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Author: This article is the author's permission Chunlan Qiugui NMT Medical publish, please do not reprint without authorization.
The estimated annual number of new cases of diffuse large B-cell lymphoma (DLBCL) is 150,000, accounting for 30% of all non-Hodgkin’s lymphomas (NHL).
Patients usually present with progressive lymphadenopathy or extranodal involvement.
Diagnosis requires immediate treatment.
Most DLBCL patients are at an advanced stage at the onset of the disease.
The standard immunochemotherapy regimen R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone) can only cure nearly 60% of the disease patient.
Accurate pathological diagnosis and molecular classification are the key to optimizing the treatment plan of DLBCL and further improving the efficacy.
This article aims to summarize the pathological characteristics and molecular classification of DLBCL.
Pathological diagnosis of DLBCL.
The diagnosis of large B-cell lymphoma depends on the diagnosis of histopathology.
Professional hematology pathologists are required to conduct detailed evaluation of the excised tissue specimens to make the most accurate diagnosis.
In addition to histomorphological characteristics, precise subtype classification requires corresponding special inspections, including immunohistochemistry (IHC), flow cytometry (FCM), fluorescence in situ hybridization (FISH), and molecular testing.
In addition, biopsy specimens obtained by fine needle aspiration are not sufficient for accurate pathological evaluation.
Therefore, a needle biopsy should only be selected when a complete lymphoma lesion resection biopsy is not feasible.
In 2017, the World Health Organization (WHO) updated the classification of large B-cell lymphoma, the most common of which is diffuse large B-cell lymphoma (non-specific type) (DLBCL-NOS).
This article focuses on the pathological diagnosis and characteristics of DLBCL-NOS (hereinafter referred to as DLBCL).
The pathological characteristics and classification gene expression profile (GEP) of DLBCL describe two different molecular subtypes of DLBCL, namely the germinal center B cell-like (GCB) subtype and the activated B cell-like (ABC) subtype; in addition, 10 %-15% of cases cannot be classified.
It is currently believed that these subtypes come from different stages of lymphoid differentiation (cells of origin) and have separate carcinogenic mechanisms.
The prognosis of DLBCL patients with ABC subtype is poor, and the 3-year progression-free survival (PFS) rate is about 40%-50%, while the 3-year PFS rate of patients with GCB subtype is 75% [1-2].
The ABC subtype of DLBCL is characterized by chronic B cell receptor signal transduction and activation of nuclear factor kappa B, while the GCB subtype expresses genes commonly found in germinal center B cells, including BCL6 and EZH2.
This phenotypic difference makes it possible for targeted drugs to have advantageous activity in one subtype.
Algorithms based on immunohistochemistry (such as the Hans algorithm) can divide DLBCL cases into GCB and non-GCB (non-GCB) subtypes (the latter includes ABC subtypes and most unclassified cases), although these algorithms only provide approximations Analysis of gene expression profiles, but there is a risk of misclassification [3].
With the in-depth analysis of DLBCL molecular aberrations (including gene mutations and copy number gains or deletions) in recent years, researchers have proposed a new molecular classification for DLBCL independent of cell origin (Figure 1) [4].
These newly proposed classification schemes may better describe the biological heterogeneity of DLBCL patients and provide greater potential for individualized treatment.
Figure 1: New molecular classification of DLBCL In addition to the above-mentioned molecular heterogeneity related to DLBCL, FISH can also be used to detect clinically significant recurrent genetic rearrangements.
MYC rearrangement is seen in 12% of cases, while MYC rearrangement and BCL2 and/or BCL6 rearrangement are seen in 4%-8% of cases, most of which are GCB subtypes, and BCL2 rearrangements only occur in GCB subtypes.
These cases are now classified as "high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements", are commonly referred to as double or triple-hit lymphomas, and are associated with poor prognosis for R-CHOP treatment.
Studies have shown that in double- or triple-hit high-grade B-cell lymphoma, the worst prognosis is the presence of MYC and immunoglobulin gene chaperone translocation [5].
Retrospective studies have shown that [6], these patients have poor treatment effects through R-CHOP, which has prompted people to continue to explore new treatment methods, such as DA-EPOCH-R (dose-adjusted etoposide, prednisone, Vincristine, cyclophosphamide, doxorubicin, and rituximab) may improve patient outcomes.
Therefore, it is currently recommended to use DA-EPOCH-R under appropriate circumstances to treat patients with double or triple blow high-grade B-cell lymphoma.
Double- or triple-hit high-grade B-cell lymphoma detected by FISH is relatively rare.
Compared with the overexpression of MYC protein detected by IHC analysis, it occurs in about 45% of cases, while the overexpression of BCL2 protein occurs in about 65%.
Of cases.
And in about 30% of DLBCL cases, the overexpression of MYC and BCL2 occurs at the same time, which is called dual expression lymphoma.
Compared with patients with simple or no overexpression of MYC or BCL2 protein, dual expression lymphoma has a poorer prognosis [7].
The epidemiological features of DLBCL were diagnosed as DLBCL with a median age of 60 years; 30% of patients were over 75 years old.
Although most patients currently have no history of lymphoma, DLBCL may be transformed from potentially known or occult low-grade B-cell lymphoma.
Epidemiological studies support the complex and multifactorial causes of DLBCL.
Risk factors include genetic characteristics, clinical characteristics and immune disorders, as well as viral, environmental or occupational exposure [8].
Although DLBCL is not considered a genetic disease, genome-wide association studies have identified multiple genetic susceptibility loci, suggesting pathways related to immune function.
References: 1.
Lenz G, Wright G, Dave SS, et al.
Stromal gene signatures in large-B-cell lymphomas.
N Engl J Med 2008;359:2313-23.
2.
Scott DW, Mottok A, Ennishi D, et al.
Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies.
J Clin Oncol 2015;33:2848-56.
3.
Meyer PN, Fu K, Greiner TC, et al.
Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab.
J Clin Oncol 2011;29:200-7.
4.
Laurie H.
Sehn, and Gilles Salles.
Diffuse Large B-Cell Lymphoma .
N Engl J Med 2021;384:842-58.
5.
Rosenwald A, Bens S, Advani R, et al.
Prognostic significance of MYC rearrangement and translocation partner in diffuse large B-cell lymphoma:a study by the Lunenburg Lymphoma Biomarker Consortium.
J Clin Oncol 2019;37:3359-68.
6.
Petrich AM, Gandhi M, Jovanovic B, et al.
Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis.
Blood 2014;124:2354-61.
7.
Johnson NA, Slack GW, Savage KJ,et al.
Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, andprednisone.
J Clin Oncol 2012;30:3452-9.
8.
Cerhan JR, Kricker A, Paltiel O, et al.
Medical history, lifestyle, family history, and occupational risk factors for diffuse large B-cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project .
J Natl Cancer Inst Monogr 2014;2014:15-25.
Stamp "Read the original", we make progress togetheret al.
Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis.
Blood 2014;124:2354-61.
7.
Johnson NA, Slack GW, Savage KJ,et al.
Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, andprednisone.
J Clin Oncol 2012;30:3452-9.
8.
Cerhan JR, Kricker A, Paltiel O, et al.
Medical history, lifestyle, family history ,and occupational risk factors for diffuse large B-cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
J Natl Cancer Inst Monogr 2014;2014:15-25.
Stamp "Read the original text" and we will make progress togetheret al.
Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis.
Blood 2014;124:2354-61.
7.
Johnson NA, Slack GW, Savage KJ,et al.
Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, andprednisone.
J Clin Oncol 2012;30:3452-9.
8.
Cerhan JR, Kricker A, Paltiel O, et al.
Medical history, lifestyle, family history ,and occupational risk factors for diffuse large B-cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
J Natl Cancer Inst Monogr 2014;2014:15-25.
Stamp "Read the original text" and we will make progress togetherSavage KJ,et al.
Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, andprednisone.
J Clin Oncol 2012;30:3452-9.
8.
Cerhan JR, Kricker A, Paltiel O , et al.
Medical history, lifestyle, family history,and occupational risk factors for diffuse large B-cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
J Natl Cancer Inst Monogr 2014;2014:15-25.
Stamp" read the original text "We make progress togetherSavage KJ,et al.
Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, andprednisone.
J Clin Oncol 2012;30:3452-9.
8.
Cerhan JR, Kricker A, Paltiel O , et al.
Medical history, lifestyle, family history,and occupational risk factors for diffuse large B-cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
J Natl Cancer Inst Monogr 2014;2014:15-25.
Stamp" read the original text "We make progress togetherthe InterLymph Non-Hodgkin Lymphoma Subtypes Project.
J Natl Cancer Inst Monogr 2014;2014:15-25.
Stamp "read the original text", we make progress togetherthe InterLymph Non-Hodgkin Lymphoma Subtypes Project.
J Natl Cancer Inst Monogr 2014;2014:15-25.
Stamp "read the original text", we make progress together
The estimated annual number of new cases of diffuse large B-cell lymphoma (DLBCL) is 150,000, accounting for 30% of all non-Hodgkin’s lymphomas (NHL).
Patients usually present with progressive lymphadenopathy or extranodal involvement.
Diagnosis requires immediate treatment.
Most DLBCL patients are at an advanced stage at the onset of the disease.
The standard immunochemotherapy regimen R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone) can only cure nearly 60% of the disease patient.
Accurate pathological diagnosis and molecular classification are the key to optimizing the treatment plan of DLBCL and further improving the efficacy.
This article aims to summarize the pathological characteristics and molecular classification of DLBCL.
Pathological diagnosis of DLBCL.
The diagnosis of large B-cell lymphoma depends on the diagnosis of histopathology.
Professional hematology pathologists are required to conduct detailed evaluation of the excised tissue specimens to make the most accurate diagnosis.
In addition to histomorphological characteristics, precise subtype classification requires corresponding special inspections, including immunohistochemistry (IHC), flow cytometry (FCM), fluorescence in situ hybridization (FISH), and molecular testing.
In addition, biopsy specimens obtained by fine needle aspiration are not sufficient for accurate pathological evaluation.
Therefore, a needle biopsy should only be selected when a complete lymphoma lesion resection biopsy is not feasible.
In 2017, the World Health Organization (WHO) updated the classification of large B-cell lymphoma, the most common of which is diffuse large B-cell lymphoma (non-specific type) (DLBCL-NOS).
This article focuses on the pathological diagnosis and characteristics of DLBCL-NOS (hereinafter referred to as DLBCL).
The pathological characteristics and classification gene expression profile (GEP) of DLBCL describe two different molecular subtypes of DLBCL, namely the germinal center B cell-like (GCB) subtype and the activated B cell-like (ABC) subtype; in addition, 10 %-15% of cases cannot be classified.
It is currently believed that these subtypes come from different stages of lymphoid differentiation (cells of origin) and have separate carcinogenic mechanisms.
The prognosis of DLBCL patients with ABC subtype is poor, and the 3-year progression-free survival (PFS) rate is about 40%-50%, while the 3-year PFS rate of patients with GCB subtype is 75% [1-2].
The ABC subtype of DLBCL is characterized by chronic B cell receptor signal transduction and activation of nuclear factor kappa B, while the GCB subtype expresses genes commonly found in germinal center B cells, including BCL6 and EZH2.
This phenotypic difference makes it possible for targeted drugs to have advantageous activity in one subtype.
Algorithms based on immunohistochemistry (such as the Hans algorithm) can divide DLBCL cases into GCB and non-GCB (non-GCB) subtypes (the latter includes ABC subtypes and most unclassified cases), although these algorithms only provide approximations Analysis of gene expression profiles, but there is a risk of misclassification [3].
With the in-depth analysis of DLBCL molecular aberrations (including gene mutations and copy number gains or deletions) in recent years, researchers have proposed a new molecular classification for DLBCL independent of cell origin (Figure 1) [4].
These newly proposed classification schemes may better describe the biological heterogeneity of DLBCL patients and provide greater potential for individualized treatment.
Figure 1: New molecular classification of DLBCL In addition to the above-mentioned molecular heterogeneity related to DLBCL, FISH can also be used to detect clinically significant recurrent genetic rearrangements.
MYC rearrangement is seen in 12% of cases, while MYC rearrangement and BCL2 and/or BCL6 rearrangement are seen in 4%-8% of cases, most of which are GCB subtypes, and BCL2 rearrangements only occur in GCB subtypes.
These cases are now classified as "high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements", are commonly referred to as double or triple-hit lymphomas, and are associated with poor prognosis for R-CHOP treatment.
Studies have shown that in double- or triple-hit high-grade B-cell lymphoma, the worst prognosis is the presence of MYC and immunoglobulin gene chaperone translocation [5].
Retrospective studies have shown that [6], these patients have poor treatment effects through R-CHOP, which has prompted people to continue to explore new treatment methods, such as DA-EPOCH-R (dose-adjusted etoposide, prednisone, Vincristine, cyclophosphamide, doxorubicin, and rituximab) may improve patient outcomes.
Therefore, it is currently recommended to use DA-EPOCH-R under appropriate circumstances to treat patients with double or triple blow high-grade B-cell lymphoma.
Double- or triple-hit high-grade B-cell lymphoma detected by FISH is relatively rare.
Compared with the overexpression of MYC protein detected by IHC analysis, it occurs in about 45% of cases, while the overexpression of BCL2 protein occurs in about 65%.
Of cases.
And in about 30% of DLBCL cases, the overexpression of MYC and BCL2 occurs at the same time, which is called dual expression lymphoma.
Compared with patients with simple or no overexpression of MYC or BCL2 protein, dual expression lymphoma has a poorer prognosis [7].
The epidemiological features of DLBCL were diagnosed as DLBCL with a median age of 60 years; 30% of patients were over 75 years old.
Although most patients currently have no history of lymphoma, DLBCL may be transformed from potentially known or occult low-grade B-cell lymphoma.
Epidemiological studies support the complex and multifactorial causes of DLBCL.
Risk factors include genetic characteristics, clinical characteristics and immune disorders, as well as viral, environmental or occupational exposure [8].
Although DLBCL is not considered a genetic disease, genome-wide association studies have identified multiple genetic susceptibility loci, suggesting pathways related to immune function.
References: 1.
Lenz G, Wright G, Dave SS, et al.
Stromal gene signatures in large-B-cell lymphomas.
N Engl J Med 2008;359:2313-23.
2.
Scott DW, Mottok A, Ennishi D, et al.
Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies.
J Clin Oncol 2015;33:2848-56.
3.
Meyer PN, Fu K, Greiner TC, et al.
Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab.
J Clin Oncol 2011;29:200-7.
4.
Laurie H.
Sehn, and Gilles Salles.
Diffuse Large B-Cell Lymphoma .
N Engl J Med 2021;384:842-58.
5.
Rosenwald A, Bens S, Advani R, et al.
Prognostic significance of MYC rearrangement and translocation partner in diffuse large B-cell lymphoma:a study by the Lunenburg Lymphoma Biomarker Consortium.
J Clin Oncol 2019;37:3359-68.
6.
Petrich AM, Gandhi M, Jovanovic B, et al.
Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis.
Blood 2014;124:2354-61.
7.
Johnson NA, Slack GW, Savage KJ,et al.
Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, andprednisone.
J Clin Oncol 2012;30:3452-9.
8.
Cerhan JR, Kricker A, Paltiel O, et al.
Medical history, lifestyle, family history, and occupational risk factors for diffuse large B-cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project .
J Natl Cancer Inst Monogr 2014;2014:15-25.
Stamp "Read the original", we make progress togetheret al.
Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis.
Blood 2014;124:2354-61.
7.
Johnson NA, Slack GW, Savage KJ,et al.
Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, andprednisone.
J Clin Oncol 2012;30:3452-9.
8.
Cerhan JR, Kricker A, Paltiel O, et al.
Medical history, lifestyle, family history ,and occupational risk factors for diffuse large B-cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
J Natl Cancer Inst Monogr 2014;2014:15-25.
Stamp "Read the original text" and we will make progress togetheret al.
Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis.
Blood 2014;124:2354-61.
7.
Johnson NA, Slack GW, Savage KJ,et al.
Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, andprednisone.
J Clin Oncol 2012;30:3452-9.
8.
Cerhan JR, Kricker A, Paltiel O, et al.
Medical history, lifestyle, family history ,and occupational risk factors for diffuse large B-cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
J Natl Cancer Inst Monogr 2014;2014:15-25.
Stamp "Read the original text" and we will make progress togetherSavage KJ,et al.
Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, andprednisone.
J Clin Oncol 2012;30:3452-9.
8.
Cerhan JR, Kricker A, Paltiel O , et al.
Medical history, lifestyle, family history,and occupational risk factors for diffuse large B-cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
J Natl Cancer Inst Monogr 2014;2014:15-25.
Stamp" read the original text "We make progress togetherSavage KJ,et al.
Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, andprednisone.
J Clin Oncol 2012;30:3452-9.
8.
Cerhan JR, Kricker A, Paltiel O , et al.
Medical history, lifestyle, family history,and occupational risk factors for diffuse large B-cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
J Natl Cancer Inst Monogr 2014;2014:15-25.
Stamp" read the original text "We make progress togetherthe InterLymph Non-Hodgkin Lymphoma Subtypes Project.
J Natl Cancer Inst Monogr 2014;2014:15-25.
Stamp "read the original text", we make progress togetherthe InterLymph Non-Hodgkin Lymphoma Subtypes Project.
J Natl Cancer Inst Monogr 2014;2014:15-25.
Stamp "read the original text", we make progress together
