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Background Double-hit or triple-hit B-cell lymphoma that carries both MYC, BCL2, and/or BCL6 gene rearrangements is usually a type of lymphoma with poor prognosis, involving B cells translocated in MYC, BCL2, BCL6, and CCND1 genes (four-hit) Lymphoma is even rarer, with very limited cases reported so far
.
1-3 The translocation of CCND1 gene and immunoglobulin heavy chain (IGH) gene is considered to be the genetic basis of mantle cell lymphoma (MCL).
The high expression of cyclin Cyclin D1 can cause cell cycle disorders and lead to disease
.
This time we invited Professor Huang Haiwen from the First Affiliated Hospital of Soochow University to share a case of early diagnosis and four-strike polymorphic MCL, and to share its diagnosis and treatment process.
The case report has been published in the latest publication of the British Journal of Hematology
.
4 Medical history and diagnosis.
The patient was a 76-year-old male with pharyngeal obstruction for 2 months
.
Positron emission tomography showed multiple cervical lymph node lesions (Figure A)
.
Laboratory tests were unremarkable, including normal serum lactate dehydrogenase (LDH) levels
.
Figure 1 Positron emission tomography (PET)/computed tomography (CT) scan showed multiple lesions in the head and neck area at the time of diagnosis (A), and the patient achieved complete remission after four cycles of R2-CHOP (B) ( CR) Cell morphology, immunophenotype and genetic examination results Cell morphology: The left neck lymph node biopsy showed diffuse infiltration of medium to large lymphocytes leading to the disappearance of the structure.
Visible macrophages were observed under low power, high power The tumor cells under the microscope showed a moderate amount of cytoplasm, round or slightly irregular nuclei, moderately dispersed chromatin, and one or more small and occasionally prominent nucleoli (Figure A)
.
Flow cytometry immunophenotype: 58.
4% gating showed κ immunoglobulin light chain restriction, expression of pan-B markers, CD19, CD20 and FMC7, CD23 was weakly positive
.
CD200, CD79b, CD5 and CD10 are all negative
.
Immunohistochemistry (IHC) staining: Lymphoma cells were positive for CD20, CD79a, BCL6, Cyclin D1, CD21, BCL2, and MYC, and P53 was positive for incidental cells (Figure BH)
.
Ki67 is 60% (Figure I)
.
In situ hybridization showed that the tumor cells were negative for CD3, CD5, SOX11, MUM1 and EBER
.
Bone marrow biopsy showed negative tumor invasion
.
Figure 2 Morphology and immunophenotype of quadruple-strike pleomorphic MCL: Lymphoma cells have pleomorphic morphology (A) and express CD20 (B), BCL2 (C), BCL6 (D), Cyclin D1 (E) , MYC (F), CD21 (G), P53 (H), and have a high Ki67 index (I) In view of the overexpression of BCL6, MYC, Cyclin D1 and BCL2, interphase fluorescence in situ hybridization of these related genes ( FISH) analysis
.
FISH analysis uses 4μm paraffin-embedded tissue sections.
If more than 15% of the tumor cells show fusion or separation signals, it is considered positive
.
The dual-color dual-fusion (D-FISH) probe was selected for MYC-IGH, CCND1-IGH and IHG-BCL2 fusion analysis, and the split probe was used for BCL6 fragmentation analysis
.
Genetic analysis results: D-FISH of IGH-MYC (Figure J), IGH-CCND1 (Figure K) and IGH-BCL2 (Figure L), 34% of 100 suspension cells showed a fusion signal, indicating MYC-IGH , CCND1-IGH and IGH-BCL2 rearrangement
.
Similarly, breakage of BCL6 (Figure M) was detected in 38% of 100 suspension cells, indicating gene translocation
.
Figure 3 FISH results show that MYC/IGH (J), CCND1/IGH (K), BCL2/IGH (L) and BCL6 (M) gene translocation.
Therefore, based on morphology, immunophenotype and FISH results, the final diagnosis is four Combat polymorphic MCL
.
Treatment and effects The patient received 6 cycles of R2-CHOP (R-CHOP on days 1–5 of each cycle, and 25 mg of lenalidomide per day on days 1-14)
.
The patient was assessed to achieve complete remission after 4 cycles, and entered the observation follow-up after completing the sixth cycle of treatment
.
As of press time, the relief has continued for 18 months
.
Professor Huang Haiwen concluded that the MYC gene rearrangement in MCL is rare, and there are few reported cases so far
.
It is related to higher neutrophils, blast-like pleomorphic morphology, moderate to high MIPI risk, and shorter overall survival
.
The prognosis of this patient is good, which may be related to early diagnosis, normal LDH level, and negative TP53 mutation
.
In order to further describe the prognosis of this patient, we evaluated the MCL International Prognostic Index (MIPI) and the Biological Prognostic Index MIPI (MIPIb).
The patient is classified as high-risk in terms of MIPI and MIPIb scores, and the expected overall survival is 37.
Months, a longer follow-up is needed to evaluate the patient’s clinical outcome
.
It is worth noting that these quadruple-hit lymphoma cases showed high-grade histological features
.
Therefore, the detection of MYC protein in MCL with pleomorphic blasts may help identify those four-strike lymphomas that carry additional MYC gene rearrangements.
More cases with detailed clinicopathological and biological data are needed to better characterize this Biological characteristics and prognosis of patients with type lymphoma
.
Professor Huang Haiwen, Professor and Chief Physician, Department of Hematology, First Affiliated Hospital of Soochow University, Member of Lymphatic Disease Group, Chinese Medical Association Hematology Branch, Member of Lymphhematology Group, Chinese Medical Association Oncology Branch, Vice Chairman, Lymphoma Professional Committee, Chinese Medical Education Association, China Member of the Lymphoma Group of the Hematological Oncology Committee of the Anti-Cancer Association Member of the Chronic Lymphocytic Leukemia Working Group of the Chinese Anti-Cancer Association Vice Chairman of the Jiangsu Lymphoma Professional Committee Vice Chairman of the Jiangsu Lymphoma Alliance Vice Chairman of the Hematology Branch of the Jiangsu Medical Association Lymphoma Bone Marrow References for members of the tumor group: 1.
Bacher U, Haferlach T, Alpermann T, Kern W, Schnittger S, Haferlach C.
Several lymphoma-specific genetic events in parallel can be found in mature B-cell neoplasms.
Genes Chromosomes Cancer.
2011; 50(1): 43– 50.
2.
Ittel A, Hélias C, Wissler MP, Toussaint E, Miguet L, Chenard MP, et al.
Four genetic lymphoma-specific events (MYC, BCL2, BCL6 and CCND1) identified in a high grade B lymphoma case.
Blood Cancer J.
2015; 5:e374.
3.
Cheng J, Hashem MA, Barabé F, Cloutier S, Xi L, Raffeld M, et al.
CCND1 genomic rearrangement as a secondary event in high grade B-cell lymphoma.
Hemasphere.
2021; 5(1): e505.
4.
Wei Liu, et al.
Quadruple-hit pleomorphic mantle cell lymphoma with MYC, BCL2,BCL6, and CCND1 gene rearrangements Br J Haematol.
2021; Volume: 195, Issue: 4, Pages: 634-637.
Stamp "read the original text", we make progress together
.
1-3 The translocation of CCND1 gene and immunoglobulin heavy chain (IGH) gene is considered to be the genetic basis of mantle cell lymphoma (MCL).
The high expression of cyclin Cyclin D1 can cause cell cycle disorders and lead to disease
.
This time we invited Professor Huang Haiwen from the First Affiliated Hospital of Soochow University to share a case of early diagnosis and four-strike polymorphic MCL, and to share its diagnosis and treatment process.
The case report has been published in the latest publication of the British Journal of Hematology
.
4 Medical history and diagnosis.
The patient was a 76-year-old male with pharyngeal obstruction for 2 months
.
Positron emission tomography showed multiple cervical lymph node lesions (Figure A)
.
Laboratory tests were unremarkable, including normal serum lactate dehydrogenase (LDH) levels
.
Figure 1 Positron emission tomography (PET)/computed tomography (CT) scan showed multiple lesions in the head and neck area at the time of diagnosis (A), and the patient achieved complete remission after four cycles of R2-CHOP (B) ( CR) Cell morphology, immunophenotype and genetic examination results Cell morphology: The left neck lymph node biopsy showed diffuse infiltration of medium to large lymphocytes leading to the disappearance of the structure.
Visible macrophages were observed under low power, high power The tumor cells under the microscope showed a moderate amount of cytoplasm, round or slightly irregular nuclei, moderately dispersed chromatin, and one or more small and occasionally prominent nucleoli (Figure A)
.
Flow cytometry immunophenotype: 58.
4% gating showed κ immunoglobulin light chain restriction, expression of pan-B markers, CD19, CD20 and FMC7, CD23 was weakly positive
.
CD200, CD79b, CD5 and CD10 are all negative
.
Immunohistochemistry (IHC) staining: Lymphoma cells were positive for CD20, CD79a, BCL6, Cyclin D1, CD21, BCL2, and MYC, and P53 was positive for incidental cells (Figure BH)
.
Ki67 is 60% (Figure I)
.
In situ hybridization showed that the tumor cells were negative for CD3, CD5, SOX11, MUM1 and EBER
.
Bone marrow biopsy showed negative tumor invasion
.
Figure 2 Morphology and immunophenotype of quadruple-strike pleomorphic MCL: Lymphoma cells have pleomorphic morphology (A) and express CD20 (B), BCL2 (C), BCL6 (D), Cyclin D1 (E) , MYC (F), CD21 (G), P53 (H), and have a high Ki67 index (I) In view of the overexpression of BCL6, MYC, Cyclin D1 and BCL2, interphase fluorescence in situ hybridization of these related genes ( FISH) analysis
.
FISH analysis uses 4μm paraffin-embedded tissue sections.
If more than 15% of the tumor cells show fusion or separation signals, it is considered positive
.
The dual-color dual-fusion (D-FISH) probe was selected for MYC-IGH, CCND1-IGH and IHG-BCL2 fusion analysis, and the split probe was used for BCL6 fragmentation analysis
.
Genetic analysis results: D-FISH of IGH-MYC (Figure J), IGH-CCND1 (Figure K) and IGH-BCL2 (Figure L), 34% of 100 suspension cells showed a fusion signal, indicating MYC-IGH , CCND1-IGH and IGH-BCL2 rearrangement
.
Similarly, breakage of BCL6 (Figure M) was detected in 38% of 100 suspension cells, indicating gene translocation
.
Figure 3 FISH results show that MYC/IGH (J), CCND1/IGH (K), BCL2/IGH (L) and BCL6 (M) gene translocation.
Therefore, based on morphology, immunophenotype and FISH results, the final diagnosis is four Combat polymorphic MCL
.
Treatment and effects The patient received 6 cycles of R2-CHOP (R-CHOP on days 1–5 of each cycle, and 25 mg of lenalidomide per day on days 1-14)
.
The patient was assessed to achieve complete remission after 4 cycles, and entered the observation follow-up after completing the sixth cycle of treatment
.
As of press time, the relief has continued for 18 months
.
Professor Huang Haiwen concluded that the MYC gene rearrangement in MCL is rare, and there are few reported cases so far
.
It is related to higher neutrophils, blast-like pleomorphic morphology, moderate to high MIPI risk, and shorter overall survival
.
The prognosis of this patient is good, which may be related to early diagnosis, normal LDH level, and negative TP53 mutation
.
In order to further describe the prognosis of this patient, we evaluated the MCL International Prognostic Index (MIPI) and the Biological Prognostic Index MIPI (MIPIb).
The patient is classified as high-risk in terms of MIPI and MIPIb scores, and the expected overall survival is 37.
Months, a longer follow-up is needed to evaluate the patient’s clinical outcome
.
It is worth noting that these quadruple-hit lymphoma cases showed high-grade histological features
.
Therefore, the detection of MYC protein in MCL with pleomorphic blasts may help identify those four-strike lymphomas that carry additional MYC gene rearrangements.
More cases with detailed clinicopathological and biological data are needed to better characterize this Biological characteristics and prognosis of patients with type lymphoma
.
Professor Huang Haiwen, Professor and Chief Physician, Department of Hematology, First Affiliated Hospital of Soochow University, Member of Lymphatic Disease Group, Chinese Medical Association Hematology Branch, Member of Lymphhematology Group, Chinese Medical Association Oncology Branch, Vice Chairman, Lymphoma Professional Committee, Chinese Medical Education Association, China Member of the Lymphoma Group of the Hematological Oncology Committee of the Anti-Cancer Association Member of the Chronic Lymphocytic Leukemia Working Group of the Chinese Anti-Cancer Association Vice Chairman of the Jiangsu Lymphoma Professional Committee Vice Chairman of the Jiangsu Lymphoma Alliance Vice Chairman of the Hematology Branch of the Jiangsu Medical Association Lymphoma Bone Marrow References for members of the tumor group: 1.
Bacher U, Haferlach T, Alpermann T, Kern W, Schnittger S, Haferlach C.
Several lymphoma-specific genetic events in parallel can be found in mature B-cell neoplasms.
Genes Chromosomes Cancer.
2011; 50(1): 43– 50.
2.
Ittel A, Hélias C, Wissler MP, Toussaint E, Miguet L, Chenard MP, et al.
Four genetic lymphoma-specific events (MYC, BCL2, BCL6 and CCND1) identified in a high grade B lymphoma case.
Blood Cancer J.
2015; 5:e374.
3.
Cheng J, Hashem MA, Barabé F, Cloutier S, Xi L, Raffeld M, et al.
CCND1 genomic rearrangement as a secondary event in high grade B-cell lymphoma.
Hemasphere.
2021; 5(1): e505.
4.
Wei Liu, et al.
Quadruple-hit pleomorphic mantle cell lymphoma with MYC, BCL2,BCL6, and CCND1 gene rearrangements Br J Haematol.
2021; Volume: 195, Issue: 4, Pages: 634-637.
Stamp "read the original text", we make progress together
