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Fulltext Small cell variant of anaplastic large cell lymphoma with positive immunoreactivity for CD99

Shiran MS, Tan GC, Sabariah AR, Chye PC, Pathmanathan R

Med J Malaysia, 2008 Jun;63(2):150-1.
PMID: 18942305 MyJurnal

A 13 year old boy presented with a huge mass on his right arm of 6 months duration. Histopathological examination revealed sheets of malignant small round blue cells with immunopositivity for LCA, CD43, CD45Ro, CD30, EMA, ALK-1 and CD99, and negativity for CD20, TdT, myogenin, myoD1, NSE, bcl-6, bcl-2 and CD10. Fluorescent In-Situ Hybridization (FISH) testing excluded the diagnosis of Ewing's sarcoma/PNET. Pathologists need to be aware of the diagnosis of a small cell variant of ALCL, as well as of the fact that CD99 expression commonly occurs in cases of ALK-positive ALCL, in order to distinguish this entity from Ewing's sarcoma/PNET.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology
Primary mediastinal large B-cell lymphoma and its mimickers: a rare case report with literature review

Win TT, Kamaludin Z, Husin A

Malays J Pathol, 2016 Aug;38(2):153-7.
PMID: 27568673 MyJurnal

Primary mediastinal large B-cell lymphoma (PMLBL) is an uncommon non-Hodgkin lymphoma with a distinct clinicopathological entity in the WHO classification of lymphoid malignancies. It is known to originate from B-cells of the thymus. It mimics thymic neoplasms and other lymphomas clinically and histopathologically. We reported a 33-year-old obese man who presented with shortness of breath off and on for 4 years. Radiologically, there was a huge anterior mediastinal mass. Tru-cut biopsy was initially diagnosed as type-A thymoma. Histopathological examination of the excised specimen revealed PMLBL with stromal fibrosis and sclerosis which created a diagnostic difficulty. The neoplastic cells varied from medium-sized to large pleomorphic cells, including mononuclear cells with centroblastic and immunoblastic features as well as bi-lobed Reed Sternberg (RS)-like cells and horse-shoe like hallmark cells. Some interlacing spindle cells and epithelioid cells were also present. Immunohistochemically, tumour cells expressed diffuse positivity for LCA, CD20, CD79a, CD23, Bcl2, MUM-1 and heterogenous positivity for CD30 and EMA, and were negative for CD10, CD15 and ALK. Ki67 scoring was very high. Tumour cells infiltrated into peri-thymic fat and pericardium. No malignant cells were detected in the pleural fluid and there was no bone marrow infiltration. The patient showed partial response to 6 cycles of RICE chemotherapy, and was planned for second line chemotherapy using hyper-CVAD regimen followed by autologous stem cell transplantation. This case illustrates the importance of thorough sampling and immunohistochemistry in differentiating PMLBL from its differential diagnoses.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology
Fulltext Diffuse large B-cell lymphoma presenting with extensive cutaneous infiltration

Shamsudin N, Chang CC

Singapore Med J, 2012 Sep;53(9):e198-200.
PMID: 23023915

We report a case of systemic diffuse large B-cell lymphoma presenting with extensive infiltration of the skin. A 56-year-old woman presented with a two-month history of pruritic erythematous plaques and nodules over the neck, trunk and upper limbs. She also had night sweats, weight loss, lethargy and reduced effort tolerance. Systemic examination revealed a pale, ill appearance with hepatosplenomegaly and lymphadenopathy. Blood investigations showed pancytopenia (haemoglobin 6.3 g/dL, total white cell count 3.0 × 10(9)/L, platelet count 138 × 10(9)/L) with a few suspicious mononuclear cells and a mildly elevated lactate dehydrogenase level (478 U/L). Skin biopsy demonstrated diffuse sheets and nodular infiltrates of CD20 and CD79a positive neoplastic cells in the dermis and subcutis. Computed tomography revealed multiple cervical, axillary, mediastinal, para-aortic and mesenteric lymph nodes. Bone marrow aspiration and trephine biopsy confirmed marrow involvement by non-Hodgkin's lymphoma. The patient was treated with chemotherapy, which resulted in resolution of the skin lesions.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology*
Waldeyer ring lymphoma: a case series

Teh CS, Jayalakshmi P, Chong SY

Ear Nose Throat J, 2014 Sep;93(9):E22-5.
PMID: 25255354

We encountered a patient with a tongue base lymphoma that we initially diagnosed as a lingual tonsil in view of its benign appearance. We established the correct diagnosis of Waldeyer ring lymphoma by histology. This case led us to conduct a study of all cases of Waldeyer ring lymphoma that had been treated at our center during a 10-year period. We retrospectively examined our case records and found 35 such cases. From this group, we excluded 5 cases because of incomplete data. Thus our final study group was made up of 30 patients-14 males and 16 females, aged 14 to 76 years (mean: 51.6; median 54). The primary presenting signs and symptoms were dysphagia (n = 17 [57%]), a neck mass (n = 7 [23%]), nasal symptoms (n = 5 [17%]), and pain (n = 1 [3%]). Only 4 patients (13%) had B symptoms. A total of 20 patients (67%) presented with tonsillar involvement, 8 (27%) with nasopharyngeal involvement, 1 (3%) with tongue base lymphoma, and 1 with anterior tongue involvement. Most patients (77%) presented at an early stage. Histologically, 25 patients (83%) had high-grade diffuse large B-cell lymphoma, 4 (13%) had T-cell lymphoblastic lymphoma, and 1 (3%) had follicular lymphoma. Twenty-one patients (70%) were treated with chemotherapy, 4 (13%) received adjuvant chemotherapy with either radiotherapy or surgery, 3 (10%) resorted to other forms of treatment (primarily traditional remedies), and 2 (7%) declined treatment altogether. There were 14 patients (47%) alive at the end of the study period.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology
Expression and alteration of p16 in diffuse large B cell lymphoma

Lee ES, Kim LH, Abdullah WA, Peh SC

Pathobiology, 2010;77(2):96-105.
PMID: 20332669 DOI: 10.1159/000278291

This study aimed to examine (1) the expression of P16 protein relative to sites of presentation, immunophenotypic subgroups and proliferative indices of tumour cells, and (2) the relationship between p16 gene alterations and P16 protein overexpression in 70 cases of diffuse large B cell lymphoma (DLBCL).

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology
Clinical relevance of CD10, BCL-6 and multiple myeloma-1 expression in diffuse large B-cell lymphomas in Malaysia

Peh SC, Gan GG, Lee LK, Eow GI

Pathol. Int., 2008 Sep;58(9):572-9.
PMID: 18801072 DOI: 10.1111/j.1440-1827.2008.02273.x

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, and it is recognized to constitute a heterogenous group of neoplasms. It can be divided into germinal center B-cell-like (GCB) and non-GCB subgroups. The aim of the present study was to evaluate the utility of immunophenotype subgrouping of DLBCL in a cohort of multi-ethnic Asian patients. A total of 84 reconfirmed de novo DLBCL were immunostained for the expression of CD10, BCL-2, BCL-6 and multiple myeloma-1. Thirty-three (39.3%) had the GCB phenotype, and the remainder (60.7%), the non-GCB phenotype. The results concur with most reports using a similar method of stratification. Forty-five patients had complete demographic and phenotype studies and 42 patients did not have rituximab treatment and had sufficient data for survival rate analysis. Similar to other studies, patients with combined low and low-intermediate International Prognostic Index score had better overall survival (P = 0.006). But patients with GCB phenotype did not have better prognosis, and BCL-2 expression was not associated with better prognosis. The expression of BCL-6 was associated with lower overall survival rate (P = 0.038). No apparent difference in overall and disease-free survival was noted between patients with GCB and non-GCB disease. BCL-6 expression by tumor cells appears to be associated with poorer prognosis.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology
Higher frequency of p53 gene mutations in diffuse large B-cell lymphoma with MALT component

Tai YC, Tan JA, Peh SC

Pathol. Int., 2004 Nov;54(11):811-8.
PMID: 15533223

p53 gene mutation is not a frequent event in the tumorigenesis of lymphomas and the expression of p53 protein is independent of p53 gene mutations. The present study aimed to investigate mutations in the p53 gene in a series of extranodal B-cell lymphomas, and its association with p53 protein expression. A total of 52 cases were graded histologically into Grade 1, Grade 2 and Grade 3 tumors and p53 protein expression was detected using immunohistochemistry. Mutations in the p53 gene were analyzed using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) and mobility shifts were confirmed by direct sequencing. The tumors comprised 26 (50%) Grade 1, 9 (17%) Grade 2 and 15 (29%) Grade 3. A high proportion of Grade 2 (25%) tumors expressed p53 protein (P = 0.051) and carried p53 gene mutation (33%) (P = 0.218). However, p53 protein expression was not associated with p53 gene mutations (P = 0.057). Transversion mutations (88%) were more frequently detected than transition mutations (12%). The present study revealed that p53 gene mutations and p53 protein expression occurred in higher frequencies in Grade 2 tumors, which may be of pathogenetic importance. The high frequency of transversion mutations may reflect the influence of an etiological agent in the tumorigenesis of mucosa-associated lymphoid tissue (MALT lymphoma).

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology*
TARC, a CC chemokine, is frequently expressed in classic Hodgkin's lymphoma but not in NLP Hodgkin's lymphoma, T-cell-rich B-cell lymphoma, and most cases of anaplastic large cell lymphoma

Peh SC, Kim LH, Poppema S

Am. J. Surg. Pathol., 2001 Jul;25(7):925-9.
PMID: 11420464

Thymus and activation-regulated chemokine (TARC) has been identified as a lymphocyte-directed CC chemokine that attracts activated T-helper type 2 (Th2) cells in humans. Recent studies showed that the T cells surrounding Reed-Sternberg cells in Hodgkin's lymphomas (HL) are Th2 type. Anaplastic large cell lymphomas (ALCL), T-cell-rich B-cell lymphoma (TCRBCL) can mimic HL in some instances. This study aimed to establish the pattern of TARC expression in these diseases. Immunohistochemical stain using a polyclonal goat anti-human antibody to TARC was performed on 119 cases of confirmed HL; 99 were classical type (43 mixed cellularity, 43 nodular sclerosis, 5 lymphocyte depleted, 4 lymphocyte rich, 4 unclassifiable) and 20 lymphocyte predominant HL. Additional 27 ALCL (9 T-, 18 null-cell phenotype), 16 T-cell and 8 B-cell non-Hodgkin's lymphoma (NHL) were studied. A total of 85.8% of the classical HL, one case of ALCL, and one case of large cell B-cell lymphoma with anaplastic morphology showed positive TARC expression in the tumor cells. The expression was paranuclear and/or diffuse in the cell cytoplasm. The tumor cells in all cases of lymphocyte predominant HL, TCRBCL, null ALCL, and T-NHL did not express TARC. The high frequency of TARC expression in the Reed-Sternberg cells of classical HL may explain the characteristic T-cell infiltrate in this disease. The absence in other types that may be morphologically similar indicates that staining for TARC may aid in differential diagnosis.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology
DNMT1 is predictive of survival and associated with Ki-67 expression in R-CHOP-treated diffuse large B-cell lymphomas

Loo SK, Ch'ng ES, Lawrie CH, Muruzabal MA, Gaafar A, Pomposo MP, et al.

Pathology, 2017 Dec;49(7):731-739.
PMID: 29074044 DOI: 10.1016/j.pathol.2017.08.009

DNMT1 is a target of approved anti-cancer drugs including decitabine. However, the prognostic value of DNMT1 protein expression in R-CHOP-treated diffuse large B-cell lymphomas (DLBCLs) remains unexplored. Here we showed that DNMT1 was expressed in the majority of DLBCL cases (n = 209/230, 90.9%) with higher expression in germinal centre B-cell-like (GCB)-DLBCL subtype. Low and negative DNMT1 expression (20% cut-off, n = 33/230, 14.3%) was predictive of worse overall survival (OS; p < 0.001) and progression-free survival (PFS; p < 0.001). Nonetheless, of the 209 DNMT1 positive patients, 33% and 42% did not achieve 5-year OS and PFS, respectively, indicating that DNMT1 positive patients showed considerably heterogeneous outcomes. Moreover, DNMT1 was frequently expressed in mitotic cells and significantly correlated with Ki-67 or BCL6 expression (r = 0.60 or 0.44, respectively; p < 0.001). We demonstrate that DNMT1 is predictive of DLBCL patients' survival, and suggest that DNMT1 could be a DLBCL therapeutic target due to its significant association with Ki-67.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology
Prognostic subgroup distribution in diffuse large B-cell lymphoma of the upper aerodigestive tract

Wong KK, Prepageran N, Peh SC

Pathology, 2009 Feb;41(2):133-9.
PMID: 18972319 DOI: 10.1080/00313020802436790

AIMS: To stratify upper aerodigestive tract (UAT) diffuse large B-cell lymphoma (DLBCL) into prognostic subgroups by immunohistochemical staining (IHC) method, and to evaluate the association rate of UAT DLBCL with Epstein-Barr virus (EBV).
METHODS: Using a panel of antibodies to CD10, Bcl-6, MUM1 and CD138, consecutive cases of primary UAT DLBCL were stratified into subgroups of germinal centre B-cell-like (GCB) and non-GCB, phenotype profile patterns A, B and C, as proposed by Hans et al. and Chang et al., respectively. EBER in situ hybridisation technique was applied for the detection of EBV in the tumours.
RESULTS: In this series of 32 cases of UAT DLBCL, 34% (11/32) were GCB, and 66% (21/32) were non-GCB types; 59% (19/32) had combined patterns A and B, and 41% (13/32) had pattern C. Statistical analysis revealed no significant difference in the occurrence of these prognostic subgroups in the UAT when compared with series of de novo DLBCL from all sites. There was also no site difference in phenotype protein expressions, with the exception of MUM1. EBER in situ hybridisation stain demonstrated only one EBV infected case.
CONCLUSIONS: Prognostic subgroup distribution of UAT DLBCL is similar to de novo DLBCL from all sites, and EBV association is very infrequent.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology
Common ALK gene rearrangement in Asian CD30+ anaplastic large cell lymphoma: an immunohistochemical and fluorescence in situ hybridisation (FISH) study on paraffin-embedded tissue

Tai YC, Kim LH, Peh SC

Pathology, 2003 Oct;35(5):436-43.
PMID: 14555389

AIMS: The most common recurrent genetic aberration in anaplastic large cell lymphoma (ALCL) is translocation involving the ALK gene that results in ectopic expression of ALK protein in lymphoid tissue. This study aims to investigate the frequency of ALK gene rearrangement in a series of Asian ALCL.
METHODS: ALK gene rearrangement was detected by immunostaining of ALK protein and fluorescence in situ hybridisation (FISH) targeting at the 2p23 region.
RESULTS: The expression of ALK protein was detected in 24/34 (71%) of the cases, and it was significantly higher in childhood cases (100%) when compared to adult cases (47%). The analyses by FISH were consistent with the results from immunostaining of ALK protein, but the analyses were only successful in 15/34 (44%) cases. FISH analyses detected extra copies of ALK gene in three cases, including one case that expressed ALK protein and showed 2p23 rearrangement.
CONCLUSIONS: The current series revealed a high frequency of ALK gene rearrangement, especially in the children. Immunostaining of ALK protein is a reliable indication of ALK gene rearrangement, and is superior to FISH. However, FISH analysis is useful in detecting other genetic aberrations that are not related to ALK gene rearrangement.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology
Comparison of protein-based cell-of-origin classification to the Lymph2Cx RNA assay in a cohort of diffuse large B-cell lymphomas in Malaysia

Phang KC, Akhter A, Tizen NMS, Rahman FA, Zahratul Azma R, Elyamany G, et al.

J Clin Pathol, 2018 Mar;71(3):215-220.
PMID: 28775174 DOI: 10.1136/jclinpath-2017-204548

AIMS: The cell of origin (COO) based molecular characterisation into germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) subtypes are central to the pathogenesis and clinical course in diffuse large B-cell lymphoma (DLBCL). Globally, clinical laboratories employ pragmatic but less than ideal immunohistochemical (IHC) assay for COO classification. Novel RNA-based platforms using routine pathology samples are emerging as new gold standard and offer unique opportunities for assay standardisation for laboratories across the world. We evaluated our IHC protocols against RNA-based technologies to determine concordance; additionally, we gauged the impact of preanalytical variation on the performance of Lymph2Cx assay.
METHODS: Diagnostic biopsies (n=104) were examined for COO classification, employing automated RNA digital quantification assay (Lymph2Cx). Results were equated against IHC-based COO categorisation. Assay performance was assessed through its impact on overall survival (OS).
RESULTS: 96 (92%) informative samples were labelled as GCB (38/96; 40%) and non-GCB (58/96; 60%) by IHC evaluation. Lymph2Cx catalogued 36/96 (37%) samples as GCB, 45/96 (47%) as ABC and 15/96 (16%) as unclassified. Lymph2Cx being reference, IHC protocol revealed sensitivity of 81% for ABC and 75% for GCB categorisation and positive predictive value of 81% versus 82%, respectively. Lymph2Cx-based COO classification performed superior to Hans algorithm in predicting OS (log rank test, p=0.017 vs p=0.212).
CONCLUSIONS: Our report show that current IHC-based protocols for COO classification of DLBCL at UKM Malaysia are in line with previously reported results and marked variation in preanalytical factors do not critically impact Lymph2Cx assay quality.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology
TRPM4 expression is associated with activated B cell subtype and poor survival in diffuse large B cell lymphoma

Loo SK, Ch'ng ES, Md Salleh MS, Banham AH, Pedersen LM, Møller MB, et al.

Histopathology, 2017 Jul;71(1):98-111.
PMID: 28248435 DOI: 10.1111/his.13204

AIMS: Transient receptor potential channel melastatin 4 (TRPM4) is an ion channel that regulates influx of calcium cations (Ca2+ ). Recent studies suggest that TRPM4 is an oncoprotein, and its up-regulated transcript level has been reported in diffuse large B cell lymphoma (DLBCL). We aimed to investigate TRPM4 protein expression pattern in non-malignant tissues and DLBCL cases, and its association with clinico-demographic parameters and survival in DLBCL.
METHODS AND RESULTS: Analysis of publicly available DLBCL microarray data sets showed that TRPM4 transcripts were up-regulated in DLBCL compared to normal germinal centre B (GCB) cells, were expressed more highly in the activated B cell-like DLBCL (ABC-DLBCL) subtype and higher TRPM4 transcripts conferred worse overall survival (OS) in R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL cases (P < 0.05). Our immunohistochemical analysis showed that TRPM4 was expressed in various human tissues but not in normal B cells within lymphoid tissues (reactive tonsil, lymph node and appendix). TRPM4 protein was present in 26% (n = 49 of 189) of our cohort of R-CHOP-treated DLBCL cases and this was associated significantly with more aggressive clinical parameters, including higher lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group (ECOG) scores or stage (P < 0.01 for each of the parameters) and the ABC-DLBCL subtype (P = 0.016). TRPM4 positivity conferred significantly worse OS (P = 0.004) and progression-free survival (PFS) (P = 0.005). Worse OS remained associated significantly with TRPM4 positivity in multivariate analysis, including higher International Prognostic Index (IPI) or the non-GCB DLBCL phenotype (P < 0.05).
CONCLUSIONS: TRPM4 protein expression is up-regulated in DLBCL cases compared to non-malignant B cells with preferential expression in ABC-DLBCL cases, and it confers significantly poorer DLBCL patient outcomes.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology*
pSTAT3 and MYC in Epstein-Barr virus-positive diffuse large B-cell lymphoma

Teoh SH, Khoo JJ, Abdul Salam DSD, Peh SC, Cheah SC

Malays J Pathol, 2019 Dec;41(3):273-281.
PMID: 31901912

INTRODUCTION: Epstein-Barr Virus (EBV) is associated with several B-cell non-Hodgkin's lymphoma (NHL), but the role of EBV in diffuse large B-cell lymphoma (DLBCL) is poorly defined. Several studies indicated the expression of phosphorylated STAT3 (pSTAT3) is predominant in EBV(+)- DLBCL, of which its activated form can promote the downstream oncogenes expression such as c-MYC. c-MYC gene rearrangements are frequently found in aggressive lymphoma with inferior prognosis. Furthermore, EBV is a co-factor of MYC dysregulation. JAK1/STAT3 could be the downstream pathway of EBV and deregulates MYC. To confirm the involvement of EBV in JAK1/ STAT3 activation and MYC deregulation, association of EBV, pSTAT3 and MYC in EBV(+)- DLBCL cases were studied. The presence of pSTAT3 and its upstream proteins: pJAK1 is identify to delineate the role of EBV in JAK1/STAT3 pathway.
MATERIALS AND METHODS: 51 cases of DLBCL paraffin-embedded tissue samples were retrieved from a single private hospital in Kuala Lumpur, Malaysia. EBER-ISH was performed to identify the EBV expression; ten EBV(+)-DLBCL cases subjected to immunohistochemistry for LMP1, pJAK1, pSTAT3 and MYC; FISH assay for c-MYC gene rearrangement.
RESULTS: Among 10 cases of EBV(+)-DLBCL, 90% were non-GCB subtype (p=0.011), 88.9% expressed LMP1. 40% EBV(+)-DLBCL had pJAK1 expression.
CONCLUSION: 66.7% EBV(+)-DLBCL showed the positivity of pSTAT3, which implies the involvement of EBV in constitutive JAK/STAT pathway. 44.5% EBV(+)-DLBCL have co-expression of pSTAT3 and MYC, but all EBV(+)-DLBCL was absence with c-MYC gene rearrangement. The finding of clinical samples might shed lights to the lymphomagenesis of EBV associated with non-GCB subtypes, and the potential therapy for pSTAT3-mediated pathway.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology*
The expression of Bcl-2 by proliferating cells varies in different categories of B-cell lymphoma

Masir N, Jones M, Lee AM, Goff LK, Clear AJ, Lister A, et al.

Histopathology, 2010 Apr;56(5):617-26.
PMID: 20459572 DOI: 10.1111/j.1365-2559.2010.03524.x

To investigate the relationship between Bcl-2 protein expression and cell proliferation at single-cell level in B-cell lymphomas using double-labelling techniques.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology
Impact of Double Expression of C-MYC/BCL2 Protein and Cell of Origin Subtypes on the Outcome among Patients with Diffuse Large B-Cell Lymphoma: a Single Asian Center Experience

Teoh CS, Lee SY, Chiang SK, Chew TK, Goh AS

Asian Pac J Cancer Prev, 2018 May 26;19(5):1229-1236.
PMID: 29801406

Background: Diffuse large B-cell lymphoma (DLBCL) with double expression of c-MYC and BCL2 protein is
associated with dismal outcome after treatment with R-CHOP. Local data on disease burden and survival outcome in
DLBCL is limited. We investigated the prognostic values of c-MYC/BCL2 protein co-expression and cell of origin
subtypes using immunohistochemistry (IHC) and to determine their associations with multiethnic groups under
resource limited setting. Methods: This was a retrospective study which recruited 104 patients in between June 2012
and December 2015 for IHC review and analysis. Result: We demonstrated that patients with high International
Prognostic Index (IPI) (score 3-5) and co-expression of c-MYC/BCL2 protein had significant inferior overall survival
(OS) and event free survival (EFS) respectively (P<0.05). c-MYC/BCL2 protein co-expression was more common in
non-germinal center B-cell (non-GCB) (P=0.048) and contributed to adverse prognosis in this group of patients (OS,
P=0.004; EFS, P=0.005). In multivariate analysis, double-protein co-expression was a significant independent predictor
of inferior outcome after adjusted for IPI and cell of origin subtypes (OS hazard ratio [HR], 2.11; 95% CI, 1.01 to 4.04;
P=0.048; EFS HR, 2.31; 95% CI, 1.05 to 5.04; P=0.036). In addition, non-GCB subtype was more common than GCB
in Malays (60% vs 40%, P=0.106) and Chinese (81.2% vs 18.8%, P=0.042). Indians had more DLBCL without c-MYC/
BCL2 protein co-expression compared to double-protein positive cases (66.7% vs 33.3%, P=0.414). Otherwise, the
prognostic impact of ethnicity on survival outcome was insignificant (P=0.961). Conclusion: c-MYC/BCL2 protein
co-expression in non-GCB subtype constituted a unique group with extremely inferior outcome regardless of ethnicity.
Gene expression profile (GEP) may possibly provide insights into the cause of discrepancies in DLBCL subtypes and
protein expression among the multiethnic groups.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology*
High frequency of germinal centre derivation in diffuse large B cell lymphoma from Asian patients

Shia AK, Gan GG, Jairaman S, Peh SC

J Clin Pathol, 2005 Sep;58(9):962-7.
PMID: 16126878

Recent reports have divided diffuse large B cell lymphoma (DLBCL) into germinal centre B cell-like and activated B cell-like subgroups with implicated differences in prognosis.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology*
Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients

Wong KK, Gascoyne DM, Brown PJ, Soilleux EJ, Snell C, Chen H, et al.

Leukemia, 2014 Feb;28(2):362-72.
PMID: 23884370 DOI: 10.1038/leu.2013.224

We previously identified autoantibodies to the endocytic-associated protein Huntingtin-interacting protein 1-related (HIP1R) in diffuse large B-cell lymphoma (DLBCL) patients. HIP1R regulates internalization of cell surface receptors via endocytosis, a process relevant to many therapeutic strategies including CD20 targeting with rituximab. In this study, we characterized HIP1R expression patterns, investigated a mechanism of transcriptional regulation and its clinical relevance in DLBCL patients treated with immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, R-CHOP). HIP1R was preferentially expressed in germinal center B-cell-like DLBCL (P<0.0001) and inversely correlated with the activated B-cell-like DLBCL (ABC-DLBCL) associated transcription factor, Forkhead box P1 (FOXP1). HIP1R was confirmed as a direct FOXP1 target gene in ABC-DLBCL by FOXP1-targeted silencing and chromatin immunoprecipitation. Lower HIP1R protein expression (≤ 10% tumoral positivity) significantly correlated with inferior overall survival (OS, P=0.0003) and progression-free survival (PFS, P=0.0148) in R-CHOP-treated DLBCL patients (n=157). Reciprocal expression with ≥ 70% FOXP1 positivity defined FOXP1(hi)/HIP1R(lo) patients with particularly poor outcome (OS, P=0.0001; PFS, P=0.0016). In an independent R-CHOP-treated DLBCL (n=233) microarray data set, patients with transcript expression in lower quartile HIP1R and FOXP1(hi)/HIP1R(lo) subgroups exhibited worse OS, P=0.0044 and P=0.0004, respectively. HIP1R repression by FOXP1 is strongly associated with poor outcome, thus further understanding of FOXP1-HIP1R and/or endocytic signaling pathways might give rise to novel therapeutic options for DLBCL.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology
Fulltext Germline TET2 loss of function causes childhood immunodeficiency and lymphoma

Stremenova Spegarova J, Lawless D, Mohamad SMB, Engelhardt KR, Doody G, Shrimpton J, et al.

Blood, 2020 Aug 27;136(9):1055-1066.
PMID: 32518946 DOI: 10.1182/blood.2020005844

Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.

Matched MeSH terms: Lymphoma, Large B-Cell, Diffuse/pathology

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