received R-DA-EPOCH (Rituximab – Dose Adjusted etoposide, vincristine, prednisolone, cyclophosphamide, and adriamycin) while high-risk disease patients received either CODOX-MR/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose Methotrexate, rituximab/ifosfamide, etoposide, and high-dose cytarabine) or Hyper CVAD (Cyclophosphamide, Vincristine, Adriamycin, and Dexamethasone) depending upon treating physician's discretion. An interim PET assessment was done post 2 cycles in high-risk patients and those in CR are followed up. For patients not in CR, treatment was upgraded to more intensive protocols. For patients receiving R DA EPOCH, post 3 cycles, interim assessment was done and those with responding disease received 3 more cycles. Those in CR after 6 cycles were followed up while those with residual disease were typically kept for more intensive protocols. The clinico-pathologic characteristics and treatment outcome of the thirty-six cases have been described below in [Table 1].

Table 1: Clinico-pathologic characteristics and treatment outcome of Classical BL patients versus HGBCL-NOS

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Classical BL patients presented at a younger age, were associated with higher serum LDH levels, and showed a proclivity for renal failure. HGBCL-NOS patients were associated with higher incidences of advanced stage at presentation and chemo-resistance. No case of 11q aberrations was observed in the present study. The lack of 11q aberrations in our subset of patients despite such extensive workup makes us conclude that the Indian population may be behaving differently from the West and it may not be imperative to investigate all patients with morphologically and IHC defined Burkitt lymphomas for 11q aberrations in resource-constrained settings except in refractory cases. More comprehensive studies are required for drawing final conclusions as BL- directed therapy in BL-11q may drastically improve the treatment outcomes of such patients.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J (Eds): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition). IARC: Lyon 2017.
2.	Salaverria I, Martin-Guerrero I, Wagener R, Kreuz M, Kohler CW, Richter J, et al. A recurrent 11q aberration pattern characterizes a subset of MYC negative high-grade B-cell lymphomas resembling Burkitt lymphoma. Blood 2014;123:1187-98.
3.	Ferreiro JF, Morscio J, Dierickx D, Marcelis L, Verhoef G, Vandenberghe P, et al. Post-transplant molecularly defined Burkitt lymphomas are frequently MYC-negative and characterized by the 11q-gain/loss pattern. Haematologica 2015;100:e275-9.
4.	Gonzalez-Farre B, Enric Ramis-Zaldivar J, Salmeron-Villalobos J, Balagué O, Celis V, Verdu-Amoros J, et al. Burkitt-like lymphoma with 11q aberration: A germinal center derived lymphoma genetically unrelated to Burkitt lymphoma. Haematologica 2019;104:1822-9.
5.	Wagener R, Seufert J, Raimondi F, Bens S, Kleinheinz K, Nagel I, et al. The mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma. Blood 2019;133:962-6.
6.	Rymkiewicz G, Grygalewicz B, Chechlinska M, Blachnio K, Bystydzienski Z, Romejko-Jarosinska J, et al. A comprehensive flow-cytometry-based immunophenotypic characterization of Burkitt–like lymphoma with 11q aberration. Mod Pathol 2018;31:732-43.