Comparative Study of Marginal Zone Lymphoma Involving Bone Marrow

Abstract In the early 1990’s we described a series of patients from Kumasi, Ghana, West Africa who appeared to have a distinctive lymphoproliferative disorder (LPD) characterised by massive splenomegaly and lymphocytosis with characteristic morphology. At the time this was termed tropical splenic lymphoma (TSL). These patients, in contrast to most patients with LPD’s, tended to be female and relatively young and were frequently diagnosed as having hyper-reactive malarial splenomegaly. An aetiological role for chronic malaria infection has been postulated but remains as yet unproven. Only limited phenotypic and genotypic characterisation of such patients has been possible previously. Given the clinical features and potential aetiological role for malaria infection we wanted to determine whether TSL represented a distinct entity or may be more appropriately considered as splenic marginal zone lymphoma (SMZL). We have therefore evaluated the clinical, immunophentypic and genotypic features of 19 pts (median age 63 years, range 40–78) with a clinical diagnosis of TSL. Peripheral blood, bone marrow aspirate and trephine biopsies were obtained in all patients and the laboratory assessment were performed in the HMDS laboratory, Leeds, UK as part of an on-going collaborative project investigating lymphomas in Ghana. 14 of the 19 patients (73%) were female and all had significant splenomegaly (median length below the costophrenic margin of 17cm, range 6–30 cm). 5/19 patients (26%) had lymphadenopathy and 17/19 patients (89%) had a lymphocytosis - median 30.1×09/l (range 5.4×09/l - unrecordable). Bone marrow infiltration was evident in the trephine biopsies of all patients and was extensive in the majority. Immunophenotyping was performed primarily by immunohistochemistry on the trephine sections although flow cytometry was possible in a proportion of patients. The majority of cases were characterised by a CD5− CD10− CD20+ CD23− CD79+ BCL2+ BCL6− MUM1/IRF4- cyclin D1- immunophenotype. The rate of cell proliferation was low in all cases. FISH studies were performed and these demonstrated del7q31 in 4/18 cases and del6q21 in 1/19 cases. There was no evidence of the t(11;14), t(9;14) or MALT1 rearrangements. IgH sequence analysis was also performed in 16 cases and this demonstrated that 9/16 cases (56%) were germline (>98% homology) and 7/16 (44%) were mutated (<98% homology). Within the mutated group the overall mutation load appeared to be relatively low - median 3.3% (range 3–6%) with most utilising the VH3 family genes. This is the first detailed clinicopathological assessment of patients with a clinical diagnosis of TSL. These patients clearly have some pathological features seen in patients with SMZL such as a CD5− CD10− CD23− immunophenotype, 7q31 deletions and cases with both germline and mutated Ig genes. Definitive phenotypic and genotypic features are unfortunately lacking in SMZL and it remains uncertain whether patients with a clinical diagnosis of TSL should be considered as having SMZL.

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Lymphoplasmacytic Lymphoma and Marginal Zone Lymphoma in the Bone Marrow: Paratrabecular Involvement As an Important Distinguishing Feature

Blood ◽

10.1182/blood.v124.21.5399.5399 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5399-5399

Author(s):

Assia Bassarova ◽

Gunhild Trøen ◽

Signe Spetalen ◽

Francesca Micci ◽

Anne Tierens ◽

...

Keyword(s):

Bone Marrow ◽

Marginal Zone ◽

Plasma Cells ◽

Bone Marrow Involvement ◽

Marginal Zone Lymphoma ◽

Lymphoplasmacytic Lymphoma ◽

Waldenström Macroglobulinemia ◽

Bone Marrow Trephine ◽

Waldenstrom Macroglobulinemia ◽

Myd88 L265p Mutation

Abstract Lymphoplasmacytic lymphoma and marginal zone lymphoma in the bone marrow: paratrabecular involvement as an important distinguishing feature Assia Bassarova, Gunhild Tr¿en, Signe Spetalen, Francesca Micci, Anne Tierens, Delabie Abstract Lymphoplasmacytic lymphoma (LPL) is a neoplasm of small B-lymphocytes, lymphoplasmacytoid and plasma cells involving bone marrow and sometimes lymph nodes and spleen. Lymphoplasmacytic lymphoma is often accompanied by Waldenström macroglobulinemia. Since the original description, Waldenström macroglobulinemia has become recognized as a distinct clinicopathological entity defined by serum IgM paraprotein and bone marrow involvement by lymphoplasmacytic lymphoma. Since serum IgM paraprotein in itself is not specific and can be seen in a variety of small B-cell lymphoproliferative disorders, notable chronic lymphatic leukemia and marginal zone lymphoma, as well as in rare cases of myeloma, the diagnosis of Waldenström macroglobulinemia rests largely upon the proper diagnosis of LPL in the bone marrow. The differential diagnosis between bone marrow involvement by lymphoplasmacytic lymphoma (LPL) and marginal zone lymphoma (MZL) is challenging because histology and immunophenotype of both diseases overlap. The diagnosis may be helped by demonstrating the MYD88 L265P mutation, seen in most LPL. However, the mutation is also present in MZL, although at a lower frequency. To better define the distinguishing features of LPL we studied a series of bone marrow trephine biopsies of 59 patients with Waldenström's macroglobulinemia (WM) without extramedullary involvement and compared the findings with bone marrow biopsies from 23 patients with well-characterized MZL who also had bone marrow involvement. H&E and immunoperoxidase-stained sections of bone marrow trephine biopsies as well as flow cytometry and classical cytogenetics performed on aspirations were reviewed. The study was complemented with MYD88L265P mutation analysis on the bone marrow trephine biopsies of all patients. The features are summarized in Table 1. The most distinguishing features of LPL with respect to MZL were focal paratrabecular involvement (p<0.001), the presence of lymphoplasmacytoid cells (p<0.001), Dutcher bodies (p<0.001), increased numbers of mast cells (p<0.001) and the MYD88L265P mutation (p<0.001). Other features such as sinusoidal infiltration and immunophenotype were not distinguishing. Table 1. Summary of the pathology features of lymphoplasmacytic and marginal zone lymphoma in bone marrow trephine biopsies Lymphoplasmacytic lymphoma Marginal zone lymphoma p Infiltration pattern* Paratrabecular Nodular non-paratrabecular Paratrabecular and non-paratrabecular Intrasinusoidal Diffuse 37% (10/27) 0% (0/27) 56% (15/27) 37% (10/27) 0% (0/27) 0% (0/16) 75% (12/16) 0% (0/16) 37% (6/16) 25% (4/16) <0,001 <0,001 <0,001 1 0,015 Cytology Small lymphoid cells Plasmacytoid cells Plasma cells Dutcher nuclear inclusions Mast cells 100% (59/59) 100% (59/59) 93% (55/59) 90% (53/59) 87% (49/56) 100% (23/23) 0% (0/23) 78% (18/23) 0% (0/23) 9% (2/23) - <0,001 0,108 <0,001 <0,001 Immunophenotype of the lymphoma CD20 CD138 (plasma cells) CD5 CD23 IgK IgL IgM IgG Focal CD21+ or CD23+ follicular dendritic cell network in the stroma 100% (59/59) 88% (50/57) 21% (12/52) 29% (15/51) 81% (48/59) 19% (11/59) 97% (57/59) 3% (2/59) 20% (10/51) 100% (23/23) 80% (12/15) 0% (0/23) 13% (5/23) 26% (5/19) 10% (2/19) 64% (7/11) 0% (0/11) 48% (11/23) - - 0,014 0,580 - - - - 0,024 MYD88 L265P mutation 96% (45/47) 20% (3/15) 0,001 *the analysis was only performed on bone marrow trephine biopsies showing less than 66% lymphoma infiltration In conclusion, LPL can reliably be distinguished from MZL in the bone marrow by using a combination of pathology characteristics. In contrast to other studies, our findings stress the diagnostic importance of paratrabecular infiltration in LPL. Disclosures No relevant conflicts of interest to declare.

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Reply to Pich et al.: intrasinusoidal bone marrow infiltration and splenic marginal zone lymphoma: a quantitative study

European Journal Of Haematology ◽

10.1111/j.1600-0609.2006.00726.x ◽

2006 ◽

Vol 77 (4) ◽

pp. 360-360

Author(s):

Claudio Tripodo ◽

Ada Maria Florena ◽

Emilio Iannitto ◽

Vito Franco

Keyword(s):

Bone Marrow ◽

Quantitative Study ◽

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Bone Marrow Infiltration ◽

Splenic Marginal Zone Lymphoma

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Omission of Staging Bone Marrow Biopsy Does Not Affect Outcomes in Patients with Stage I Extranodal Marginal Zone Lymphoma (EMZL) Treated with Radiation Therapy

Blood ◽

10.1182/blood-2019-124964 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2829-2829

Author(s):

Juan Pablo Alderuccio ◽

Derek Isrow ◽

Isildinha M. Reis ◽

Sunil Iyer ◽

Jessica Meshman ◽

...

Keyword(s):

Bone Marrow ◽

Radiation Therapy ◽

Family Member ◽

Board Of Directors ◽

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Stage I ◽

Competing Risk ◽

Advisory Committees ◽

Significant Difference

INTRODUCTION: Patients with stage I localized extranodal marginal zone lymphoma (EMZL) treated with radiation therapy (RT) have excellent outcomes. Negative bone marrow (BM) biopsy at diagnosis is key to confirm early stage disease. However, BM biopsy is not performed in some patients for various reasons such as comorbidities, patient refusal or physician decision. The aim of this study was to assess the effects of BM status (negative vs. not done) on disease recurrence/progression and survival in EMZL patients presenting with otherwise localized disease by imaging and treated with RT. METHODS: From January 1995 to January 2019, we identified 188 patients with stage I EMZL treated with frontline RT at the University of Miami Health Care System. All patients had biopsy proven EMZL and scans (CT, MRI, and/or PET-CT) at the time of diagnosis. Medical records were reviewed and pertinent information gathered. Relapse/progression was subclassified based on disease location: inside, outside, or inside and outside of the radiation field (RF). The competing risk method and the Gray's test were used in analysis of incidence rates of type of relapse/progression and lymphoma-specific death. The Kaplan-Meier method and the log-rank test were used in analyses of progression-free survival (PFS) and overall survival (OS). RESULTS: Among 188 patients included in this study, 104 (55.3%) were ≤60 years and 135 (71.8%) <70 years. 117 (62.2%) females and 98 (52.1%) non-Hispanic Whites. EMZL location was as follows: Orbit 118 (62.8%), gastric 19 (10.1%), head & neck 14 (7.4%), dural 13 (6.9%), skin 12 (6.4%), and other 12 (6.4%). Most patients had a negative staging BM biopsy (148, 78.7%); however, in 40 (21.3%) patients BM biopsy was not performed. Patients without BM biopsy at diagnosis were mainly >60 years (26, 65%). Radiation doses broadly varied but most patients (176, 93.6%) received ≥30 Gy. 183 patients (97.3%) achieved complete response (CR) following RT with 2 (1.1%) achieving partial response (PR), 2 (1.1%) stable disease and 1 (0.5%) demonstrating disease progression. Among 176 patients receiving ≥30 Gy RT, 173 (98.2%) achieved CR. With a median follow-up of 6.2 years (range 0.3-22.3 years) the 10 years-PFS was 64.4% (95%CI:54.9%-72.5%). No difference in PFS was observed by location of disease or BM biopsy (negative vs. not done). Patients treated with ≥30Gy had statistically significantly longer PFS compared to patients treated with <30Gy, whether or not BM biopsy was done. There were 52 progression events, including 5 inside RF (4 relapses/1 progression), 6 inside & outside (5 relapses/1 progression), 25 outside alone (24 relapses/1 progression), and 16 non-lymphoma deaths. Taking into account non-lymphoma death as a competing risk, the 5-year incidence of lymphoma relapse/progression was 2.9% (95%CI:1.1-6.3%) inside RF, 3.4% (95%CI:1.2-7.3%) inside & outside RF and 9.8% (5.8-15.0%) outside RF. Importantly, there was no higher cumulative incidence of each type of relapse/progression relative to RF (inside p=0.2490, inside & outside p=0.1617, and outside alone p=0.3070) in patients without vs. negative staging BM biopsy. There were 23 deaths, 7 attributed to lymphoma. The 10-year OS was 83.3% (95%CI:75.0-89.0%), and there was no difference in OS by EMZL location. Patients without staging BM biopsy had shorter OS (p=0.0062). However, when lymphoma-specific death was analyzed (non-lymphoma death as competing risk) the estimated 10-year cumulative incidence of lymphoma-specific death was 5.3% (2.3%-10.2%) and there was a non-statistically significant difference between patients with and without staging BM biopsy (p=0.5201). The cumulative 10-years incidence of non-lymphoma specific death (lymphoma death as competing risk) was 11.4% (95% CI:6.3%-18.2%). There was a statistically significant difference by BM biopsy status (p=0.0107), with patients without staging BM biopsy having higher incidence of non-lymphoma death compared to negative BM biopsy patients (10-yr rate 26.7% vs 7.9%, respectively), likely due to coexistent comorbidities. CONCLUSION: In this large cohort of patients with stage I EMZL treated with RT we demonstrate for the first time that omission of BM biopsy at diagnosis does not affect lymphoma-specific survival or the incidence of disease relapse/progression overall or by relapse location type, suggesting that diagnostic BM biopsy may not be necessary. Disclosures Alderuccio: Foundation Medicine: Other: Immediate family member; Inovio Pharmaceuticals: Other: Immediate family member; Targeted Oncology: Honoraria; Agios: Other: Immediate family member; Puma Biotechnology: Other: Immediate family member; OncLive: Consultancy. Lossos:NIH: Research Funding; Janssen Scientific: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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