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1
Meloni-Ehrig, Aurelia, Christine A. Curtis, Sean P. Mahoney, et al. "Significance of Conventional Cytogenetics in Improving the Diagnosis and Prognosis of Lymphoid Neoplasms in Tissue Samples." Blood 126, no. 23 (2015): 5033. http://dx.doi.org/10.1182/blood.v126.23.5033.5033.
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Abstract Cytogenetic analysis is invaluable for the detection of chromosome abnormalities in tumor samples and is the "gold standard" technique (unique in providing a complete overview of the chromosome complement). Cytogenetic studies of lymph node specimens (LN) can be challenging due to progressively smaller biopsies being procured, low viability, and low proliferative rates. Typically, the initial laboratory evaluation of LN includes flow cytometry and/or immunohistochemistry. Due to overlapping immunophenotypic and morphologic features of some lymphomas, these studies can be insufficient to properly classify a lymphoid neoplasm. Interphase FISH is the test most frequently utilized for LN genetic evaluation. Although FISH has higher sensitivity than conventional cytogenetics, there is vast literature on the existence of cytogenetic abnormalities that are not targeted by the FISH probe(s) used in most laboratories. This is predominantly true for CLL/SLL, but it is also seen in other lymphomas, particularly those characterized by variant translocations involving closely related genes, such as mantle cell lymphoma with alternate translocations involving the CCND2 or CCND3 genes, or lymphomas carrying MYC rearrangements where the partner is not IGH (translocation partners other than Ig genes might merit less aggressive therapy). To achieve the same information obtained from an abnormal karyotype, it is usually necessary to perform multiple FISH tests with significantly increased costs. Genomic microarray and sequencing also have limitations. Microarray can only detect DNA unbalances (missing the balanced translocations that characterize most lymphomas). These whole genomic tests cannot detect multiple related clones indicative of clonal evolution, or unrelated clonal populations indicative of distinct lymphoid neoplasms in the same specimen. Successful cytogenetics offers the best visual representation of the whole chromosome complement and often yields information making it unnecessary to perform additional genetic tests. It should be noted that alternative genetic tests are extremely useful for cases with normal chromosome results or those that lack metaphase cells for analysis, as well as those with cytogenetically cryptic rearrangements or mutations. Recent studies indicate that complex karyotypes in lymphomas are, in general, indicative of transformation and/or worse prognosis. In the present study, for example, several follicular lymphoma cases displayed other abnormalities in addition to the typical t(14;18), some of which are known to be associated with transformation, i.e., deletions 1p, 6q, and 10q. We present our experience with 362 LN received over a 15 month period during 2014 and 2015. See Table below. Through correlation with all diagnostic test results from our laboratory, we demonstrate the unique value of cytogenetic evaluation of lymphoid tissues, optimizing diagnostic/prognostic assessment and, thereby, improving patient management/therapeutic decisions, while achieving cost reduction. Table. A) Summary of cases and subdivision based on successful cytogenetics and normal or abnormal flow/morphology versus normal or abnormal cytogenetics; B) Detailed information on the number of the various lymphoid neoplasms included in our study. Total Cases: 362 No metaphases: 67 (19%) With metaphases: 295 (81%) Normal flow/morphology and normal cytogenetics 74 (25%) Abnormal flow and/or morphology 221 (75%) Normal cytogenetics: 59 (27%) Abnormal Cytogenetics: 162 (73%) Table. Final Diagnosis (Abnormal cytogenetic cases) # cases Sex (M/F) # FISH FISH Abnormal/normal FL 56 25/31 43 43/0 SLL/CLL 32 20/12 21 20/1 HGL 14 7/7 0 0 TCL 14 7/7 5 3/2 MZBCL 13 8/5 8 5/3 DH/THL 10 6/4 10 10/0 DLBCL 8 4/4 8 7/1 MCL 7 4/3 5 4/1 CD30+ 2 0/2 2 1/1 NGCL 2 0/2 2 1/1 BL 1 1/0 1 1/0 LPL 1 1/0 0 0 B-ALL/LBL 1 0/1 1 1/0 HL 1 1/0 1 1/0 Totals 162 84/78 107 (66%) 97/10 Abbreviations: FL, follicular lymphoma; SLL/CLL, small lymphocytic lymphoma/chronic lymphocytic leukemia; HGL, high-grade lymphoma; TCL, T-cell lymphoma; MZBCL, marginal zone B-cell lymphoma; DH/THL, double hit/triple-hit lymphoma; DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma,; CD30+, CD30-positive large B-cell lymphoma; NGCL, non-germinal center lymphoma; BL, Burkitt lymphoma; LPL, lymphoplasmacytic lymphoma; B-ALL/LBL, B-cell acute lymphoblastic leukemia/lymphoblastic lymphoma; HL, Hodgkin lymphoma. Disclosures No relevant conflicts of interest to declare.
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O’Neill, John Patrick, Fiona Quinn, Anita Dowling, et al. "Composite t(14;18)-Negative Follicular Lymphoma and Nodular Lymphocyte-Predominant Hodgkin Lymphoma." Case Reports in Hematology 2018 (August 2, 2018): 1–4. http://dx.doi.org/10.1155/2018/4312594.
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A composite lymphoma is the rare simultaneous occurrence of two or more distinct lymphomas within a single tissue or organ. Herein, we describe a case of a 51-year-old man presenting with a history of lower limb rash, fatigue, and bulky abdominopelvic lymphadenopathy. An excisional left iliac lymph node biopsy was notable for the composite presence of two distinct lymphoid neoplasms, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), and follicular lymphoma (FL). Multiplex PCR and FISH analyses failed to demonstrate a t(14;18)(q32;q21) translocation in either composite lymphoma component. A clonal light-chain kappa (V/JC intron-kde) gene rearrangement was detected in the FL component only.
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Streubel, Berthold, Andrea Lamprecht, Judith Dierlamm, et al. "T(14;18)(q32;q21) involving IGH andMALT1 is a frequent chromosomal aberration in MALT lymphoma." Blood 101, no. 6 (2003): 2335–39. http://dx.doi.org/10.1182/blood-2002-09-2963.
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T(11;18)(q21;q21) is the most common structural abnormality in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) leading to the fusion of the apoptosis inhibitor-2 (API2) gene and the MALT lymphoma-associated translocation (MALT1) gene. In 2 patients with MALT lymphoma of the liver and skin, respectively, t(14;18)(q32;q21) was observed by cytogenetic analysis. Subsequent fluorescence in situ hybridization (FISH) studies disclosed that the immunoglobulin heavy-chain locus (IGH) and the MALT1 gene were rearranged by this translocation. In order to screen a large series of MALT lymphomas for this aberration, a 2-color interphase FISH assay was established. Among a total of 66 cases, t(14;18)(q32;q21) involving IGH and MALT1 was detected in MALT lymphomas of the liver (4 of 4), skin (3 of 11), ocular adnexa (3 of 8), and salivary gland (2 of 11), but did not occur in MALT lymphomas of the stomach (n = 10), intestine (n = 9), lung (n = 7), thyroid (n = 4), or breast (n = 2). In total, 12 of 66 (18%) MALT lymphomas harbored t(14;18)(q32;q21); 7 additional cases of splenic marginal zone lymphoma tested negative. All of the 12 MALT lymphomas featuring the t(14;18)(q32;q21) were negative for t(11;18)(q21;q21) by reverse transcriptase–polymerase chain reaction (RT-PCR). However, trisomy 3 and/or 18 was found in 4 of 12 cases, suggesting that the t(14;18)(q32;q21) does not occur as the sole genetic abnormality. This study identifies IGH as a new translocation partner of MALT1 in MALT lymphomas, which tend to arise frequently at sites other than the gastrointestinal tract and lung. In contrast to t(11;18)(q21;q21)+ MALT lymphomas, those with t(14;18)(q32;q21) may harbor additional genetic abnormalities.
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Zhang, John, David Chin, Adam Anthony, et al. "CD5 and CD23 Positive Mantle Cell Lymphoma Detected by Flow Cytometry and Confirmed by FISH Study t(11;14)." Blood 104, no. 11 (2004): 4814. http://dx.doi.org/10.1182/blood.v104.11.4814.4814.
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Abstract The differential diagnoses of CD5 positive B-cell lymphoproliferative disorders mainly include chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma. Occasionally large cell and marginal zone lymphomas may also be CD5 positive. An accurate diagnosis effects patient management. The classical immunophenotype for chronic lymphocytic leukemia/small lymphocytic lymphoma is CD19/CD5/CD23 positive FMC-7 negative cells with dim CD20 and dim light chain expressions, while mantle cell lymphoma is CD19/CD5/FMC-7 positive with bright CD20 and bright light chain expressions. The diagnosis of mantle cell lymphoma is usually confirmed by either immunostain for cyclin D1 or FISH study for t(11;14). In reality, immunostaining for cyclin D1 can be difficult and may show variable results in different laboratories and FISH study may not be readily available. Generally, when it comes to the diagnosis of lymphoma, immunohistochemical positivity of both CD5 and CD23 is almost pathognomic for chronic lymphocytic leukemia/small lymphocytic lymphoma if no fresh tissue is saved for flow cytometry analysis. Flow cytometry analysis of 44 FISH-confirmed mantle cell lymphomas was reviewed in our lab. Among these, 37 showed the classical immunophenotype of mantle cell lymphoma. However, 7 cases (16%) were positive for both CD5 and CD23. The expression of CD23 varied from dim to bright. When compared to typical CLL, they showed FMC-7 expression and brighter than dim light chain expression. In one case, the light chain expression was dim. In conclusion, CD23 expression which was thought to be a specific marker for CLL/SLL may also be seen with mantle cell lymphoma. Although FMC-7 expression is seen in all CD23 positive mantle cell lymphomas, bright light chain expression is not universal. We recommend that FISH or immunohistochemical studies for cyclin D1 be performed on CD5/CD19 clonal B cell proliferations with CD23 expression if morphology or immunophenotype is atypical for CLL/SLL.
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O'Connor, Sheila J. M., Kathryn Turner, Catherine H. Burton, and Andrew Jack. "Detection of BCL2 Gene Rearrangements in the Reed-Sternberg Cells of Composite Lymphomas or Newly Diagnosed Hodgkin Lymphoma in Patients with a Previous Diagnosis of Follicular Lymphoma." Blood 124, no. 21 (2014): 137. http://dx.doi.org/10.1182/blood.v124.21.137.137.
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Abstract Introduction: Composite lymphomas involving Hodgkin lymphoma (HL) and non-Hodgkin lymphomas (CLL, DLBCL, FL, MZL, MCL, T-NHL) are relatively rare but are increasingly frequently diagnosed. This may be a function of the change in diagnostic practice, the more varied and increased treatment of the presenting disease or simply reflect better monitoring post treatment with re-biopsy of lymph nodes. Composite lymphoma is defined as the synchronous and metachronous development of two or more lymphomas in the same patient. The mechanism of pathogenesis underlying its occurrence is not clearly established and in particular the relationship between entities when HL is diagnosed a number of years following successful treatment for follicular lymphoma (FL). Methods: We identified 48 patients with a diagnosis of Hodgkin lymphoma at our centre between January 2005 and June 2014 who had a previous or concurrent diagnosis of another lymphoproliferative disorder. Diagnoses included CLL = 14; follicular lymphoma = 13; DLBCL = 8; mantle cell lymphoma = 1; marginal zone lymphoma = 5; T-cell lymphoma = 3; not specified = 3 and a single patient had CLL, MZL and most recently MCL. The diagnosis of Hodgkin lymphoma was confirmed on the tissue biopsy by using a standard panel of immunohistochemistry markers (CD3, CD20, CD30, IRF4, TARC, CD79, LMP1, BCL6, BOB1, OCT2). This study is focussed on the 13 cases with follicular lymphoma. The aim of the study was to identify a relationship between the Hodgkin lymphoma and the follicular lymphoma using interphase FISH studies to look for identical chromosomal translocations. Results: 8/13 patients had follicular lymphoma diagnosed on an earlier tissue biopsy, range 1-9 years prior to the diagnosis of Hodgkin lymphoma; 7/8 of these FL cases had bone marrow staging carried out at presentation and 5/7 had involvement by FL. 5/13 were newly presenting patients with composite lymphoma; 3/5 had a staging marrow which in each case showed evidence of follicular lymphoma alone with no evidence of Hodgkin lymphoma. In total, 7/13 patients fit the criteria for composite lymphoma with Hodgkin lymphoma and follicular lymphoma occupying distinct zones within the same tissue biopsy. The remaining 6/13 patients show no evidence of follicular lymphoma in the current biopsy and are indistinguishable from de novo presentation of Hodgkin lymphoma. Interphase FISH was used to assess for a genetic relationship between the disease entities. 3µ sections were cut from formalin fixed paraffin processed tissue, using the same block where possible as the H&E and immunohistochemistry. All cases were independently assessed by two experienced scientists with knowledge of histology and FISH reporting on thin sections. 8/13 cases had suitable samples for FISH, the remaining 5 cases had insufficient material remaining in the block. Commercial probes for BCL2 ‘Split-Signal’ (Abbott/Vysis or Dako) were used and FISH results were examined using a Zeiss microscope with MetaSystem image capture. All 8 cases showed BCL2 gene rearrangement in the Reed-Sternberg (RS) cells (5/8 cases were de novo group of Hodgkin lymphoma with no morphological or phenotypic evidence of FL in the tissue and 3/8 were composite lymphoma with distinct zoning). One rare case contained RS cells in a dab/imprint preparation made from the fresh tissue, FICTION technique was carried out on this case combining CD30 immunofluorescent staining with FISH for BCL2 gene rearrangement confirming RS cell type with BCL2 gene rearrangement. CONCLUSIONS The identification of BCL2 gene rearrangement in RS cells, the hallmark cell of Hodgkin lymphoma, in this series of composite lymphomas suggests a relationship between the B cells of follicular lymphoma and the RS cells of HL. The presence of the same chromosomal abnormalities identified in more than one lymphoma cell type indicates the same clonal cell of origin. Disclosures Jack: Roche: Research Funding; Genentech: Collaboration, Collaboration Other.
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Safley, Anne M., Patrick J. Buckley, Andrew J. Creager, et al. "The Value of Fluorescence In Situ Hybridization and Polymerase Chain Reaction in the Diagnosis of B-Cell Non-Hodgkin Lymphoma by Fine-Needle Aspiration." Archives of Pathology & Laboratory Medicine 128, no. 12 (2004): 1395–403. http://dx.doi.org/10.5858/2004-128-1395-tvofis.
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Abstract Context.—Molecular genetic analyses have been predicted to improve the diagnostic accuracy of fine-needle aspiration of B-cell non-Hodgkin lymphoma. Objective.—To determine the value of routine molecular genetic assays, polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH), in the diagnosis of B-cell non-Hodgkin lymphoma by fine-needle aspiration (FNA). Design.—A multiparametric method, including cytology, flow cytometry, PCR, and FISH, was prospectively evaluated in the diagnosis of B-cell non-Hodgkin lymphoma by FNA. Aspirates from 30 consecutive patients with suspected hematolymphoid malignancies were collected. All aspirates were triaged through a uniform program including cell-size analysis, B- and T-cell clonality studies, flow cytometric immunophenotyping, and bcl-1 and bcl-2 gene rearrangements by PCR and FISH. After completion of FNA evaluations, FNA results were compared with diagnoses from prior or subsequent surgical biopsies. Results.—Monoclonal B-cell populations were detected in 18 of 20 B-cell non-Hodgkin lymphomas by flow cytometry and PCR. bcl-1 gene rearrangement was detected in 2 of 2 cases of mantle cell lymphoma. bcl-2 rearrangement was detected in 5 cases including 4 of 4 low-grade follicular lymphomas and 1 transformed follicular lymphoma. By incorporating the results of molecular genetic and ancillary diagnostics, a definitive classification was reached in 12 cases of B-cell non-Hodgkin lymphoma by FNA, including all cases of low-grade follicular lymphoma (4/4) and mantle cell lymphoma (2/2) and approximately 50% of small lymphocytic lymphoma (2/4) and large B-cell lymphoma (4/8). Ten of the 12 cases with a final classification reached by FNA had either prior or follow-up surgical biopsies, and all 10 cases showed agreement between the diagnoses rendered on FNA and surgical biopsies. Conclusions.—With proper handling and management of specimens, FNA can routinely provide samples adequate for molecular genetic studies, in addition to cytomorphology and flow cytometry, making it possible to consistently render accurate and definitive diagnoses in a subset of B-cell non-Hodgkin lymphomas. By incorporating FISH and PCR methods, FNA may assume an expanded role for the primary diagnosis of B-cell non-Hodgkin lymphoma.
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Mitter, Navnit S., Stephen Lanno, Jason Blackson, Michelle Donskoy, and Ralph Ehrenpreis. "Development of a Reflex FISH Assay Panel for Lymphoid Neoplasms Resulted Negative by Cytogenetics and Current FISH Panel and Positive by Hematopathology." Blood 114, no. 22 (2009): 4722. http://dx.doi.org/10.1182/blood.v114.22.4722.4722.
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Abstract Abstract 4722 Fluorescence in situ hybridization (FISH) panel for detecting lymphoid neoplasms in interphase nuclei currently used at most of the laboratories initially utilizes the IGH (14q32.3) locus specific probe and based on negative or positive results obtained, additional testing is done with either the BCL6 (3q27), MYC (8q24) and MALT1 (18q21) locus specific probes, or the MYC/IGH (8q24/14q32.3), CCND1/IGH (11q13/14q32.3) and IGH/BCL2 (14q32.3/18q22) locus specific probes, respectively. Although these probes detect a large number of lymphoma-related abnormalities, approximately 10% of cases are still resulted negative by this FISH panel, as well as cytogenetics analysis on lymphoid mitogens stimulated bone marrow/peripheral blood cultures, but positive by hematopathology. Apparently, a need exists for either an expansion of this FISH panel or development of a reflex FISH panel to be used only when the current FISH panel fails to detect any abnormality in such cases. We selected three additional probes, TCR a/d, MYB and ALK to test further in a pilot study including twenty-five such patients, based on a high number of studies describing involvement of specific loci in gene rearrangements in lymphoid neoplasms. TCR a/d (14q11) locus is frequently involved in gene rearrangements in T-cell lymphomas and leukemias. These rearrangements include t(1;14)(q32;q11), t(1;14)(q34;q11), t(7;14)(p15;q11), t(7;14)(q34-35;q11), t(8;14)(q24;q11), t(10;14)(q24;q11), t(11;14)(p13;q11), t(11;14) (p15;q11) and inv(14)(q11;q32)/t(14;14)(q11;q32), among others. MYB (6q23) locus shows loss of heterozygosity in a high proportion of patients with peripheral T-cell and NK/T-cell lymphomas. ALK (2p23) locus has also been well documented as involved in gene fusion with multiple partner loci, including 1q21, 2q11-13, 2q35, 3q21, 5q35, 17q23, 19p13.1 and Xq11-12 in Ki-1-positive anaplastic large cell lymphoma, a subtype of non-Hodgkin lymphoma involving Ki-1 antigen. A known negative control for each probe and a known MYB-positive control were used in a blind-coded set-up with the criteria of a positive result with abnormal probe signal pattern in at least 5% (10/200) of cells examined with the validated standard FISH protocols. This experimental reflex panel succeeded in detecting abnormalities in three of the twenty-five (12%) patients included in this pilot study. Two cases were positive for the loss of heterozygosity for the MYB locus, while one case was positive for involvement of TCR a/d locus in a translocation. The ALK probe did not detect any additional abnormality, but none of the patients had a hematopathology diagnosis of Ki-1+ anaplastic large cell lymphoma. Only four of the twenty-five patients studied had a hematopathology diagnosis of a T-cell disorder. Further, some of the patients included in this study had a low percentage of cells found abnormal by hematopathology. These factors could have affected the observed rate of abnormalities by this reflex FISH panel. Still, with 12% of patients showing abnormalities with this reflex FISH panel, this pilot study clearly demonstrates the usefulness of incorporation of this reflex FISH panel in the standard protocols for FISH studies in lymphoid neoplasms. We plan to continue investigation on additional patients meeting the criteria for inclusion in this study. Disclosures: No relevant conflicts of interest to declare.
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Verghese, Cherian, Weihong Li, Nanuli Gvazava, et al. "IGH/BCL2 Status Better Predicts Clinico-Pathological Behavior in Primary Splenic Follicular Lymphoma than Histological Grade and Other Molecular Markers." Clinical Pathology 15 (January 2022): 2632010X2211292. http://dx.doi.org/10.1177/2632010x221129242.
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Splenic lymphoma may be primary or secondary. Primary splenic lymphoma’s are rare and usually of follicular cell origin representing <1% of Non-Hodgkin’s Lymphoma’s. Most are secondary with 35% representing Marginal Cell sub-type with the rest being Diffuse Large B-Cell Lymphoma’s. Unlike the uniformly aggressive clinical course of Diffuse Large B-Cell Lymphoma’s, biological behavior of Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma remains less well defined. We present here a solitary splenic mass confirmed as Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma after a diagnostic splenectomy. Biopsy revealed monomorphic small lymphoid cells with low grade mitotic activity. Flow cytometry showed a lambda restricted population of B-Cells displaying dim CD19 and CD10. The cells were negative for CD5, CD11c, and CD103. FISH was negative for IGH/BCL2 fusion unlike nodal Follicular Lymphoma’s which are usually positive for this translocation. Evidence from this case and a review of literature support the finding that Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma is less likely to have the classic IGH-BCL2 fusion and the associated chromosomal 14;18 translocation. This profile is associated with less aggressive clinical behavior even when histopathology represents a high-grade pattern. In such cases splenectomy alone is adequate for localized disease when negative for IGH/BCL2 fusion regardless of histological grade.
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Dierlamm, Judith, Mathijs Baens, Margarita Stefanova-Ouzounova, et al. "Detection of t(11;18)(q21;q21) by interphase fluorescence in situ hybridization using API2 and MLTspecific probes." Blood 96, no. 6 (2000): 2215–18. http://dx.doi.org/10.1182/blood.v96.6.2215.
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Abstract The translocation of chromosome 11, long arm, region 2, band 1, to chromosome 18, long arm, region 2, band 1 (t(11;18)(q21;q21)) represents a recurrent chromosomal abnormality in extranodal marginal zone B-cell lymphoma (MZBCL) of mucosa-associated lymphoid tissue (MALT) type and leads to a fusion of the apoptosis inhibitor-2 (API2) gene on chromosome 11 and the MALT lymphoma-associated translocation (MLT) gene on chromosome 18. A 2-color fluorescence in situ hybridization (FISH) assay, which can be used for the detection of t(11;18) in interphase nuclei and metaphase chromosomes on fresh and archival tumor tissue, was developed. The P1 artificial chromosome (PAC) clone located immediately telomeric to the MLT gene and the PAC clone spanning the API2 gene were differentially labeled and used to visualize the derivative chromosome 11 resulting from t(11;18), as evident by the overlapping or juxtaposed red and green fluorescent signals. The assay was applied to interphase nuclei of 20 cases with nonmalignant conditions and 122 B-cell non-Hodgkin's lymphomas (NHLs). The latter group comprised 20 cases of nodal follicle center cell lymphoma and diffuse large B-cell NHL, 10 cases of gastric diffuse large B-cell lymphoma, 10 cases of hairy cell leukemia, and 82 cases of MZBCL (41 extranodal from various locations, 19 nodal, and 22 splenic MZBCL) including 35 cases with an abnormal karyotype, 2 of which revealed t(11;18). By interphase FISH, t(11;18) was detected in 8 gastrointestinal low-grade MALT-type lymphomas including the 2 cytogenetically t(11;18)+ cases. In the 8 t(11;18)+ cases, the FISH results were confirmed by reverse transcriptase–polymerase chain reaction (RT-PCR) usingAPI2 and MLT specific primers. Our results indicate that t(11;18)(q21;q21) specifically characterizes a subgroup of low-grade MZBCL of the MALT-type and that the FISH assay described here is a highly specific and rapid test for the detection of this translocation.
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Dierlamm, Judith, Mathijs Baens, Margarita Stefanova-Ouzounova, et al. "Detection of t(11;18)(q21;q21) by interphase fluorescence in situ hybridization using API2 and MLTspecific probes." Blood 96, no. 6 (2000): 2215–18. http://dx.doi.org/10.1182/blood.v96.6.2215.h8002215_2215_2218.
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The translocation of chromosome 11, long arm, region 2, band 1, to chromosome 18, long arm, region 2, band 1 (t(11;18)(q21;q21)) represents a recurrent chromosomal abnormality in extranodal marginal zone B-cell lymphoma (MZBCL) of mucosa-associated lymphoid tissue (MALT) type and leads to a fusion of the apoptosis inhibitor-2 (API2) gene on chromosome 11 and the MALT lymphoma-associated translocation (MLT) gene on chromosome 18. A 2-color fluorescence in situ hybridization (FISH) assay, which can be used for the detection of t(11;18) in interphase nuclei and metaphase chromosomes on fresh and archival tumor tissue, was developed. The P1 artificial chromosome (PAC) clone located immediately telomeric to the MLT gene and the PAC clone spanning the API2 gene were differentially labeled and used to visualize the derivative chromosome 11 resulting from t(11;18), as evident by the overlapping or juxtaposed red and green fluorescent signals. The assay was applied to interphase nuclei of 20 cases with nonmalignant conditions and 122 B-cell non-Hodgkin's lymphomas (NHLs). The latter group comprised 20 cases of nodal follicle center cell lymphoma and diffuse large B-cell NHL, 10 cases of gastric diffuse large B-cell lymphoma, 10 cases of hairy cell leukemia, and 82 cases of MZBCL (41 extranodal from various locations, 19 nodal, and 22 splenic MZBCL) including 35 cases with an abnormal karyotype, 2 of which revealed t(11;18). By interphase FISH, t(11;18) was detected in 8 gastrointestinal low-grade MALT-type lymphomas including the 2 cytogenetically t(11;18)+ cases. In the 8 t(11;18)+ cases, the FISH results were confirmed by reverse transcriptase–polymerase chain reaction (RT-PCR) usingAPI2 and MLT specific primers. Our results indicate that t(11;18)(q21;q21) specifically characterizes a subgroup of low-grade MZBCL of the MALT-type and that the FISH assay described here is a highly specific and rapid test for the detection of this translocation.
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Buño, Ismael, Paola Nava, Angela Alvarez-Doval, et al. "Lymphoma Associated Chromosomal Abnormalities Can Be Easily Detected by FISH on Tissue Imprints. an Underused Diagnostic Alternative." Blood 104, no. 11 (2004): 4270. http://dx.doi.org/10.1182/blood.v104.11.4270.4270.
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Abstract Detection of specific chromosomal abnormalities is essential in the diagnosis of several lympholiferative disorders. However, conventional cytogenetic studies are not frequently carried out from biopsies as it is in bone marrow (BM) specimens. On the contrary, FISH is usually performed on paraffin embedded tissue, an alternative with potential technical nuances both in its application and its interpretation. In our experience, FISH on tissue imprints is the ideal alternative to overcome these problems. In the present study, 46 tissue imprints and 17 BM smears from 43 patients with lymphomas were selected to investigate the presence of t(14;18)(q32;q21), t(11;14)(q13;q32), t(8;14)(q24;q32) and t(3;var)(q27;var). Representativity of the samples was assured prior to FISH by rapid May-Grümwald staining (Diff-Quick, QCA, Spain). Twenty imprints from reactive palatine tonsils and adenoids were used as negative controls. FISH was performed with specific dual-color dual-fusion FISH (D-FISH) probes for the first 3 translocations and a dual-color break-apart FISH probe for t(3;var)(q27;var) following the instructions of the probes supplier (Vysis, Inc). All except one sample (a BM smear stored at room temperature over 9 years), rendered satisfactory FISH hybridizations. In any case, all 43 patients could be successfully studied by FISH (the case referred above in which FISH failed in a first attempt was successfully analyzed using a different sample). The results supported the suspected diagnosis of follicular lymphoma in 22 patients, mantle cell lymphoma in 12 patients, large B-cell lymphoma in 5 patients, marginal zone lymphoma in 2 patients and B chronic lymphocytic leukemia in 2 patients. In one case, the observation of t(11;14) by FISH allowed to reclassify the case from follicular to mantle cell lymphoma and also to demonstrate clonal evolution by studying sequential tissue imprints stored for more than 6 years. Negative results also aided in the assignment of patients to proper diagnostic categories. FISH performed on tissue imprints and BM smears constitutes an optimal strategy for retrospective and prospective investigation of chromosomal abnormalities in lymphomas. Tissue imprints and BM smears conventionally stored at room temperature even for long periods of time can be safely used and sent by ordinary mail without special considerations for this purpose. Based on our experience we recommend to perform and routinely store tissue imprints whenever fresh tissue is available.
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Troen, Gunhild, Iwona Wlodarska, Abdirashid Warsame, Silvia H. Llodrà, Christiane De Wolf-Peeters, and Jan Delabie. "NOTCH2 Mutations in Marginal Zone Lymphoma." Blood 108, no. 11 (2006): 2426. http://dx.doi.org/10.1182/blood.v108.11.2426.2426.
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Abstract Notch2 is a membrane receptor and transcription factor that is indispensable for marginal zone cell differentiation. Also, marginal zone cell lymphomas express increased levels of Notch2 when compared with other B-cell lymphomas. Of interest, activating mutations have previously been described for Notch1, a homologous transcription factor which is important for T-cell differentiation, in up to 50% of cases of acute T-lymphoblastic leukemia, and are thought to contribute to leukemogenesis. We therefore investigated whether activating mutations in the NOTCH2 gene could be identified, especially in marginal zone lymphoma (MZL). We analyzed 41 cases of MZL and 28 other B-cell lymphomas cases for the presence of potentially activating mutations in exons 26, 27 and 34 of the NOTCH2 gene. These exons code for the heterodimerization and the C-terminal transcriptional activation domains. We identified four cases with mutations among the MZL cases, but none in the other B-cell lymphoma cases. Mutations were found in two cases of splenic marginal zone lymphoma and two cases of extranodal marginal zone lymphoma of MALT type, respectively. To investigate whether elevated Notch2 expression in most of the other marginal zone lymphomas, as investigated by quantitative RT-PCR, was due to structural changes within the NOTCH2 locus, FISH analysis was performed. FISH analysis did not reveal structural changes of the NOTCH2 locus in any of the MZL cases. In conclusion, we have shown potentially oncogenic NOTCH2 mutations in 10% of MZL. It remains to be shown whether elevated Notch2 expression in most MZL can be caused by as yet other disease mechanisms.
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Yamashita, Saori, Yayoi Matsuda, Hiroki Muta, et al. "Sarcoidosis-Lymphoma Syndrome Associated With Primary Thyroid Lymphoma: A Case Report." Journal of the Endocrine Society 5, Supplement_1 (2021): A900. http://dx.doi.org/10.1210/jendso/bvab048.1837.
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Abstract Background: Sarcoidosis is occasionally accompanied by hematologic malignancies, including lymphoma, called sarcoidosis-lymphoma syndrome. Although the mechanism underlying the induction of lymphomas is still unknown, understanding the immunological background of sarcoidosis could help explain the possible mechanisms of the induction of lymphomas. Case Presentation: A 52-year-old woman was diagnosed chronic thyroiditis with normal thyroid function. One year later, she underwent a screening chest radiograph and identified bilateral hilar adenopathy and mediastinum lymphadenopathy. Subsequent mediastinoscopy demonstrated sarcoidosis. Because of the lack of clinical symptoms, steroid treatment was not initiated and regular follow-up was performed. One and a half years after the diagnosis of chronic thyroiditis, she presented with rapid swelling of the thyroid gland. FDG-PET/CT showed intense uptake of FDG in the thyroid gland and multiple lymphadenopathy. Fine-needle aspiration (FNA) cytology of the thyroid gland was only suggestive of a lymphoproliferative disorder and did not provide a definitive diagnosis. Partial thyroidectomy was performed, and the pathology indicated diffuse large B-cell lymphoma (DLBCL) such as high-grade transformation of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma. The results of an examination of a paraffin block histopathology specimen by fluorescence in-situ hybridization (FISH) detected BCL6 rearrangement (3q27), which is the most common chromosomal abnormality in DLBCL. After the treatment with R-EPOCH (rituximab, etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone) chemotherapy, the thyroid gland enlargement has improved markedly, while the lymph nodes remained swelling, that suggested lymph node involvements were due to sarcoidosis. Conclusions: Rapid swelling of the thyroid gland in the setting of chronic thyroiditis should raise suspicion for thyroid lymphoma. Furthermore, our present case might suggest that sarcoidosis accelerate the development and high-grade transformation of thyroid lymphoma. To our knowledge, this is the first reported case of sarcoidosis and primary thyroid lymphoma in the same patient.
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Ferti, Angeliki D., Anna D. Panani, Maria I. Stamouli, Dimitra P. Rondogianni, Sotirios A. Raptis, and Bryan D. Young. "M-FISH in gastric lymphoma." Cancer Genetics and Cytogenetics 155, no. 1 (2004): 63–66. http://dx.doi.org/10.1016/j.cancergencyto.2004.02.015.
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Gascoyne, Randy D. "Hematopathology Approaches to Diagnosis and Prognosis of Indolent B-Cell Lymphomas." Hematology 2005, no. 1 (2005): 299–306. http://dx.doi.org/10.1182/asheducation-2005.1.299.
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Abstract The advent of new technologies has contributed to improvements in the diagnosis and classification of the non-Hodgkin lymphomas (NHL). Use of a more extensive test menu of paraffin active monoclonal antibodies for immunohistochemistry, molecular cytogenetic studies including standard cytogenetics, multi-color fluorescence in-situ hybridization (FISH), polymerase chain reaction and locus-specific FISH, as well as developments in high-resolution techniques including microarray gene expression profiling and array comparative genomic hybridization (CGH) allow more accurate diagnosis and precise definition of biomarkers of value in risk stratification. The identification of disease-specific gene lists resulting from expression profiling provides a number of potential protein targets that can be validated using immunohistochemistry. We will highlight how improvements in our understanding of lymphoma biology rapidly facilitate the development of new diagnostic reagents that could be used to alter clinical practice. These changing trends allow the development of new diagnostic strategies used to render accurate sub-classification of entities within the category of indolent B-cell lymphomas, including their distinction from related but more aggressive disorders, such as mantle cell lymphoma. A comprehensive understanding of the biology of these distinct lymphoid tumors will allow us to identify novel disease-related genes and should facilitate the development of improved diagnostics, outcome prediction, and personalized approaches to treatment.
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Sesques, Pierre, and Nathalie A. Johnson. "Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements." Blood 129, no. 3 (2017): 280–88. http://dx.doi.org/10.1182/blood-2016-02-636316.
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Abstract High-grade B-cell lymphomas (HGBLs) with MYC and BCL2 and/or BCL6 rearrangements, so-called “double-hit” lymphomas (HGBL-DH), are aggressive lymphomas that form a separate provisional entity in the 2016 revised World Health Organization Classification of Lymphoid Tumors. Fluorescence in situ hybridization (FISH) will be required to identify HGBL-DH and will reclassify a subset of diffuse large B-cell lymphomas (DLBCLs) and HGBLs with features intermediate between DLBCL and Burkitt lymphoma into this new category. Identifying patients with HGBL-DH is important because it may change clinical management. This poses a challenge for centers that may not be ready to handle the additional workload and financial burden associated with the increase in requests for FISH testing. Herein, we review the mechanisms of deregulation of these oncogenes. We identify the factors associated with a poor prognosis and those that can guide diagnostic testing. Restricting FISH analysis to the 10% of DLBCL patients who have a germinal center B-cell phenotype and coexpress MYC and BCL2 proteins would be cost-effective and would identify the subset of patients who are at highest risk of experiencing a relapse following conventional therapy. These patients may benefit from intensified chemotherapy regimens or, ideally, should enroll in clinical trials investigating novel regimens.
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Sun, Guoxian, Lya Montella, and Min Yang. "MYC Gene FISH Testing in Aggressive B-Cell Lymphomas: Atypical Rearrangements May Result in Underreporting of Positive Cases." Blood 120, no. 21 (2012): 1552. http://dx.doi.org/10.1182/blood.v120.21.1552.1552.
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Abstract Abstract 1552 Background: Multifunctional MYC oncogene overexpression resulting from genomic rearrangement plays a critical role in lymphomagenesis and lymphoma manifestation, particularly in aggressive B-cell lymphomas such as Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and B-cell lymphoma unclassifiable with features intermediate between DLBCL and BL including double hit or triple hit lymphomas (DHL/THL). Accurate detection of MYC gene rearrangement, its presence or absence, has become increasingly important with its diagnostic and consequent therapeutic implications. In practice, FISH is the best test for MYC alterations. However, this is technically challenging, requiring knowledgeable and skillful cytogeneticists to design probe panels, correctly analyze and interpret atypical as well as typical signal patterns. For instance, up to 10% of patients with otherwise typical BL can be MYC rearrangement negative by FISH and, gene amplification and miRNA deregulation have been reported as possible reasons in occasional cases, although some of the FISH negative patients could be detected by better application of probes and interpretation of FISH findings. Here we retrospectively analyze FISH results from 879 consecutive MYC positive cases and share our experience with other FISH labs and physicians who are involved in diagnosis, differential diagnosis and treatment of aggressive lymphomas. Results: A MYC/IGH dual fusion translocation probe and a MYC break apart (ba) probe (Vysis) were applied to paraffin embedded tissue, lymph node biopsy, bone marrow and peripheral blood specimens. Of the 879 cases, MYC ba was positive in 258, MYC ba and MYC-IGH both positive in 331, MYC ba positive/MYC-IGH negative in 276, and MYC-IGH positive/MYC ba negative in 14 cases. Two subsets of cases with significant atypical signal patterns were observed. Firstly, in 14 cases with both probes tested, MYC ba was negative but MYC/IGH positive, including 6 BLs, 3 DLBCLs, 1 MCL, 1 Burkitt leukemia transformed from BL, 1 subtype unknown lymphoma and 2 DHLs with history of Hodgkin lymphoma and Burkitt-like lymphoma respectively and with concomitant BCL6 gene rearrangement in both. Eleven of these cases showed a single fusion signal pattern suggesting an insertion of IGH sequences into MYC or vise versa. This single insertion fusion pattern can also be resulted from complex chromosome changes as seen cytogenetically in 2 of the 11 cases. Secondly, 26 cases with various diagnoses including 4 DHLs and 2 THLs showed MYC rearrangement with a concomitant partial deletion of the MYC ba probe with 17 cases for 3' and 9 for 5' deletion. Three of these cases were also positive for concomitant probe deletion and amplification, two with 3' deletion and 5' amplification and one with 5' deletion and 3' amplification. Conclusion and discussion: MYC gene rearrangement detection by FISH in aggressive B-cell lymphomas is widely used. However, FISH labs should realize the technical limitations of each probe/panel based on underlying mechanisms involving MYC rearrangement and minimize false negative results. From our experience and previous studies by other groups, it is recommended that MYC ba probe should not be tested alone but together with a MYC/IGH t(8;14) translocation probe to detect cryptic insertions and variant translocations which often present as MYC ba negative yet MYC/IGH positive with a single fusion signal pattern inserting IGH promoter/enhancer elements into MYC or part or all of the MYC probe into IGH locus. Another observation that can also be misinterpreted is that the MYC ba probe often shows a deletion of either 5' or 3' flanking sequence. This is not because of tissue sectioning but indicative of MYC rearrangement with a concomitant loss of the DNA sequences adjacent to the breakpoints. A flanking sequence deletion revealed at translocation breakpoints using a FISH ba probe is a common finding. As well documented, BCR/ABL translocation results in an ASS deletion upstream of ABL in ∼15% of CMLs, and a 5' probe deletion in ∼30% ALK rearrangement positive NSCLC cases. Three of 26 such cases in our study also showed simultaneous retained MYC probe amplification making FISH interpretation even more difficult. As a diagnostic, prognostic and predictive biomarker, MYC gene plays a pivotal role in aggressive B-cell lymphomas, and its accurate detection will help improve disease risk stratification and therapy selection. Disclosures: No relevant conflicts of interest to declare.
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Alrajjal, Ahmed, Moumita Choudhury, Jay Yang, and Ali Gabali. "Cell-blocks and hematolymphoid lesions." Cytojournal 18 (March 31, 2021): 7. http://dx.doi.org/10.25259/cytojournal_10_2021.
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Cell-blocks are an important component for evaluation for hematolymphoid lesions. They are especially critical for immunocharacterization of the lymphoid population especially when flow cytometry is not available or cannot be performed. In addition, cell-blocks allow various molecular pathology tests including gene rearrangement studies and FISH, proteomics analysis, and microbiology/histochemical special stains. Fine-needle aspiration (FNA) for mass lesions, lymphadenopathy, and effusion fluids are common cytopathology specimens which are frequently cell-blocked. The differential diagnosis of enlarged lymph nodes (LNs) and mass lesions is broad and includes reactive processes, granulomatous lesions and malignancies including solid tumor metastases and various types of hematological malignancies, of which lymphoma would be most common. Depending on the patient population, most lymphomas may be diagnosed with immunocharacterization on cell-block or/and flow cytometry in concert with excellent cytomorphology in Diff-Quik stained FNA aspirate smears. However, a proportion of lymphoma cases (up to 12-30%) may still require an excisional LN biopsy to evaluate architectural parameters. Similarly, various effusion fluids suspicious for lymphoma can be immunocharacterized by immunostaining of cell-block sections (or/and by flow cytometry). Availability of quantitatively and qualitatively optimum cell-blocks of specimens to be evaluated for hematolymphoid processes is critical for immunohistochemistry, polymerase chain reaction, in situ hybridization (FISH), and gene expression profiling studies.
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Landsburg, Daniel J., Sunita Dwivedy Nasta, Jakub Svoboda, Jennifer JD Morrissette, and Stephen J. Schuster. "“Double-Hit” Cytogenetic Status Is Not Predicted By Baseline Clinicopathologic Characteristics and Is Highly Associated With Overall Survival In B Cell Lymphoma Patients." Blood 122, no. 21 (2013): 4338. http://dx.doi.org/10.1182/blood.v122.21.4338.4338.
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Abstract Background “Double-Hit” (DH) lymphomas are most commonly defined as B cell lymphomas demonstrating a MYC gene rearrangement and additional rearrangement(s) involving BCL2 and/or BCL6. DH lymphomas respond poorly to standard immunochemotherapy regimens, often prompting the use of more intensive treatments. DH gene rearrangements can be identified through metaphase cytogenetic testing or more sensitive fluorescence in situ hybridization (FISH) on diagnostic tissue specimens, although these studies are not routinely performed. Here, we analyze a cohort of B cell lymphoma patients to determine whether DH status can be predicted by clinicopathologic features as well as the impact of DH status on survival. Methods Fifty-three patients diagnosed with B cell lymphoma treated at the University of Pennsylvania from 2006-2013 who underwent diagnostic FISH for MYC gene rearrangements using probes to detect either an 8q24 split or t(8;14) were included in this analysis. FISH was performed at request of the interpreting pathologist or treating clinician. Patients with classic Burkitt lymphoma were excluded. Cases of DH lymphoma (DH+) were defined as demonstrating at least one of either 8q24 split, t(8;14), t(2;8) or t(8;22) as well as a BCL2, BCL6 and/or BCL1 rearrangement. Therapy was given at the discretion of the treating clinician. Response was defined using the Revised Response Criteria for Malignant Lymphoma (J Clin Oncol. 2007 Feb 10;25(5):579-86.). Results DH+ was detected in 17 patients (32%) and a sole MYC gene rearrangement was detected in an additional 9 patients (17%). MYC gene rearrangements were detected by metaphase cytogenetics in 4 (15%) and by FISH in 22 (85%) of these patients. No factor, including age, LDH, stage, International Prognostic Index (IPI) or histology was predictive of DH status (Table I). DH+ patients were treated with R-hyperCVAD (41%), R-CHOP (41%) and other regimens (18%). Complete response was less frequent in DH+ compared to non-DH patients (41% vs. 81%, p=0.002). With a median follow-up of 10.4 months (range 1.2-72.4), the median overall survival was significantly shorter for DH+ compared to non-DH patients (8.2 vs. 56.8 months, p<0.001). Median overall survival was not significantly different for non-DH patients with and without a sole MYC gene rearrangement (50.8 months vs. not yet reached, p=0.33). Univariate Cox regression analysis showed that the presence of a MYC gene rearrangement (MYC+) and DH+ had statistically significant associations with overall survival; however, only DH+ retained statistical significance on multivariate analysis (Table II). Conclusions DH status cannot be inferred by baseline disease- or patient-related characteristics and is most predictive of overall survival in this cohort of B cell lymphoma patients. These findings support the practice of routine FISH for DH gene rearrangements in order to better identify DH+ patients who may benefit from risk-adapted and/or targeted therapies. We plan to validate our findings in a larger unselected cohort of diffuse large B cell lymphoma patients. Disclosures: No relevant conflicts of interest to declare.
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Harris, Nancy Lee, Harald Stein, Sarah E. Coupland, et al. "New Approaches to Lymphoma Diagnosis." Hematology 2001, no. 1 (2001): 194–220. http://dx.doi.org/10.1182/asheducation-2001.1.194.
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Abstract Recent years have brought an explosion of new diagnostic tools to the pathology of lymphomas, which have permitted more precise disease definition and recognition of factors that can predict prognosis and response to treatment. These new methods exploit both the biological features of normal lymphocytes as they progress through differentiation pathways and the genetic abnormalities that characterize malignant transformation. These features can be assessed in individual tumors with techniques that detect proteins (immunophenotyping), messenger RNA (in-situ hybridization), or changes in DNA [Southern blot, PCR, fluorescence in-situ hybridization (FISH), and gene sequencing]. Recently, the novel technology of “gene chips” or DNA microarrays has greatly enhanced the efficiency of analyzing expression of many genes simultaneously at the RNA level. Understanding the relationship of lymphoid neoplasms to their normal counterparts and the genetic events that lead to malignant transformation in lymphoid cells are essential for physicians caring for patients with lymphoma, since these are the basis of modern classification, diagnosis, and prognosis prediction. Although microarray technology is not ready for prime time in the daily diagnosis of lymphoma, practitioners should understand its potential and limitations. The vast majority of lymphoid neoplasms worldwide are derived from B lymphocytes at various stages of differentiation. The review by Harald Stein and colleagues present the events of normal B-cell differentiation that are relevant to understanding the biology of B-cell neoplasia. These include antigen receptor [immunoglobulin (Ig)] gene rearrangement, somatic mutations of the Ig variable region genes, receptor editing, Ig heavy chain class switch, and differential expression of a variety of adhesion molecules and receptor proteins as the cell progresses from a precursor B cell to a mature plasma cell. Most lymphoid neoplasms have genetic abnormalities, many of which appear to occur during the gene rearrangements and mutations that characterize normal B-cell differentiation. Dr. Riccardo Dalla Favera reviews the mechanisms of these translocations and other abnormalities, and their consequences for lymphocyte biology. The association of specific abnormalities with individual lymphomas is reviewed. Dr. Wing C. Chan reviews the technology and applications of DNA microarray analysis, its promises and pitfalls, and what it has already told us about the biology of lymphomas. Finally, what does this all mean? The applications, both current and future, of these discoveries to the diagnosis and treatment of patients with lymphoma are discussed by Dr. Nancy Lee Harris.
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Salaverria, Itziar, Claudia Philipp, Ilske Oschlies, et al. "Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults." Blood 118, no. 1 (2011): 139–47. http://dx.doi.org/10.1182/blood-2011-01-330795.
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Abstract The prognosis of germinal center–derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. Children have a more favorable outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes of DLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma.
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Di Rocco, Alice, Luigi Petrucci, Giovanni Manfredi Assanto, Maurizio Martelli, and Alessandro Pulsoni. "Extranodal Marginal Zone Lymphoma: Pathogenesis, Diagnosis and Treatment." Cancers 14, no. 7 (2022): 1742. http://dx.doi.org/10.3390/cancers14071742.
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Extranodal Marginal Zone Lymphoma (EMZL lymphoma) is an indolent B-cell lymphoma with a median age at diagnosis of about 60 years. It accounts for 7–8% of all B-cell lymphomas. It can occur in various extranodal sites, including stomach, lung, ocular adnexa, and skin; furthermore, the disseminated disease can be found in 25–50% of cases. Several infectious agents, such as Helicobacter pylori (H. Pylori) in the case of gastric Mucosa Associated Lymphoid Tissue (MALT) Lymphoma, can drive the pathogenesis of this cancer, through the autoantigenic stimulation of T cells, but there may also be other factors participating such autoimmune diseases. Initial staging should include total body computed tomography, bone marrow aspirate, and endoscopic investigation if indicated. Fluorescence in situ hybridization (FISH), should be performed to detect the presence of specific chromosomal translocations involving the MALT1 and BCL10 genes, which leads to the activation of the NF-κB signaling pathway. Depending on the location and dissemination of the disease, different therapeutic choices may include targeted therapy against the etiopathogenetic agent, radiotherapy, immunochemotherapy, and biological drugs. The purpose of this review is to illustrate the complex biology and the diagnosis of this disease and to better define new treatment strategies.
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Fukumoto, Kota, Sou Nakaji, Yasuhito Suehara, et al. "Endoscopic Ultrasound-Guided Fine Needle Aspiration Biopsy for Diagnosis of Intra-Abdominal Lymphoma without Accessible Peripheral Lymphadenopathy." Blood 124, no. 21 (2014): 5380. http://dx.doi.org/10.1182/blood.v124.21.5380.5380.
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Abstract Introduction: Endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) is considered the procedure of choice for the diagnosis and staging of intra-abdominal non-Hodgkin’s lymphoma (NHL) without accessible peripheral lymphadenopathy. However, diagnosis and subclassification lymphoma by FNAB is often challenging due to variable cellularity and lack of architecture. Recent advances of ancillary techniques such as immunohistochemical staining, flowcytometry (FCM), fluorescence in situ hybridization (FISH) analysis and molecular analysis allowed classify lymphoma more precisely, although sufficient information can be obtained through this procedure remained undetermined. The present study was performed to evaluate the yield of EUS-FNAB using a standard 19 or 22-gauge needle for diagnosis and subclassification of lymphoma, assessing the feasibility of immunohistological, FCM, molecular and cytogenetic assessments. Methods: Between April 2008 and July 2014, 90 patients with malignant lymphoma who had an intra-abdominal mass without accessible peripheral lymphadenopathy underwent EUS-guided fine needle aspiration biopsy at our hospital. All patients received positron emission tomography/computed tomography and had 2-deoxy-2-(18F)fluoro-D-glucose-avid lesions in abdomen before examination. The aspirated materials were processed for flowcytometry (FCM), molecular analysis of immunoglobulin heavy (IgH) and T-cell receptor (TCR) gene rearrangement, cytogenetic analysis by conventional G banding, and FISH analysis, in addition to standard histopathological studies. Patients’ baseline data, including age, sex, laboratory examinations, imaging studies, and final diagnosis of lymphoma, were collected and examined to determine the feasibility and sensitivity for diagnosis and subclassification of lymphoma. Results: The mean of the diameter of mass was 37mm (9.7-149mm). Among the 90 patients, conventional G banding, FCM analysis, standard cytogenetic analysis, and FISH were successfully performed in 67 (74%), 78 (87%), 44 (49%), and 58 (64%) cases, respectively. G banding analysis were successful in 45 patients (67%) that showed normal karyotype in 5 cases (7%), t(14;18)(q32;q21) in 7 cases (10%), t(8;14)(q24;q32) in one case, and complex abnormality in 32 cases (48%), respectively. FCM analysis showed immunoglobulin light chain restriction in 48 cases (62%) and were diagnosed as B-cell lymphoma. FCM could not determine the T-cell clonality. Molecular analyses for TCR and/or IgH receptor rearrangements were successful in 35 patients (83%), 31 rearranged in IgH and 4 rearranged in TCR, respectively. There were 32 cases with IgH/Bcl2 fusions by FISH analysis, 26 cases in follicular lymphoma (FL) and 6 cases in diffuse large B-cell lymphoma (DLBCL), respectively. IgH/Bcl6 fusion was seen in 2 case of DLBCL and IgH/C-myc fusion was seen in 1 case of Burkitt lymphoma (BL). Finally, our cohort included 82 B-cell lymphomas (91%) and 8 T-cell lymphomas (9%). Subclassification of lymphoma in accordance with WHO system included 40 cases of FL, 39 cases of DLBCL, one case of BL, 2 cases of lymphoblastic lymphoma, 7 cases of peripheral T cell lymphoma not specified, and one case of angioimmunoblastic lymphoma. Although all of the outpatients were hospitalized until the day after biopsy, there were no serious complications related to this procedure like bleeding, perforation, ileus, and infection. Conclusions: EUS-FNAB using a standard 19 or 22-gauge needle is safe and feasible and has high diagnostic value for subclassification of intra-abdominal lymphoma without accessible peripheral lymphadenopathy. With the use of simultaneous immunophenotyping, molecular, and cytogenetic studies, lymphoma subclassification was possible in most of the cases. Disclosures No relevant conflicts of interest to declare.
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Sun, Guoxian, and Lya Montella. "Oncogene Amplification as an Incidental Finding in FISH Testing for Gene Rearrangements in Lymphoid Hematopoietic Neoplasms." Blood 118, no. 21 (2011): 2505. http://dx.doi.org/10.1182/blood.v118.21.2505.2505.
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Abstract Abstract 2505 Oncogene amplification resulting in overexpression, although common in solid tumors, is rare in hematopoietic neoplasms. This is particularly true in lymphoid neoplasms compared to AML where MYC, MLL or RUNX1 (AML1) amplification has been mostly seen, and to CML where BCR/ABL fusion gene amplification has been also reported. Typically, lymphoid neoplasms are tested at diagnosis by FISH for specific reciprocal chromosome translocations that lead to overexpression of deregulated oncogenes such as BCL1, BCL2, BCL6 and MYC in B-cell lymphoma and myeloma or BCR/ABL gene fusion in ALL. Nevertheless, we have unexpectedly seen oncogene amplification from time to time in our FISH lab. To study the incidence of gene amplification and its diagnostic and clinical implications, we retrospectively analyzed FISH results routinely performed on paraffin embedded lymphoma tissues, lymph nodes, bone marrow aspirates and peripheral bloods in the past three and half years using translocation probes for BCL2/IGH, BCL1/IGH, MYC/IGH and BCR/ABL and break apart probes for BCL6 and MYC. The highest amplification rate seen was in BCL2/IGH testing: 11 of the 1,710 cases were positive (0.643%). In 2 cases with follicular lymphoma (FL), BCL2 amplification presented as homogenously staining regions (hsr), one case with diffuse large B-cell lymphoma (DLBCL) showed double minutes (dmin), and two cases with FL had a pattern of combined hsr and dmin. Five cases with low grade FL intriguingly showed a similar pattern of BCL2/IGH translocation and concomitant amplification of the rearranged BCL2 as a small hsr. The remaining case diagnosed as Burkitt lymphoma (BL) was positive for MYC/IGH translocation and for BCL2 amplification present as large hsr. BCL6 amplification was observed in 4 of 1,537 cases tested (0.26%). In all these cases, amplification presented as hsr. One case diagnosed as EBV+ DLBLC was positive for MYC/IGH translocation and 3' BCL6 high level amplification. Another case with FL showed BCL6 rearrangement and 5' BCL6 amplification. BCL1 amplification with translocation was seen as hsr in 1 case with mantle cell lymphoma out of 2,898 tested. BCL1 amplification was observed in another case with plasma cell myeloma as hsr out of 3,413 tests performed. MYC gene amplification was positive in 3 of 2,186 (0.137%). One case with BL showed MYC rearrangement with a concomitant 3' deletion and 5' amplification. The second case diagnosed as B-cell lymphoma with features intermediate between DLBCL and BL showed highly amplified MYC gene as hsr. The third case was DLBCL with 15–50 copies of MYC gene per cell as dmin. Among 530 BCR/ABL tests ordered for acute leukemia or ALL, 2 (0.377%) cases with T cell lymphoblastic leukemia/lymphoma (T-ALL/LBL) showed ABL amplification as episomes (4–8 copies in one case; 6–30 in another). Both were abnormal by cytogenetics analysis, but negative for t(9;22)(q34;q11.2) and without dmin or hsr identified. Although detection rates of oncogene amplification seem to be very low with limited specific translocation probes applied to lymphoid neoplasms, they may well be higher when FISH signal patterns are analyzed more carefully. In our study, 5 of the 11 FL cases tested for IGH/BCL2 showed a peculiar pattern positive for the t(14;18)-IGH/BCL2 and a concomitant red signal amplification of BCL2, the size of which is usually small and may be overlooked under microscope. All these 5 cases had low grade FL, suggesting that oncogene amplification can be an early genomic event in lymphomagenesis. MYC gene amplification is generally considered a late stage genomic alteration. When MYC is rearranged, amplification of BCL2, BCL6 or BCL1 may need to be taken into consideration for disease stratification, or vice versa. For instance, so called “double-hit” or “triple-hit” lymphomas currently require two or three concurrent translocations for diagnosis. Oncogene amplification, equally important for deregulation/overexpression as a translocation, should be considered as a second or a third hit in diagnosis and differential diagnosis of B-cell lymphoma unclassifiable with features intermediate between DLBCL and BL. FISH is a very useful tool to identify episomal oncogene amplification. Episomes, unlike cytogenetically evident dmin and hrs, are invisible by chromosome analysis, but their detection is important as reported for integration of targeted tyrosine kinase inhibitors into chemotherapeutic regimens. Disclosures: No relevant conflicts of interest to declare.
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Campbell, Neil, Joseph J. Kramer, Katherine Piso, et al. "The Role of ETV6/TEL in Hematopoiesis and Lymphoid Neoplasia." Blood 114, no. 22 (2009): 972. http://dx.doi.org/10.1182/blood.v114.22.972.972.
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Abstract Abstract 972 The transcriptional repressor TEL (Translocation Ets Leukemia) also known as ETV6 (Ets variant gene 6) located on human chromosome 12 is essential for hematopoietic stem cell (HSC) maintenance. Abnormalities involving TEL on the short arm of chromosome 12 including deletions and translocations are common in a surprisingly wide spectrum of hematological and non-hematological malignancies. Genome-wide analysis of leukemic samples revealed the loss of TEL expression and loss of heterozygousity (LOH) in more than half of B-cell ALL patients. We have previously reported on the generation of transgenic zebrafish expressing TEL-AML1 that develop pre-B ALL after long latency, and recapitulate the same phenotype and molecular events in human leukemias. In this study, we first used these transgenic fish to investigate the role of TEL in leukemia development. Our data shows that the loss of TEL expression contributes to, and accelerates the leukemic phenotype in our TEL-AML1 transgenic zebrafish. TEL is a selective regulator of lymphoid and HSC survival. The mechanism by which TEL modulates adult lymphoid and HSC renewal is yet to be elucidated. Moreover, studies of TEL expression and role in lymphoma development are lacking. At the genetic level, the highly conserved alternative start codon, and the initiation of translation at Methionine-43 of TEL creates a shorter isoform that is mostly nuclear. Utilizing specific antibodies that distinguish between the expression patterns of the two TEL isoforms, we demonstrate that the differential cytoplasmic and nuclear localization of TEL isoforms in human cells is involved in B- and T-cell lymphoid maturation. Our studies uncover a nuclear trafficking mechanism that is likely to regulate the nuclear repression and tumor suppressor functions of TEL. We next investigated the role of TEL in normal hematopoiesis, and TEL tumor suppressor functions in lymphoid malignancies in a novel model of zebrafish lymphoma. To study the role of TEL in hematopoiesis, we isolated the zebrafish TEL coding region and promoter elements from a BAC library, and found that TEL is expressed in early embryonic stages, in hematopoietic and neural lineages, and its expression colocalized with the hematopoietic stem cell (HSC) markers cMyb, Flk1 and RUNX1. In this model, the loss of TEL expression using morpholinos and dominant negative approaches in wild type zebrafish led to the development of lymphomas in 15% of these fish. This prompted us to investigate the expression of TEL in human lymphomas. Loss of TEL expression or the cytoplasmic localization of TEL isoforms in tumor cells from lymphoma patients were detected in eleven out of twenty three patients investigated so far (48%), and correlated with the non-Hodgkin diffuse large B-cell lymphomas and follicular subtypes as well as the aggressiveness of lymphomas. Flow cytometric analyses of lymphoma samples associated with loss of TEL expression demonstrated a CD19+ve, CD20+ve, CD10+ve, and CD45+ve phenotype. In cellular assays, we demonstrate that the activity and cellular localization of TEL are tightly regulated at multiple levels, and coordinated by P38 kinase activity. Our studies highlight a novel tumor suppressor role of TEL/ETV6 in lymphoma development, and establish TEL/ETV6 expression as a useful biomarker for non-Hodgkin lymphoma diagnosis and disease progression. Disclosures: No relevant conflicts of interest to declare.
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Kern, Wolfgang, Torsten Haferlach, Susanne Schnittger, and Claudia Haferlach. "Correlation of Multiparameter Flow Cytometry and Fluorescence In Situ Hybridization in Quantifying Malignant Cells at Low Frequencies in B-Cell Lymphoproliferative Diseases." Blood 110, no. 11 (2007): 4428. http://dx.doi.org/10.1182/blood.v110.11.4428.4428.
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Diagnostic and follow-up evaluation of patients with B-cell lymphoproliferative diseases includes the assessment of peripheral blood and bone marrow samples by both multiparameter flow cytometry (MFC) and fluorescence in situ hybridization (FISH) for the detection and quantification of malignant cells. Depending on the type of aberrant immunophenotype and on the probes applied for FISH sensitivity may vary particularly if small populations of malignant cells are present. We evaluated 61 peripheral blood (n=20) and bone marrow (n=41) samples from patients with B-cell lymphoproliferative diseases in which malignant cell populations as quantified by MFC were <15% and in which chromosomal aberrations were identified by FISH analysis. The diagnoses included CLL and CLL/PL (n=23), follicular lymphoma (FL, n=16), mantle cell lymphoma (MCL, n=10), and other B-cell lymphoproliferative diseases comprizing mainly marginal zone lymphomas and lymphoplasmacytic lymphomas (B-NHL, n=12). A standardized panel was used for MFC including antibodies against CD5, CD10, CD11c, CD19, CD20, CD22, CD23, CD25, CD38, CD45, CD79b, CD103, FMC7, IgM, Kappa, and Lambda. FISH was performed including probes for del(6q), del(11q), trisomy 12, del(13q), del(17p), t(11;14), t(14;18), IGH, CMYC, and BCL6. The median number of malignant cells as quantified by MFC amounted to 8% (range, 2% to 14%). The median number of malignant cells as quantified by FISH amounted to 9% (range, 1% to 42%). Overall, there was a high degree of correlation between both methods (r=0.544, p<0.0001). In particular, there were good correlations within the subgroups CLL (r=0.402, p=0.057) and MCL (r=0.876, p=0.001). Accordingly, correlations were significant for results obtained by FISH probes for trisomy 12 (r=0.649, p=0.005) and for t(11;14) (r=0.693, p=0.009) while the correlation for cases with t(14;18) were less strong (r=0.411, p=0.101). The present results confirm that in patients with B-cell lymphoproliferative diseases malignant cells may be detected and quantified by both MFC and FISH with good correlation even if present at very low frequencies only. So far our data are not in favor of either MFC or FISH for analyzing low percentages of lymphoma infiltration. Future studies should assess the clinical relevance of low level infiltration of peripheral blood and bone marrow and the respective roles of MFC and FISH in their detection.
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Bagg, Adam. "B Cells Behaving Badly: A Better Basis to Behold Belligerence in B-Cell Lymphomas." Hematology 2011, no. 1 (2011): 330–35. http://dx.doi.org/10.1182/asheducation-2011.1.330.
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Abstract A plethora of genetic abnormalities has been described in B-cell lymphomas, some of which arise when physiologic mechanisms involved in the generation of immunologic diversity go awry. Several different lymphoma types, such as follicular lymphoma (FL), mantle cell lymphoma (MCL), and Burkitt lymphoma (BL), are associated with hallmark translocations that occur as a consequence of these errors (t(14;18)(q32;q21), t(11;14)(q13;q32), and t(8;14)(q24;q32), respectively); however, none of these associations is absolute and none is completely diagnostically specific or sensitive. The advantages and limitations of a variety of different testing strategies in the 2 most common lymphomas, FL and diffuse large B-cell lymphoma (DLBCL), are reviewed herein, including an evaluation of the role of PCR-based approaches, FISH, and more nascent genomic technologies. The use of immunophenotypic strategies that may potentially provide, albeit imperfectly, more user-friendly surrogates for underlying genetic aberrations and cell-of-origin designations derived from gene-expression profiling analyses are also discussed. Finally, a newly designated category of lymphoma with features intermediate between DLBCL and BL is appraised, highlighting the central role of genetic analysis in this diagnostic gray zone.
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Miura, Yukiko, Joji Yamamoto, Katsura Kohata, Kenichi Ishizawa, Ryo Ichinohasama, and Hideo Harigae. "Clinicopathological Features of Malignant Lymphoma in JAPAN- Data From the Miyagi Study." Blood 114, no. 22 (2009): 4997. http://dx.doi.org/10.1182/blood.v114.22.4997.4997.
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Abstract Abstract 4997 Background Malignant lymphoma comprises a diverse group of histologic categories. To date, several epidemiological studies in Japan have been reported, however, the data were collected from selected representative institutions, therefore, the results might not reflect the actual incidence and characteristics of malignant lymphoma in Japan. The Miyagi Study is a comprehensive epidemiologic study of malignant lymphoma, including immunologic and genetic information, constructed by a population-based registration system covering Miyagi prefecture, Japan. The population composition by age group and the population growth rate in Miyagi resembles national average figures, therefore, the clinicopathological features of in the Miyagi Study are likely representative of Japan. The purpose of this study was to determine the relative incidences and features of malignant lymphoma subtypes in Japan, compared to that of other countries. Methods A total of 1546 cases of malignant lymphoma newly diagnosed between 2002 and 2008 in Miyagi prefecture, of which the population is about 2.5 million, were enrolled in the Miyagi Study. Clinical and histopathological data including results of flow cytometry(FCM), immunohistochemistry (IHC), G-banding analysis with or without bicolor fluorescence in situ hybridization(FISH), southern blot analysis with or without polymerase chain reaction(PCR) were collected, and analysed. Results The median age of onset was 66 years and the male/female ratio was 1.13. Of the 1546 cases of newly diagnosed malignant lymphoma, 1160 cases (75%) were B-cell lymphomas, 287 cases (19%) were T-cell lymphomas, and only 81 cases (5%) were Hodgkin lymphomas. The most frequent subtype of B-cell lymphoma was diffuse large B-cell lymphoma (DLBCL), accounting for 52% of all B-cell lymphoma cases, followed by follicular lymphoma (FL) and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), accounting for 24% and 8% of B-cell lymphoma cases, respectively. The most frequent subtypes of T/NK-cell lymphoma were peripheral T-cell lymphoma, unspecified (PTCLU), angioimmunoblastic T-cell lymphoma(AILT) and adult T-cell lymphoma, accounting for 30%, 15% and 14% of cases, respectively. The relative frequency of malignant lymphoma subtypes was similar to that of Japan reported in 2000 by Lymphoma Study Group of Japanese Pathologists, though there were some differences, such as the high incident rate of FL. There was not a notable time trend in the proportion of FL in B-NHL through 7 years, since it accounted for 20.3% in 2002 and 24.0% in 2008. Within the B-cell lymphoma group, there was a higher frequency of indolent B-cell lymphomas in women (39.8%) compared to men (29.8%). The rates of CD20 and CD22 positivity, as analysed by FCM, were 94.9% and 96.3% in DLBCL, 99.2% and 98.4% in FL, and 98.4% and 100% in MALT lymphoma, respectively. The t(14;18) translocation, a frequent chromosomal abnormality of FL, was present in 63.9% of FL patients, which is less frequent compared with the reports from western countries. De novo CD5+ DLBCL, which is known to have poor outcome, accounted for 21.6% of DLBCL, a frequency higher than previously reported. Conclusions The relative frequency of the subtypes of malignant lymphomas in Miyagi is distinct from that of Western countries and shares some similarities with other Asian countries. In the present study, FL was found to be the second largest subtype of malignant lymphoma, consistent with previous reports that FL is increasing in Far East Asia including Japan, Korea and Taiwan. The results of this study reveal the clinicopathologic characteristics of malignant lymphomas in Japan. Disclosures No relevant conflicts of interest to declare.
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Coventry, Susan, Hope H. Punnett, Ewa Z. Tomczak та ін. "Consistency of Isochromosome 7q and Trisomy 8 in Hepatosplenic γδ T-cell Lymphoma: Detection by Fluorescence in Situ Hybridization of a Splenic Touch-Preparation from a Pediatric Patient". Pediatric and Developmental Pathology 2, № 5 (1999): 478–83. http://dx.doi.org/10.1007/s100249900152.
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Hepatosplenic gamma-delta (γδ) T-cell lymphoma is a rare but increasingly recognized lymphoid malignancy predominantly affecting young adult males. It is not well appreciated in the pediatric population. We report the third case of this aggressive lymphoma in a child as well as additional support for the consistency of the recently discovered cytogenetic abnormalities, isochromosome 7q and trisomy 8, which in this case were documented using fluorescence in situ hybridization (FISH) of a touch-preparation of the spleen.
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Ye, Hongtao, Liping Gong, Hongxiang Liu, et al. "Strong BCL10 Nuclear Expression Identifies Gastric MALT Lymphomas That Do Not Respond to H. pylori Eradication." Blood 106, no. 11 (2005): 982. http://dx.doi.org/10.1182/blood.v106.11.982.982.
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Abstract Purpose: In a previous retrospective study, we have shown that 75% of gastric MALT lymphomas that did not respond to H. pylori eradication could be identified by detection of t(11;18)(q21;q21). The present study examined the value of t(1;14)(p22;q32) in prediction of the response of gastric MALT lymphomas to H. pylori eradication. Patients and Methods: A total of 111 patients with H. pylori-positive gastric MALT lymphoma, who were treated by H. pylori eradication, were screened for BCL10 involved chromosome translocation by BCL10 immunohistochemistry, followed by interphase FISH and real-time quantitative reverse transcription PCR (qRT-PCR). The clinical presentation of 11 cases of MALT lymphoma including 6 from the stomach with known BCL10 involved chromosome translocation was reviewed. Results: Of the 111 cases of gastric MALT lymphoma treated by H. pylori eradication, 75 including 35 from the complete regression group and 40 from the non-responsive group, had adequate specimens for BCL10 immunohistochemistry. Two cases showed strong BCL10 nuclear staining in virtually all tumor cells, similar to that seen in those with t(1;14)(p22;q32). Both were from the H. pylori eradication non-responsive group. Although interphase FISH failed to show evidence of BCL10 gene break or amplification, one case showed an IGH break. This case also showed a high level of BCL10 mRNA expression, compatible to that seen in MALT lymphoma with t(1;14)(p22;q32). 9 of the 11 cases with known BCL10 involved translocation were at stage IIE or above, with three showing agressive clinical presentations. Conclusion: Gastric MALT lymphomas with strong BCL10 nuclear expression or t(1;14)(p22;q32) are mostly likely resistant to H. pylori eradication.
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Anand, Shankar, Akshatha C, Libin Babu Cherian, and Ramachandra C. "Ocular Extranodal Marginal Zone Lymphoma - A Study of Twenty-Two Cases Presented at Bangalore, Karnataka." Journal of Evidence Based Medicine and Healthcare 8, no. 24 (2021): 2070–76. http://dx.doi.org/10.18410/jebmh/2021/388.
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BACKGROUND Ocular adnexa lympho-proliferative disorders are a divergent diverse category of ocular malignancies, comprising roughly about 1 % to 2 % of Non-Hodgkin’s lymphomas (NHLs) and 8 % of extranodal lympho-proliferative disorders. The most frequent type, approximating for up to 80 % of cases that constitutes the primary is marginal zone lymphoma of mucosa associated lymphoid tissue (MALT) type. Marginal zone lymphomas which usually have an extranodal presentation are routinely diagnosed by histomorphology by the diffuse infiltration of atypical lymphoid cells with plasmacytoid appearance and presence of pathognomonic lymphoepithelial lesions. Lymphoepithelial lesions are the existence of lymphocytes in the cytoplasm of epithelial cells. Immunohistochemistry shows a consistent absence of CD5 and CD23 staining, hence considered as diagnosis of exclusion on histo-immunomorphology. METHODS This is a case-series study. Twenty-two cases of ocular extranodal marginal zone lymphoma were obtained from the archives of pathology from 2013 to 2015. The histopathology and immunohistochemistry slides were reviewed by three expert histopathologists for confirmation of diagnosis. Immunohistochemical markers mainly used were CD45, CD3, CD5, CD20, cyclin D1, CD10, Ki - 67, BCL - 2, PAX 5 and CD23. The immunohistochemical markers such as CD10, BCL - 2 and cyclin D1 IHC expression were studied in cases of ocular extranodal marginal zone lymphoma (OENMZL). Relevant clinical details were collected from the patients such age, sex and history of autoimmune condition if any. RESULTS Eighteen cases (81 %) of OENMZL belonged to the age group of more than 40 years. There was a definite male preponderance (77 %) and it was associated with autoimmune conditions such as Hashimoto’s thyroiditis (18 %) and Sjogren’s syndrome (22 %). 22 cases of OENMZL were analysed and all showed consistent immunoexpression for CD20, CD45 while were immunonegative for CD5, CD23 and cyclin D1. 6 cases (27 %) showed CD10 positivity while 20 cases showed Bcl2 positivity (90 %). CONCLUSIONS OENMZL shows positivity for CD20 and CD45 while immunonegative for CD5, CD23 and cyclin D1, and a fraction of cases can show IHC positivity for CD10 and Bcl-2. KEYWORDS OENMZL: Ocular Extranodal Marginal Zone Lymphoma, MZL: Marginal Zone Lymphoma, CD: Cluster Differentiation. NHL: Non-Hodgkin Lymphoma. OL: Ocular Lymphoma. PCR: Polymerase Chain Reaction, FISH: Fluorescent In Situ Hybridization
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Sanders, Lucinda, Sandrine Jayne, Ben Kennedy, et al. "A Double Hit CD10-Negative B-Cell Lymphoma with t(3;8)(q27;q24) Leading to Juxtaposition of theBCL6andMYCLoci Associated with Good Clinical Outcome." Case Reports in Hematology 2014 (2014): 1–5. http://dx.doi.org/10.1155/2014/120714.
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The WHO classification of lymphomas allows for a group of diseases that have features intermediate between those of Burkitt lymphoma and diffuse large B-cell lymphoma. These are a diverse group of diseases whose genetics and clinical course are yet to be fully described. We report an unusual case of high grade B-cell lymphoma, intermediate between DLBCL and BL, lacking CD10 expression in which the chromosomal translocation t(3;8)(q27;q24) was found to be the sole chromosomal abnormality. FISH analysis demonstrated juxtaposition of theBCL6andMYCloci without obvious involvement of theIGHlocus, suggesting constitutiveMYCexpression due to promoter substitution. The patient responded to intensive chemotherapy and remains in remission two years after finishing therapy.
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Alizadeh, Ash A., Matthew Anderson, Holbrook E. Kohrt, et al. "Clinical and Pathological Features of Non-Hodgkin Lymphomas Harboring Concurrent t(14;18) and 8q24 Anomalies." Blood 116, no. 21 (2010): 3134. http://dx.doi.org/10.1182/blood.v116.21.3134.3134.
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Abstract Abstract 3134 Background: Concurrent t(14;18) and 8q24 translocations involving BCL2 and MYC in non-Hodgkin lymphomas (NHL) are rare, but are associated with a inferior overall survival (OS) regardless of the presenting or antecedent histological features (Johnson N, et al. Blood 2009). We sought to confirm these observations in an independent cohort of patients with NHL. Methods: Metaphase karyotypes and/or fluorescence in-situ hybridization (FISH) were used to identify cases of NHL with cytogenetic abnormalities involving 18q21 and 8q24 (BCL2 and MYC). Clinical and cytogenetic characteristics of these patients were assessed for correlations with pathological and clinical variables including outcome. Histological diagnoses were determined according to the 2008 World Health Organization Classification. Overall survival (OS) was calculated from the date a biopsy demonstrated an abnormality involving MYC to the last follow up date or death, as some cases acquired these lesions during their clonal evolution. Result: Among ∼1700 NHL patients diagnosed and/or treated at Stanford University Medical Center on whom cytogenetic studies were routinely performed, we identified 26 patients with evidence for concurrent cytogenetic abnormalities involving BCL2 and MYC. The histological diagnoses at the time of BCL2 and MYC rearrangements were available for 25 of the patients and included follicular lymphoma (FL1-2, n=3; FL3A, n=4), diffuse large B-cell lymphoma (DLBCL, n=2), and B cell lymphoma, unclassifiable, with features intermediate between Burkitt Lymphoma and DLBCL (BCLU, n=16). Cytogenetic analysis revealed that 13/26 cases with both BCL2 and MYC rearrangements had MYC translocations involving the immunoglobulin (Ig) loci. However, in striking contrast to the <10% prevalence of IgL or IgK partners in NHL harboring Ig-MYC, without Ig-BCL2 rearrangements, 9 of these13 cases (69%) involved IgL t(8;22), and only 4 of these 13 cases (31%) involved IgH t(8;14). 9/26 MYC translocations involved various non-Ig loci (35%). One case (1/26) demonstrated amplification of ?both the BCL2 and the MYC loci by FISH, while one case showed trisomy 8 (1/26). Three cases had FISH analysis only, precluding assessment of the MYC rearrangement partner. No correlation between MYC partner and histology was observed, although this analysis was limited by small sample sizes. Non-FL histology correlated with significantly poorer than expected outcome, with a median OS of 4 months compared to 2 y for FL (p=0.003). Interestingly, we found cases with low-grade follicular lymphoma (FL1-2) histology which harbored both BCL2 and MYC rearrangements. To better define the frequency of 8q24 anomalies in an unselected cohort of follicular lymphoma cases, FISH for MYC and BCL2 rearrangements was performed on 192 independent low-grade follicular lymphoma (FL1-2) cases. While a subset of these cases (71) showed the expected frequency of BCL2 rearrangements (72%) by FISH, none showed concomitant 8q24 anomalies by FISH, suggesting that routine FISH analysis of low-grade follicular lymphoma for MYC rearrangements would have a low diagnostic yield. Conclusion: NHL with rearrangements of both BCL2 and MYC are under-recognized due to lack of routine karyotyping or FISH analysis. Comprehensive analysis of BCL2 and MYC status should be performed on all HGBCL in the new WHO (2008) classification, though the low frequency of these lesions among FL tumors precludes a similar conclusion for low grade NHL. Disclosures: No relevant conflicts of interest to declare.
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Swerdlow, Steven H. "Diagnosis of ‘double hit’ diffuse large B-cell lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma: when and how, FISH versus IHC." Hematology 2014, no. 1 (2014): 90–99. http://dx.doi.org/10.1182/asheducation-2014.1.90.
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Abstract Identification of large B-cell lymphomas that are “extra-aggressive” and may require therapy other than that used for diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), is of great interest. Large B-cell lymphomas with MYC plus BCL2 and/or BCL6 rearrangements, so-called ‘double hit’ (DHL) or ‘triple hit’ (THL) lymphomas, are one such group of cases often recognized using cytogenetic FISH studies. Whether features such as morphologic classification, BCL2 expression, or type of MYC translocation partner may mitigate the very adverse prognosis of DHL/THL is controversial. Classification of the DHL/THL is also controversial, with most either dividing them up between the DLBCL, NOS and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCLU) categories or classifying at least the majority as BCLU. The BCLU category itself has many features that overlap those of DHL/THL. Currently, there is growing interest in the use of MYC and other immunohistochemistry either to help screen for DHL/THL or to identify “double-expressor” (DE) large B-cell lymphomas, defined in most studies as having ≥40% MYC+ and ≥50%-70% BCL2+ cells. DE large B-cell lymphomas are generally aggressive, although not as aggressive as DHL/THL, are more common than DHL/THL, and are more likely to have a nongerminal center phenotype. Whether single MYC rearrangements or MYC expression alone is of clinical importance is controversial. The field of the DHL/THL and DE large B-cell lymphomas is becoming more complex, with many issues left to resolve; however, great interest remains in identifying these cases while more is learned about them.
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Johansson, Ann-Sofie, Ulrika Norén-Nyström, Åsa Larefalk, Dan Holmberg, and Magnus Lindskog. "Fish oil delays lymphoma progression in theTLLmouse." Leukemia & Lymphoma 51, no. 11 (2010): 2092–97. http://dx.doi.org/10.3109/10428194.2010.522284.
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Wlodarska, Iwona, Peter Vandenberghe, Peet Nooien, Anne Hagemeijer, Peter Marynen, and Chris De Wolf-Peeters. "FOXP1, a Highly Expressed Gene in a Subset of DLBCL, Is Targeted by a Recurrent t(3;14)(p13;q32)." Blood 104, no. 11 (2004): 2891. http://dx.doi.org/10.1182/blood.v104.11.2891.2891.
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Abstract Chromosomal translocations involving the immunoglobulin heavy chain genes cluster (IGH) at 14q32 have been found in up to 70% of B-non Hodgkin’s lymphoma. These aberrations lead to deregulation of putative oncogenes by their juxtaposition with IGH enhancer elements. So far, more than 20 genes affected by t(14q32) have been identified in B-cell malignancies. The most frequently rearranged genes include BCL1/11q13, BCL2/18q21, BCL6/3q27 and CMYC/8q24. We report here a novel t(3;14)(p13;q32) involving IGH, as shown by FISH, in three lymphoma cases. One of these cases was diagnosed as gastric MALT-type lymphoma, the remaining two cases as diffuse large B-cell lymphoma with a focal nodular growth pattern reminiscent of follicular lymphoma. In order to identify the gene targeted by the t(3;14)(p13;q32) we performed FISH analysis of the first case and narrowed down the breakpoint to RP11-154H23 at 3p13 that showed a split signal on both derivative chromosomes. This BAC clone covers the FOXP1 gene. Using a pair of probes selected for the 5′ and 3′ ends of FOXP1, we demonstrated rearrangement of the gene by dual color FISH in the remaining two cases. An analysis of FOXP1 expression in present cases is being performed. FOXP1 (Forkhead box-P1) is a winged-helix transcription factor that acts as a transcriptional repressor. It is expressed in a wide variety of normal and neoplastic tissues, including lymphomas. FOXP1 has been shown to be expressed in normal activated B-cells using genomic-scale expression profiling, and in B-cells within and outside the germinal center by immunohistochemistry. Its physiological role in lymphocytes, however, is unclear. Recent studies showed that FOXP1 is strongly expressed in a subset of DLBCL. Interestingly, high expression of FOXP1 carries an independent prognostic significance, what suggests a possible role of the gene in the biology of this group of lymphoma. Although genomic rearrangements of FOXP1 have not been demonstrated so far in cancer, rearrangements of other members of FOX gene family in various pathological conditions have been reported. The involvement of FOXP1 in t(3;14)(p13;q32) found in two DLBCL cases indicates that this translocation may underlie a strong expression of FOXP1 in at least part of these lymphomas. Its rearrangement in a case of gastric lymphoma is intriguing, but additional investigations are required to find out whether t(3;14)(p13;q32) is a recurrent aberration in MALT lymphoma. Further molecular, immunophenotypic and clinical studies of the three cases with t(3;14)(p13;q32) are under progress.
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Felten, Christopher L., Joel A. Chan, Dulce R. DeCastro, Jean Lopategui, and Swapnil P. Rajurkar. "Blastoid Variant Mantle Cell Lymphoma Expressing Aberrant CD3 and CD10 with Concurrent Small Lymphocytic Lymphoma: Establishment of a Clonal Relationship by B- and T-Cell Receptor Gene Rearrangements." Case Reports in Hematology 2018 (December 5, 2018): 1–10. http://dx.doi.org/10.1155/2018/8303571.
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Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin B-cell lymphoma typically expressing CD19, CD20, CD5, FMC-7, CyclinD1, and SOX-11 and harboring the IgH/CCND1 translocation. We report a blastoid variant of mantle cell lymphoma (MCL) involving an inguinal lymph node that, in addition to classical phenotypic and genetic findings, also aberrantly coexpresses surface CD10 and cytoplasmic CD3. Small lymphocytic lymphoma (SLL) was also present in the same lymph node and in the bone marrow. B- and T-cell gene rearrangement studies by PCR show the MCL and SLL to be clonally related. Expression of multiple aberrant antigens and concurrent lymphomas of different classifications can cause a diagnostic challenge. Awareness of such a presentation and integration of the data from morphologic evaluation, flow cytometry, immunohistochemistry, and FISH studies is required for proper diagnosis, prognosis, and therapy.
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Mai, B., A. Berumen, A. Herrmann, and L. Chen. "Discordant Lymphoma: A Sequential Case of Burkitt Lymphoma and Classic Hodgkin Lymphoma." American Journal of Clinical Pathology 154, Supplement_1 (2020): S109—S110. http://dx.doi.org/10.1093/ajcp/aqaa161.239.
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Abstract Casestudy A discordant lymphoma is a rare condition in which two or more subtypes of lymphomas can occur in different anatomic sites; the distinct sub-classifications can present concurrently or sequentially. We present a rare case of a second primary Classic Hodgkin Lymphoma (CHL) several years after achieving remission from an unusual presentation of a non-Hodgkin lymphoma (NHL). Results A 40-year-old HIV-positive male presented to the emergency department for acute cholecystitis. Sections of his gallbladder revealed atypical monomorphic lymphocyte infiltrate that were diffusely positive for CD10, CD20, BCL6, and PAX5, and negative for BCL2, CD5, Cyclin D1, and MUM1. The proliferation index by Ki-67 was 100%. EBER ISH is positive. A FISH assay for the C-MYC break apart probe and dual fusion of IgH and BCL2 showed a rearrangement of 8q24, highly suspicions for a 8;14 translocation, classically seen in Burkitt Lymphoma (BL). Subsequently, he was placed on RA-DA-EPOCH and achieved remission. Seven years later, he presented with nausea, vomiting, headaches, and blurry vision. An excisional biopsy of his right cervical lymph node was performed. The histological sections showed effaced nodal architecture with sclerotic fibrosis and necrosis. There were scattered Hodgkin cells/Reed-Sternberg (HRS) cells in the background of lymphocytes, plasma cells, histiocytes, and eosinophils. The HRS cells were positive for CD15, CD20 (weak), CD30, BCL6, MUM1, and PAX5 (weak), and negative for ALK, CD10, and CD45. EBER ISH was positive and HHV8 was negative. These features were consistent with a CHL, nodular sclerosis subtype. Conclusion Malignancies in HIV patients pose a unique challenge as they often possess distinct characteristics distinct, including unique aspects of tumor localization, atypical pathological features, unusual growth behavior, and advanced stage at presentation. Epstein-Barr virus (EBV) is strongly linked with several HIV-associated lymphomas, as it encodes several proteins including LMP-1, LMP-2A, BHRF-1, EBNA-3A, and EBNA-3C that are implicated in the development of NHLs. The identification of discordant lymphomas may have variable prognoses and different treatment modalities. In addition, the study of such discordant lymphoma cases may provide more insight on the etiology and inter-relationship of clonal evolution in lymphoma.
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Sun, Guoxian, Min Yang, Lya Montella, and Valentina Mizhiritskaya. "FISH Diagnostics of Double Hit or Triple Hit B-Cell Lymphomas." Blood 120, no. 21 (2012): 1599. http://dx.doi.org/10.1182/blood.v120.21.1599.1599.
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Abstract Abstract 1599 Fluorescence in situ hybridization (FISH) is currently a widely used and most objective technology in identifying double hit or triple hit lymphomas (DHL/THL) that consist of a spectrum of genetically and pathologically heterogeneous B-cell neoplasms. Accurate detection with appropriate FISH probes or panels helps diagnosis, risk stratification and therapy selection, particularly in commonly seen aggressive lymphomas such as Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and B-cell lymphoma unclassifiable with features intermediate between DLBCL and BL. We retrospectively look into 147 DHL/THL cases out of 927 consecutive MYC FISH positive B-cell lymphomas tested in our lab in the past four and half years to analyze typical and atypical findings to attempt to improve detection rates and correctly interpret atypical FISH results. FISH probes (Vysis) for MYC breakapart (ba), MYC/IGH translocation, BCL2/IGH translocation, BCL6 ba and CCND1/IGH translocation were applied to paraffin embedded tissue, lymph node biopsy, bone marrow and peripheral blood specimens. Among 927 cases, MYC and MYC/IGH were both ordered in 627 cases, MYC ba was ordered without MYC/IGH in 252, MYC/IGH without MYC ba in 48 cases, BCL2 was ordered in 379 cases, BCL6 in 280, BCL2 and BCL6 in 277, CCND1 in 104, BCL2 and CCND1 in 94, BCL6 and CCND1 in 90, and BCL2, BCL6 and CCND1 in 90. Of the 147 cases, 12 were MYC and CCND1 positive with a diagnosis of mantle cell lymphoma (MCL); one of these cases was THL with BCL6 rearranged and its 5' probe deleted. Most common is BCL2 or BCL6 positive seen in 88 and 20 cases respectively. 24 cases were THLs with MYC and both BCL2 and BCL6 positive. In 91 cases with MYC ba and MYC/IGH both probes performed, 55 were positive for MYC ba but negative for MYC/IGH (60%) compared to 34 positives for both MYC ba and MYC/IGH (37.4%) which is significant as reported in literature that more cases with DHL/THL showed MYC rearrangements with non-IGH or non-IG partner genes unlike the majority of the Burkitt lymphomas. Interestingly, in one DHL and one THL, MYC ba was negative but MYC/IGH was positive, suggesting a cryptic/complex insertional translocation reported by other groups and our lab. For breakapart probes, a deletion of the flanking sequences concomitant with gene rearrangement is relatively common. In 147 DHL/THL cases, MYC ba positive with a deletion was seen in 11 (7 for 3' and 4 for 5'), and BCL6 ba positive with a deletion was seen in 6 (2 for 3' and 4 for 5'). One DHL showed 5' MYC probe amplification. Based on our experience concurring with studies by other groups, we suggest: 1) FISH testing in aggressive B-cell lymphomas include BCL2 and BCL6 in the probe panel as IHC results may not be as sensitive and reliable as DNA testing, 2) both MYC ba and MYC/IGH probes should be tested simultaneously to increase detection rates by minimizing false negative results caused by cryptical insertion translocation of IGH promoter/enhancer sequences into the MYC gene (locus) or vice versa, and to help differentiate MYC/IGH translocation from MYC/non-IGH or non-IG rearrangement seen more often in non-BL including DHL/THL, 3) CCND1 may be needed in the panel when transformed MCL is a diagnostic concern, and 4) atypical FISH results should be analyzed and interpreted correctly such as rearrangements with a flanking probe deletion and/or amplification. Next generation sequencing may delineate all of these atypical genetic abnormalities evidenced by FISH and/or cytogenetic studies and undetected genomic alterations as well. Disclosures: No relevant conflicts of interest to declare.
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Cassidy, Daniel P., Jennifer R. Chapman, Rafael Lopez, et al. "Comparison Between Integrated Genomic DNA/RNA Profiling and Fluorescence In Situ Hybridization in the Detection of MYC, BCL-2, and BCL-6 Gene Rearrangements in Large B-Cell Lymphomas." American Journal of Clinical Pathology 153, no. 3 (2019): 353–59. http://dx.doi.org/10.1093/ajcp/aqz172.
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Abstract Objectives To compare fluorescence in situ hybridization (FISH) and a commercially available sequencing assay for comprehensive genomic profiling (CGP) to determine the best approach to identify gene rearrangements (GRs) in large B-cell lymphomas (LBCLs). Methods Comparison of standard-of-care FISH assays (including a two-probe approach for MYC; break-apart and fusion probes) and an integrated genomic DNA/RNA sequencing CGP approach on a set of 69 consecutive LBCL cases. Results CGP detected GRs, including those involving MYC (1), BCL-2 (3), and BCL-6 (3), not detected by FISH. FISH detected non–IgH-MYC (4) and BCL-6 (2) GRs that were not detected by CGP. In four instances, standalone CGP or FISH testing would have missed a double-hit lymphoma. Conclusions CGP was superior to FISH in the detection of IgH-MYC rearrangements but was inferior for the detection of non–IgH-MYC rearrangements. Our study demonstrates the rationale for development of a customized approach to identify GRs in LBCLs.
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Penas, Eva Maria Murga, Evelyne Callet-Bauchu, Nadine Albert, et al. "Molecular Characterization of the T(14;18)(q32;q21) Involving the IGH Locus and the MALT1 Gene in MALT Lymphomas." Blood 112, no. 11 (2008): 4145. http://dx.doi.org/10.1182/blood.v112.11.4145.4145.
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Abstract The t(14;18)(q32;q21) involving the MALT1 and IGH genes is a recurrent abnormality in MALT lymphomas. So far, molecular genetic characterization of the t(14;18)/IGHMALT1 has only been performed in 2 cases and revealed a fusion of the entire coding region of MALT1 to the IGH locus. We herein report the molecular genetic analyses of 2 new cases of MALT lymphoma harboring the t(14;18)/IGH-MALT1 using fluorescence in situ hybridization (FISH) and we determined the molecular characteristics at the IGH-MALT1 junctions using long-distance PCR (LD-PCR). The first case, a 71-year-old female, presented with an extranodal MALT lymphoma of the conjunctiva, stage IEA. The second case, a 53-year-old-male patient, was diagnosed as having a MALT lymphoma originating from the lung. FISH with PAC clones 117B5 and 59N7 revealed a translocation involving MALT1. Further FISH assays with probes hybridizing to MALT1 and IGH showed the t(14;18)(q32;q21)/IGH-MALT1. By FISH with specific probes for the P53, P16, RB1, and ATM genes no deletions of these genes were found. The IGH-MALT1 fusion was confirmed by LD-PCR on patients’ DNA with nested primers for the MALT1 and IGH genes. Cloning and sequencing of the purified PCR products revealed a fusion of sequences upstream of the coding region of MALT1 to the JH segment of the IGH locus in both cases. The breaks on chromosome 18 were located in the 5′ non-coding region of MALT1, only 13 nucleotides apart from each other. The breaks at IGH were located in the JH4 joining segment in both cases and showed features of a V(D)J-mediated recombination. Deletion and “de novo” nucleotides additions at the point of joining were observed in case 1. Furthermore, a detailed analysis of the “de novo” nucleotides additions in this case revealed the presence of DH segments of the DH gene D3-10 in the JH/MALT1 junction. Our findings indicate that the pathomechanism underlying the t(14;18)/IGH-MALT1 in MALT lymphomas is probably based on an illegitimate V(D)J recombination at IGH, similar to other IGH-associated translocations, such as the t(14;18)/IGH-BCL2 in follicular lymphomas and the t(11;14)/CCND1-IGH in mantle cell lymphomas and that the events leading to the t(14;18)/IGH-MALT1 might take place during an initial DH-to-JH or a later VH-to-DJH joining.
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Racke, Frederick, Sabrina Simpson, Beth Christian, Kristie A. Blum, Robert Hasserjian, and Weiqiang Zhao. "Evidence of Long Latency Periods Prior to Development of Mantle Cell Lymphoma." Blood 116, no. 21 (2010): 323. http://dx.doi.org/10.1182/blood.v116.21.323.323.
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Abstract Abstract 323 Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by treatment failures and short survival. At presentation, MCL is often widely disseminated. Occasionally, early lymphoma can be seen as in situ lesions involving the mantle zones of secondary follicles. The primary genetic lesion involved in the pathogenesis of the disease is the t(11;14)(q13;q32)/(IGH/CCND1) which leads to the overexpression of cyclin D1, a cell cycle regulatory protein that is not normally expressed in B-cells. However, MCL frequently has numerous additional chromosomal alterations making it one of the most genetically unstable lymphomas. Thus, while the IGH/CCND1 rearrangement is the critical initiating event, it appears that additional alterations are necessary to develop MCL. However, little is known about the latency period required to accumulate sufficient lesions to develop MCL. Recently, it has been appreciated that the initiating chromosomal events in other B-cell malignancies may precede the development of overt disease by many years. In particular, the defining chromosomal events in childhood ALL may be found in the heel sticks of children at birth, even if leukemia does not develop until a number of years later. We recently reported a unique case of mantle cell lymphoma arising simultaneously in the donor and recipient 12 years following allogeneic bone marrow transplantation for chronic myelogenous leukemia(J. Clin. Oncol., in press). This suggested that MCL may exhibit long latency periods prior to the development of frank lymphoma. In order to determine whether in situ MCL may be identified in patients with MCL, we identified 7 patients who were diagnosed with mantle cell lymphoma and who had previous pathological material available that contained lymphoid tissue and that was unrelated to the subsequent MCL. Remarkably, all 7 specimens showed evidence of in situ mantle cell lymphoma, as judged by cyclin D1 over-expression localized to lymphoid cells. Pathological specimens ranged from 2.1–15.5 years prior to the diagnosis of MCL. In all 7 specimens, cyclin D1 positive collections of lymphocytes were identified, 5 with distinct homing to mantle zones, one with follicular colonization and mantle homing, and 1 with a diffuse distribution. FISH studies were undertaken to identify cyclin D1 chromosomal translocations, and evidence of chromosomal translocations could be identified in 2/3 cases evaluated whereas no signals were seen in adjacent uninvolved lymphoid tissue. Taken together, the data presented strongly suggest that a long latency period following the initiating IGH/CCND1 translocation may occur in MCL with patients harboring in situ lesions for years prior to the development of clinical disease. These findings shed interesting new light on the natural history of MCL. Pre-lymphoma location Pattern of in situ MCL Latency (yrs) Lymphoma location CCND1 FISH in pre-lymphoma specimen Obturator node from radical prostatectomy CyclinD1+ focal colonized follicles, scattered cells in mantles 7.4 Sigmoid colon biopsy ND Duodenal serosal lymph node (perforated benign gastric ulcer) Diffuse scattered CyclinD1+ cells 2.1 Sigmoid colon biopsy ND Right neck subcutaneous lymph node (neurofibroma excision) CyclinD1+ cells in follicular mantles 3.2 Bone marrow biopsy ND Periesophageal lymph nodes from esophagectomy Several CyclinD1+ colonized primary follicles 8.0 Right cervical lymph node ND Axillary lymph node from mastectomy CyclinD1+ cells in follicular mantles 15.5 Mesenteric lymph node <5% positive signals Mesenteric lymph node dissection for colon cancer CyclinD1+ cells in follicular mantles 10.6 Base of tongue lesion Positive Cervical lymph node involved with T cell lymphoma CyclinD1+ cells in follicular mantles 3.1 Right axillary lymph node Positive Disclosures: No relevant conflicts of interest to declare.
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Poetsch, M., K. Weber-Matthiesen, H. J. Plendl, W. Grote, and B. Schlegelberger. "Detection of the t(14;18) chromosomal translocation by interphase cytogenetics with yeast-artificial-chromosome probes in follicular lymphoma and nonneoplastic lymphoproliferation." Journal of Clinical Oncology 14, no. 3 (1996): 963–69. http://dx.doi.org/10.1200/jco.1996.14.3.963.
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PURPOSE The aim of this study was to establish a fluorescence in situ hybridization (FISH) technique for the detection of t(14;18)(q32;q21), characteristic for follicular lymphoma (Kiel classification: centroblastic centrocytic [cb-cc] lymphoma). MATERIALS AND METHODS After the FISH system had been established, parallel studies of lymph node biopsy specimens from 30 patients with cb-cc lymphoma and from 32 patients with nonneoplastic lymphoproliferation were performed by means of chromosome analysis, polymerase chain reaction (PCR), and FISH analysis. Two differently labeled yeast-artificial-chromosome (YAC) probes that contained the entire bcl-2 gene and the C-region of the immunoglobulin H (IgH) gene, respectively, were used to detect t(14;18) by FISH. RESULTS The presence of the translocation is indicated by a red (Cy3)/green (fluorescien isothiocyanate [FITC]) double signal, which corresponds to the IgH/bcl-2 fusion gene, whereas in normal cells the signals are separate. Control studies showed that the double signal is visible in less than 1% of normal cells. FISH analysis was able to identify the t(14;18) in all cases of cb-cc lymphoma we studied. All bcl-2 breakpoints can be detected. Combined immunophenotyping and interphase cytogenetics demonstrated that t(14;18) was restricted to CD22+ B lymphocytes and never occurred in CD3+ T lymphocytes. In four of 32 cases of nonneoplastic lymphoproliferation, t(14;18) was also detected. CONCLUSION FISH turned out to be the most sensitive method to detect t(14;18). Our FISH results confirm PCR data from other groups that found evidence for the presence of t(14;18) in nonneoplastic lymphoproliferation. It needs to be determined whether, in morphologically nonneoplastic processes, t(14;18) is associated with an increased risk for the development of non-Hodgkin's lymphoma.
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Sharma, Purva, Sakshi Singal, Patrick Costello, and Koyamangalath Krishnan. "Burkitt lymphoma: interpreting FISH testing for MYC gene rearrangements." BMJ Case Reports 15, no. 2 (2022): e246687. http://dx.doi.org/10.1136/bcr-2021-246687.
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Burkitt lymphoma is a highly aggressive B cell non-Hodgkin’s lymphoma characterised by translocation of MYC gene on chromosome 8. This translocation is usually detected by fluorescent in-situ hybridisation (FISH) studies as part of routine diagnostic work-up and prognostication. FISH testing is commonly done with the break-apart probe (BAP). This case illustrates how this testing can be falsely negative. This patient is a young male diagnosed with Stage I low-risk Burkitt with FISH negative for MYC translocation initially on BAP testing. Additional testing with dual FISH probe detected MYC/IGH translocation. FISH testing using BAPs alone may be falsely negative for MYC translocations creating a diagnostic challenge and compromising the treatment approach and assessment of prognosis.
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Woroniecka, Renata, Grzegorz Rymkiewicz, Lukasz M. Szafron, et al. "Cryptic MYC insertions in Burkitt lymphoma: New data and a review of the literature." PLOS ONE 17, no. 2 (2022): e0263980. http://dx.doi.org/10.1371/journal.pone.0263980.
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The occurrence of MYC-negative Burkitt lymphoma (BL) has been discussed for many years. The real frequency of the MYC insertion in MYC-negative BL is still unknown. Fine-needle aspiration biopsies of 108 consecutive patients with clinicopathologically suspected BL (suspBL) were evaluated by flow cytometry, classical cytogenetics, and fluorescence in situ hybridization (FISH). We found 12 cases (11%) without the MYC rearrangement by FISH with a MYC breakapart probe: two patients (1.9%) with cryptic MYC/IGH fusion (finally diagnosed as BL) and 10 patients (9.3%) with 11q gain/loss (finally diagnosed as Burkitt-like lymphoma with 11q aberration). The exact breakpoints of the cryptic MYC/IGH were investigated by next-generation sequencing. The MYC insertions’ breakpoints were identified in PVT1 in the first case, and 42 kb upstream of 5′MYC in the second case. To date, a molecular characterization of the MYC insertion in BL has only been reported in one case. Detailed descriptions of our MYC insertions in a routinely and consecutively diagnosed suspBL cohort will contribute to resolving the issue of MYC negativity in BL. In our opinion, the presence of the MYC insertions in BL and other lymphomas might be underestimated, because routine genetic diagnostics are usually based on FISH only, without karyotyping.
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Reddy, Kavita S., Mohammad Ansari-Lari, and Bruce Dipasquale. "Burkitt Transformation of Mantle Cell Lymphoma." Blood 110, no. 11 (2007): 4129. http://dx.doi.org/10.1182/blood.v110.11.4129.4129.
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Abstract MYC rearrangements are not included as a genetic change in the blastoid variants of mantle cell lymphoma (Jaffe, et al (2001) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press.). We present two cases both with CCND1/IGH and MYC rearrangements. Case 1. An 82-year-old male with no known history of lymphoma presented with thrombocytopenia, loss of appetite and “abdominal fullness.” Imaging studies showed enlarged retroperitoneal lymph nodes. The peripheral blood smear had 18,000 WBC with approximately 30% circulating atypical lymphocytes. Flow cytometric studies of the bone marrow revealed a surface kappa light chain restricted CD10+ B-cell population. A bone marrow biopsy showed >90% of marrow cellularity comprised of neoplastic lymphocytes. The neoplastic lymphocytes were small to intermediate in size with minimal amounts of dark blue cytoplasm and several cytoplasmic vacuoles (Burkitt like morphology). By immunohistochemical stains, the neoplastic cells were positive for CD20, CD43, CD10, BCL-6, and cyclin D1, weakly and focally positive for BCL-2, and negative for CD23. The Ki-67 proliferation fraction was ∼100%. An immunohistochemical stain for CD5 was predominantly negative with a possible very faint blush on a subset of neoplastic B-cells. The FISH tests on bone marrow interphases were positive for a CCND1/IGH, a variant MYC/IGH, a variant MYC-BA rearrangements and negative for BCL6-BA and BCL2/IGH rearrangements. The variant MYC/IGH pattern was 3xMYC, 3xIGH, 1xFusion signals and MYC-BA pattern was 2x5′MYCcon3′MYC, 1x3′MYC. rearrangements. The karyotype was 44∼45,XY,del(2)(q11.2q21),der(3;17)(p10;q10), der(5)t(3;5)(q12;q15), t(11;14) (q13;q32) [cp6]/46,XY[14]. Since the karyotype had a t(11;14) and two normal 8 chromosomes, a metaphase FISH was analyzed to localize the signals for the MYC/IGH probe. The MYC signal were on both normal 8 chromosomes, a fusion signal was on a F-G sized chromosome. While the IGH signals were on the normal 14, der(14) and der(11). This was consistent with a cryptic MYC/IGH fusion in a three way rearrangement between chromosomes 8, 11 and 14. Case 2. A 69-year-old male having had a kidney transplant in 2001 was on immunosuppressive therapy. He presented with severe leukocytosis, anemia and thrombocytopenia and weight loss of about 12 pounds over several months. A peripheral blood smear showed 74,000 WBC with approximately 30% blasts. Bone marrow biopsies revealed normocellular bone marrow (50% cellularity). Interspersed large neoplastic lymphoid cells were shown by immunohistochemical stains to be positive for CD20, BCL-1, weak positive for BCL-2 and a Ki-67 staining > 90%. Flow cytometry indicated that the neoplastic cells were positive for kappa and CD5 but negative for CD11c and CD23. Interphases FISH on peripheral blood was positive for a CCND1/IGH rearrangement. The karyotype was 42∼44,X,-Y,add(1)(p13), t(2;8)(p12;q24), der(2)t(2;15)(p25;q11.2),+3,del(9)(p22p24),+del(9)(p22p24), − 10, del(11)(q21q23), t(11;14)(q13;q32) , − 13, − 15, − 17,add(17)(p11.2)[cp7]/46,XY[17]. FISH confirmed a MYC rearrangement. Therefore, this case had both CCND1/IGH and MYC/IGK rearrangement. Concomitant occurrence of a CCND1/IGH and a MYC rearrangement is rare in lymphomas. In Mitelman database of chromosome aberrations in cancer 2007, Four cases had both a t(11;14) and a t(8;14) translocation and two cases had both a t(11;14) and a t(2;8) translocation. This study expands the repertoire of abnormalities seen in blastoid transformation of mantle cell lymphoma. Being cognizant of a possible MYC involvement in the transformation of mantle cell lymphoma and its exploration would influence therapy.
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Jiang, Shi-Ping, Derek Bouman, and Karine Hovanes. "Detection of Genetic Abnormalities for Diffuse Large B-Cell Lymphoma by Selective Interphase Analysis with FISH Method." Blood 112, no. 11 (2008): 4149. http://dx.doi.org/10.1182/blood.v112.11.4149.4149.
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Abstract Diffuse Large B-cell Lymphoma (DLBCL) accounts for approximately 30% of all lymphoid malignancies. It can be difficult to separate DLBCL from Burkitt lymphoma and plasmablastic myeloma by morphology and flow cytometric immunophenotyping alone. Fluorescent in situ hybridization (FISH) targetgene analysis can assist the differential diagnosis by detection of genetic abnormalities associated with DLBCL. Though no consistent numeric chromosomal abnormalities or translocations are observed as a hallmark for DLBCL, most cases have rearranged immunoglobulin heavy chain (IgH), BCL2 and MYC genes. Standard interphase FISH analysis is widely utilized to detect these genetic rearrangements. However, standard interphase FISH analysis could be falsely negative if the neoplastic cells are limited or if abundant benign cells are present in the background. Thus, the sensitivity to detect genetic abnormalities is low among the cases with a low number of neoplastic cells. Herein we present three DLBCL cases in which interphase FISH analysis was applied on selective cells that are morphologically consistent with neoplastic large lymphocytes. All three cases showed genetic changes in a high percentage of the selected cells. These three cases were originally analyzed for IgH gene rearrangement, IgH/BCL2 and IgH/MYC translocation by using standard non-selected interphase study and showed false negative results. However, by review of the H&E slide and the flow cytometry results prompted a re-evaluation of the FISH studies using selective analysis of neoplastic cells only. Our observations indicate that selective interphase FISH analysis improves the sensitivity of detecting genetic abnormalities in DLBCL. This analysis does require a corporation between hematopathologists and technologists performing interphase FISH studies.
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Wang, Endi, Charles Blake Hutchinson, Qin Huang, Siby Sebastian, and Catherine Rehder. "Transformation of Indolent Small B-Cell Lymphoma to Histiocytic Sarcoma: Report of Two Cases with Molecular/Genetic Evidence of Clonal Relationship Between Two Morphologically and Immunophenotypically Distinctive Neoplasms." Blood 114, no. 22 (2009): 3960. http://dx.doi.org/10.1182/blood.v114.22.3960.3960.
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Abstract Abstract 3960 Poster Board III-896 Introduction Rare cases of histiocytic sarcoma (HS) have been reported in association with indolent small B-cell neoplasms, either concurring with or following a small B-cell lymphoma. The biologic relationship between these two morphologically and immunophenotypically distinct neoplasms in same patients remains unclear, though recent data suggest a possible “transdifferentiation” from follicular lymphoma (FL) to HS. Patients and Methods We investigate the clonal relationship in two cases of B-cell lymphoma with subsequent HS, using immunohistochemical stains, PCR-based immunoglobulin heavy chain (IGH) gene rearrangement/sequencing analysis and interphase FISH study on formalin fixed, paraffin-imbedded tissue sections. Results Case 1 is a 62-year-old female with splenic marginal zone lymphoma (SMZL) who developed HS in a groin lymph node one year after the diagnosis of SMZL. PCR/sequence analysis of IGH gene showed a monoclonal rearrangement carrying identical DNA sequences of PCR products from the spleen with SMZL and the lymph node with HS. Case 2 is a 61-year-old female with a remote history of FL who developed supraclavicular lymphadenopathy and multiple other infiltrating foci. A supraclavicular lymph node biopsy demonstrated HS. PCR analysis detected a monoclonal rearrangement of the IGH gene and interphase FISH analysis revealed IGH/BCL-2 fusion, a genetic hallmark for FL. Although negative for other B-cell associated antigen markers, HSs show partial retention of primary neoplasms B-cell lymphomas' immunoprofiles, including expression of Oct-2 in both cases, and expression of bcl-6 and enhanced expression of bcl-2 in case 2. Conclusion The data provide a genotypic evidence of common clonal origin between mature B-cell lymphoma and subsequent HS in the same patients, suggesting “transdifferentiation” to HS could occur in other small B-cell lymphoma, in addition to FL. The transformed HSs might have incompletely inherited primary neoplasms' expression signatures by retaining B-cell lymphomas' characteristic immunoprofile to certain extent. The exact mechanism governing the conversion of mature B-cell lymphoma to HS is largely a mystery and remains to be elucidated by more scientific studies, though a few pathways have been proposed for the process, including transdifferentiation, dedifferentiation and common progenitor models. Disclosures: No relevant conflicts of interest to declare.
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Kwatra, Kanwardeep Singh, Preethi A. M. Paul, Nalini Calton, Joseph M. John, and James D. Cotelingam. "Systemic and primary cutaneous anaplastic large cell lymphoma: Clinical features, morphological spectrum, and immunohistochemical profile." South Asian Journal of Cancer 06, no. 03 (2017): 129–31. http://dx.doi.org/10.4103/2278-330x.214575.
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Abstract Background: T-cell lymphomas with anaplastic morphology typically comprise of anaplastic lymphoma kinase positive, anaplastic large cell lymphoma (ALK+ ALCL), ALK-negative ALCL (ALK- ALCL), and primary cutaneous ALCL (PC-ALCL). However, other entities such as diffuse large B-cell lymphoma, peripheral T-cell lymphoma, Hodgkin lymphoma, and undifferentiated carcinoma can also show similar anaplastic features. Aims: To study the clinical features and histological spectrum of ALCL and emphasize the role of immunohistochemistry (IHC) in their diagnosis and categorization. Setting and Design: Eight cases of ALCL diagnosed over a period of 4 years were selected for the study. Materials and Methods: Histopathological review and IHC was performed on all cases. Two ALK+ ALCL cases were tested by fluorescent in situ hybridization (FISH) for t(2;5)(p23;q35). Results: There were four cases of ALK+ ALCL and two each of ALK- ALCL and PC-ALCL. Histologically, all the subtypes showed pleomorphic and “hallmark” cells with strong CD30 expression and variable loss of T-cell antigens. One case of PC-ALCL was leukocyte common antigen (LCA) negative. Epithelial membrane antigen was positive in all the six systemic ALCL cases. Two cases tested for t(2;5)(p23;q35) by FISH were positive. Conclusions: Diagnosis of ALCL is based on recognizing the key morphological features, especially the presence of “hallmark” cells. IHC is essential for confirmation of diagnosis and excluding other malignancies with anaplastic morphology. The inclusion of CD30 in the initial IHC panel will help identify LCA negative cases and avoid misdiagnosis.
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Bertoni, Francesco, Andrea Rinaldi, Anna Sasso, et al. "Inhibition of the B Cell Associated Tyrosine Kinase SYK as a Potential Therapeutic Target in Aggressive Lymphomas." Blood 106, no. 11 (2005): 1469. http://dx.doi.org/10.1182/blood.v106.11.1469.1469.
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Abstract By using a combination of genomic and expression profiling (Affymetrix GeneChip Mapping 10k Xba131 and U133 set), we had previously analysed a series of 26 mantle cell lymphoma (MCL) samples to identify regions containing genes that might be relevant to MCL pathogenesis and that could represent new therapeutic targets (Rinaldi et al, Ann Oncol2005; vol. 16 suppl. 5, abstract 447). Of interest, one MCL cell line showed a genomic amplification of 9q22 with concomitant over-expression of SYK, mapped within the region. SYK is a tyrosine kinase involved in B cell receptor signaling, a pathway that is believed to play a major role in B cell lymphoma growth and survival. Western blotting experiments and FISH analysis confirmed the over-expression of SYK and the presence of extra-copies of SYK, respectively. Immunohistochemistry on twelve aggressive lymphomas [MCL and diffuse large B cell lymphomas (DLBCL)] confirmed that SYK is over-expressed in a subset of lymphomas. Based upon all these data, we treated seven established human lymphoma cell lines (four MCL, three DLBCL) with increasing doses of piceatannol (Sigma), a SYK inhibitor. All, but one, cell lines showed arrest of cell proliferation. The JeKo-1 and SU-DHL-6 (MCL and DLBCL) cell lines showed an IC50 of less than 10 μM after 72 hr of drug exposure; four cell lines had an IC50 between 30–50 μM. The two cell lines with a high-sensitivity to SYK inhibition had a constitutively high expression of SYK due to DNA gain, as shown by Western blotting and FISH. A high percentage of necrotic and apoptotic cells (39%) has been shown in JeKo-1 by Annexin V staining. Further, in vitro analyses and more extensive immunohistochemistry and FISH on MCL and DLBCL clinical samples (using tissue microarrays) are under way to elucidate the mechanism of action of cytotoxicity and the clinical relevance of SYK DNA amplification. In conclusion, our in vitro data indicate SYK inhibition as a new therapeutic target for the treatment of a subset of aggressive lymphomas, over-expressing SYK. SYK inhibitors are already in clinical development for treatment of asthma. Work partially supported by the Krebsforschung Schweiz and the Swiss Group for Clinical Research (SAKK).