Development of a Splenic Marginal Zone Lymphoma Associated with Active Chronic Visceral Leishmaniasis

Abstract Abstract 5202 We here report the observation of the development of a splenic marginal zone lymphoma (SMZL) after years of active chronic visceral Leishmania (VL) infection, implying a possible pathogenic link between these two conditions, where the neoplastic process is preceded by a prolonged period of chronic antigen stimulation. In 2004, a 60-year old male developed attack-like episodes of septic fever with chills, rigor and subsequent profound fatigue. He had a 4 years previous medical history of severe asthma-like symptoms and hypereosinophilia. A bone marrow (BM) and liver biopsy were inconclusive. A whole-body computed tomography showed a moderately enlarged spleen. No evidence of bacterial, fungal or viral infection was found; the symptoms persisted, although mitigated, with occasional exacerbations over the following 3 years. By 2007 the patient was admitted again and a new BM biopsy was taken, still showing reactive changes. Due to increased splenomegaly, a diagnostic splenectomy was performed. Examination of the spleen revealed a primary splenic marginal zone lymphoma (SMZL). In 2010 the patient was admitted with septicaemia and constitutional symptoms. A BM biopsy showed the presence of numerous Leishmania amastigotes and a retrospective review of all previous biopsies (since 2004) identified Leishmania amastigotes in all of them. In fact, a thorough travel history covering the previous two decades revealed several visits, often twice a year, to the Mediterranean basin, e.g. Greece and Malta, areas endemic for Leishmania infantum (L. infantum). Visceral Leishmaniasis is a frequent opportunistic infection in HIV-infected immunodeficient individuals but uncommon in cancer patients, and only a few cases of VL in patients with already well-established malignant lymphoma have been reported. Chronic antigenic stimulation by microbial pathogens has been proposed as a pathogenetic factor in a variety of marginal zone lymphomas. Tissue specific immune responses toward Leishmania parasites have been shown in rodents, and the spleen is a ‘safe harbor’ for the long-term persistence of visceralizing Leishmania. Sustained antigenic stimulation with upregulation of critical signaling pathways may result in prolonged polyclonal B-cell proliferation, and a subsequent increased risk of malignant transformation. This case is the first to provide evidence for a possible link between chronic antigen stimulation by long-lasting L. infantum infection and the development of a SMZL. Disclosures: No relevant conflicts of interest to declare.

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Absence of Mutations of the Histone Methyltransferase Gene EZH2 In Splenic B-Cell Marginal Zone Lymphoma

Blood ◽

10.1182/blood.v116.21.5086.5086 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5086-5086

Author(s):

Luz Martínez-Avilés ◽

Marta Salido ◽

Beatriz Bellosillo ◽

Vera Adema ◽

Ana Ferrer ◽

...

Keyword(s):

B Cell ◽

Marginal Zone ◽

Mutational Analysis ◽

Conflicts Of Interest ◽

Direct Sequencing ◽

Normal Karyotype ◽

Marginal Zone Lymphoma ◽

Low Grade ◽

Splenic Marginal Zone Lymphoma ◽

7Q Deletion

Abstract Abstract 5086 Background Splenic marginal zone lymphoma (SMZL) is a rare low-grade B-cell lymphoproliferative disorder with characteristic clinical, cytological, histological and immunophenotypical features. The most common cytogenetic abnormality, present in 30–40% of the patients is the 7q deletion, that extends from 7q21 to 7q36. This aberration may represent a primary pathogenic event in SMZL. Recently, mutations in the EZH2 gene, located at 7q36.1, have been described in different hematological malignancies including B-cell lymphomas. However, the role of the EZH2 gene in SMZL has to be elucidated. Aim To determine the prevalence of EZH2 mutations in a cohort of SMZL patients. Patients and Methods Twenty-nine patients with SMZL were screened for mutations in the EZH2 gene. From the whole cohort, 11 patients presented 7q deletion (three of them as a single anomaly), 11 had a normal karyotype and 7 had other cytogenetic aberrations. The mutational analysis of the EZH2 gene was performed by direct sequencing using primers covering the whole exome of the gene. DNA was extracted from CD19 isolated B-cells from peripheral blood or from total lymphocytes if the percentage of pathologic B-cell was higher than 50%. Results From the whole cohort of 29 SMZL patients, no pathogenic mutations (frameshift or nonsense mutations) were detected in the EZH2 gene in any of the patients analyzed. Five patients harboured the missense mutation D185H in exon 6, that has been previously described as a single nucleotide polymorphism (SNP). Conclusions In conclusion, the EZH2 gene is not mutated in our series of SMZL patients suggesting that this gene is not involved in the pathogeny of this entity. Acknowledgments: Fellowship FI2008 (AGAUR) to LMA, This work was supported (in part) by grants from Instituto de Salud Carlos III FEDER; Red Temática de Investigación Cooperativa en Cáncer (RTICC, FEDER): RD06/0020/0031 and RD07/0020/2004; Ministerio de Sanidad y Consumo (Spain): PI07/0586. Disclosures: No relevant conflicts of interest to declare.

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Splenectomy Is Still a Valid Option For Splenic Marginal Zone Lymphoma

Blood ◽

10.1182/blood.v122.21.5129.5129 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5129-5129

Author(s):

Alessandro Pulsoni ◽

Pasqualina D'Urso ◽

Gianna Maria D'Elia ◽

Giorgia Annechini ◽

Caterina Stefanizzi ◽

...

Keyword(s):

Marginal Zone ◽

Conflicts Of Interest ◽

B Cell Lymphoma ◽

Marginal Zone Lymphoma ◽

Splenic Marginal Zone Lymphoma ◽

Spleen Size ◽

Second Line ◽

Second Line Therapy ◽

Line Therapy

Abstract Introduction Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoma characterized by splenomegaly, frequent moderate lymphocytosis with or without villous morphology and possible involvement of various organs, especially the bone marrow (BM). Diagnosis is classically based on the spleen histology, but it can be made on the BM biopsy, based on the typical intrasinusoidal cell infiltration pattern and immunohistochemistry. Different therapeutic options are available, but to date there are no conclusive comparative data. Patients and methods We retrospectively analyzed 83 consecutive patients with a diagnosis of SMZL observed at our Institution between 1999 and 2013. The diagnosis was based on the BM biopsy in 79 patients; the BM was negative in 4 patients. Diagnosis was histologically confirmed on the spleen in 27 patients who underwent splenectomy. Patients presented a median age of 72.5 years (range 38-84); 43 were males. The median spleen size at diagnosis was 145 mm, ranging from 100 to 300 mm. The majority of patients were stage IV at diagnosis for BM infiltration (95%); B symptoms were present in 4 of them (4.8%). Forty-two patients (50.6%) had a lymphocytosis at diagnosis and 13 (15.6%) presented an IPI score higher than 3. Thirty-five of them (42%) had a MZL BM infiltration superior to 30% of the total bone cellularity. Forty-two patients (50.6%) underwent a watch and wait policy (WW), while 41 (49.4%) were treated within 6 months from diagnosis, mainly because of symptomatic splenomegaly; in these patients, treatment consisted of splenectomy, chemotherapy or chemotherapy plus immunotherapy with Rituximab. The features of patients submitted to WW with respect to patients treated at diagnosis were comparable for the various parameters mentioned above, except for spleen size (higher in patients treated at presentation) and lymphocyte count (higher in patients who were observed). After a median follow-up of 64 months, the overall median survival was 96%. Among the 42 WW patients, 18 (42.8%) are still untreated after a median follow-up of 57.5 months, while 24 (57.2%) have required therapy; the median treatment-free interval in these patients was 25.5 months. Concerning the 41 patients who underwent treatment at diagnosis, after a median follow-up of 50 months, 13 (31.7%) have required a subsequent second-line treatment. The interval between first-line approach and re-treatment in patients treated at diagnosis was 30 months. Overall, 27 patients were treated with splenectomy only (either at diagnosis or after a WW period): only 6 of them (22%) had a subsequent progression after a median latency of 42 months; 26 were treated with chemotherapy alone (alkylating agents in the majority of them, combination therapy in a minority): 15 of them (60%) had a subsequent relapse or progression after a median of 9 months; 12 patients received a Rituximab-containing regimen: of these, only 2 (16%) have so far required a second-line therapy after 10 and 26 months respectively. Conclusions The WW policy is a valid option for asymptomatic patients: in these patients, after 4.5 years from diagnosis more than 40% is still untreated. In patients requiring treatment, splenectomy alone is followed in the majority of patients by a long period of good disease control: only 22% required a second-line therapy after 3.5 years. The addiction of Rituximab to chemotherapy seems to reduce the probability of relapse and to prolong the response duration. However, these preliminary data need to be confirmed by larger studies. Disclosures: No relevant conflicts of interest to declare.

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Monoclonal B-Cell Lymphocytosis Exhibiting Immunophenotypic Features Consistent with Marginal Zone Origin: What Is This Entity?

Blood ◽

10.1182/blood.v120.21.1587.1587 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1587-1587

Author(s):

Aliki Xochelli ◽

Panagiotis Baliakas ◽

Anne Gardiner ◽

Sarah Mould ◽

Zadie Davis ◽

...

Keyword(s):

B Cell ◽

Marginal Zone ◽

Conflicts Of Interest ◽

Single Case ◽

B Cell Lymphoma ◽

Marginal Zone Lymphoma ◽

Gastric Malt Lymphoma ◽

Splenic Marginal Zone Lymphoma ◽

Group A ◽

Immunogenetic Analysis

Abstract Abstract 1587 Monoclonal B-cell lymphocytosis (MBL) with an immunophenotype consistent with marginal zone origin (MBL-MZ), that can be either CD5− or CD5+ but atypical for CLL, and also lacking an IGH/CCND1 translocation, is an increasingly recognised entity with poorly understood biological background and clinical significance. In particular, it is not yet clarified whether it represents a precursor state to one of the distinct lymphoma entities recognized by WHO as deriving from MZ cells or whether it constitutes a novel entity, likely with similar ontogeny. To obtain insight into this issue we retrospectively evaluated a series of 71 patients (male/female: 35/36, median age: 73.3 years) with lymphocytosis (median lymphocyte count: 5.77 × 109/l) detected incidentally on a routine blood test. No case had lymphadenopathy, organomegaly or any clinical features to suggest a concurrent marginal zone lymphoma. Hemoglobin and platelet counts were normal in all cases; 15/57 (26%) cases had paraproteinemia. Peripheral blood immunophenotyping revealed the presence of a clonal B-cell population with Matutes score <2 in all cases. Individual markers were expressed as follows: CD5: 15/71, CD23: 7/70, CD79β: 60/64, FMC7: 50/67, CD49d: 35/35, CD38: 6/53. In 8/45 cases assessed with CT-scan and/or ultrasound, borderline splenomegaly was observed. Histopathological examination of the bone marrow biopsy (BMB) was available in 11 cases and demonstrated mostly mixed patterns of neoplastic lymphocytic inflitration from small B cells. Karyotype data were available in 66 cases; 48/66 (72.7%) had abnormal karyotype. Main cytogenetic findings are as follows: (1) translocations: n=16 cases of which 3 carried t(2;7)(p11;q21/22); (2) isochromosome 17q: n=8; (3) trisomy 12: n=8; (4) del(7q): n=7; (5) trisomy 3: n=4. Immunogenetic analysis revealed overusage of the IGHV4–34 gene (15/63, 23.8%). Notably, the IGHV1–2 gene was utilized by a single case, thus sharply contrasting (p<0.0001) splenic marginal-zone lymphoma (SMZL) with a reported frequency of IGHV1–2 in excess of 30%. Seven of 63 rearrangements (11.1%) carried IGHV genes with no somatic mutations, whereas the remainder (56/63, 88.9%) exhibited some impact of somatic hypermutation (SHM), ranging from minimal to (mostly) pronounced. Overall, cases of the present study exhibited a significantly (p<0.005) higher SHM load compared to SMZL. With a median follow-up of 4.9 years (0.8–20), 54 cases (group A) remain stable with no signs of progression. The remaining 17 cases (group B) have MBL along with clinical or histopathologic evidence of lymphoma. In particular: (i) a female with MBL as an incidental finding, also carrying t(2;7), was eventually diagnosed with gastric MALT lymphoma at +11 months from presentation; immunogenetic analysis confirmed clonal identity between the MBL and the lymphoma; (ii) 2 cases developed lymphadenopathy; (iii) a single case developed diffuse large B cell lymphoma of the skin; and, (iv) 13 cases developed splenomegaly and, thus, can be considered as either SMZL or splenic lymphoma/leukemia unclassifiable (SLLU). Groups A and B did not differ in terms of demographics, diagnostic blood counts (including clonal MBL count) and SHM status; the only difference concerned cytogenetic profiles, with i(17)(q10) and del(7q) being almost exclusive to group A. In conclusion, we demonstrate that MBL-MZ can be the presenting feature of occult MZ lymphoma, most frequently SMZL/SLLU. However, in a sizeable proportion of cases, MBL-MZ remains stable over time with no evidence of organ involvement and distinct immunogenetic features from SMZL, thereby raising the possibility that it might represent a newcomer to the spectrum of B-cell lymphoproliferations of MZ origin. Disclosures: No relevant conflicts of interest to declare.

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Liver Infiltration In Splenic Marginal Zone Lymphoma: Prevalence and Prognostic Implication

Blood ◽

10.1182/blood.v116.21.4137.4137 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4137-4137 ◽

Cited By ~ 1

Author(s):

Eva Domingo-Domenech ◽

Vicente Romagosa ◽

Eva González-Barca ◽

Marta Rodriguez-Aliberas ◽

Ana Oliveira ◽

...

Keyword(s):

Overall Survival ◽

Liver Biopsy ◽

Marginal Zone ◽

Conflicts Of Interest ◽

Marginal Zone Lymphoma ◽

Splenic Marginal Zone Lymphoma ◽

Prognostic Implication ◽

Number Of Patients ◽

Almost All ◽

Baseline Demographic

Abstract Abstract 4137 Introduction: There are no studies in the literature about the frequency of liver infiltration by splenic marginal zone lymphoma (SMZL). In the last review published by the International Group of SMZL (Matutes E et al, Leukemia 2008;22:487) clinical liver infiltration seems to be infrequent and it is considered, as other organ involvement, to appear during the course of the disease and confers a bad prognosis. Objective: To investigate in a selected sample of patients with SMZL the prevalence of liver infiltration, as well as its possible prognostic implication in survival or transformation. Material and methods: In the majority of our SMZL patients who underwent a splenectomy between 1995 and 2001, a liver biopsy was realised during the surgical procedure in order to investigate hepatic infiltration by lymphoma. Results: Forty-eight patients with SMZL were diagnosed in our center during this period; of them, 19 were splenectomized being liver biopsy performed in 16 (only in those cases that gave informed consent). Splenectomy was performed at diagnosis in 11 patients (time from diagnosis to splenectomy < 3 months). Liver biopsy was positive for SMZL infiltration in 81.3% (13/16) of the cases. Baseline demographic and clinical characteristics of both groups of patients are shown in the following table; there were no significant differences between the groups. We neither find statistical significant differences in overall survival between both groups: mean overall survival for positive and negative liver biopsy patients was 116 ± SD 13 months and 74 ± 29 months, respectively (p=0.69). Conclusion: Histological hepatic infiltration is present in almost all SMZL patients when splenectomized. In our experience, this finding has no prognostic implication. Due to the small number of patients of this study, its significance is limited but to the best of our knowledge, it is the first report that investigates the prevalence of liver infiltration in SMZL and its impact in survival. Larger series are necessary to confirm our findings. Disclosures: No relevant conflicts of interest to declare.

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Clonal Selection in the Ontogeny and Evolution of Splenic Marginal Zone Lymphoma Confirming the Existence of Distinct Molecular Subtypes

Blood ◽

10.1182/blood.v120.21.1556.1556 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1556-1556

Author(s):

Vasilis Bikos ◽

Evangelia Stalika ◽

Maria Karypidou ◽

Panagiotis Baliakas ◽

Zadie Davis ◽

...

Keyword(s):

Amino Acid ◽

Light Chain ◽

Marginal Zone ◽

Molecular Subtypes ◽

Conflicts Of Interest ◽

Clonal Selection ◽

Marginal Zone Lymphoma ◽

Biological Research ◽

Splenic Marginal Zone Lymphoma ◽

Light Chain Gene

Abstract Abstract 1556 Splenic marginal-zone lymphoma (SMZL) exhibits biased immunoglobulin (IG) heavy and light chain gene repertoires, alluding to selection by antigens and/or superantigens in lymphomagenesis. We recently reported that immunogenetic analysis of the IG receptors enables the identification of molecular subtypes of SMZL, since, remarkably, greater than 30% of cases can be assigned to a single subgroup defined by usage of the *04 polymorphic variant of the IGHV1–2 gene. The IGHV1–2*04 receptors carry long and often positively charged heavy complementarity-determining region 3 with restricted motifs and show biased associations with certain light chain genes (IGKV3–20, IGKV1–8, IGLV2–14). Furthermore, they exhibit low-level, yet non-randomly targeted somatic hypermutation (SHM), likely reflecting a distinctive process of immune interaction with antigen(s). Preliminary work from our group indicated a continued influence of antigen on SMZL clones expressing IGHV1–2*04 receptors reflected in intraclonal diversification (ID) of rearranged IG heavy variable genes. Here we significantly extend our ID studies and explore whether IGHV1–2*04 SMZL are distinctive also in terms of ID compared to SMZL utilizing other IGHV genes. To this end, we performed a comprehensive subcloning analysis of IGHV-IGHD-IGHJ gene rearrangements in a total of 728 subcloned sequences from 39 SMZL cases, including 20 cases expressing IGHV1–2*04 receptors with a median identity to the germline (GI) of 98.7% and 19 cases utilizing other IGHV genes, namely IGHV1–18 (n=3), IGHV3–23 (n=6), IGHV3–30 (n=30), IGHV4–34 (n=3), IGHV4-4 (n=1) and IGHV5–51 (n=3), with a median GI of 97.9%. All non-ubiquitous sequence changes from the germline were evaluated and recorded as follows: (i) unconfirmed mutation (UCM) - a mutation observed in only one subcloned sequence from the same sample; (ii) confirmed mutation (CM) - a mutation observed in more than one but in less than all subcloned sequences from the same sample. In order to compare mutation counts between different rearrangements, mutations were normalized to both the nucleotide length and the number of subcloned sequences for each rearrangement. ID was identified in 17/20 (85%) IGHV1–2*04 rearrangements, with confirmed nucleotide substitutions ranging from 1 to 21 per case for a total of 77 unique substitutions. Of these, 51 resulted in the replacement of the germline-encoded amino acid (Replacement mutations, R), whereas the remaining 26 were silent (S). Certain codons (e.g: VH CDR1–36, VH FR2–39, VH FR3–87) were highly targeted for novel changes leading to ID. Interestingly, identical confirmed mutations were shared by subclones of different rearrangements confirming a remarkable restriction in the ongoing SHM profiles in that subclones shared identical confirmed mutations. In fact, 12 amino acid replacements were confirmed in the subclones of at least two rearrangements and were characterized as ”recurrent”. In contrast to IGHV1–2*04 rearrangements, only 8/19 (42%) rearrangements utilizing other IGHV genes showed imprints of ID (p=0.005). Moreover, the ID profiles of non-IGHV1–2*4 cases were different, as evidenced by both the lower numbers of confirmed mutations and the lack of shared mutations (per group of cases utilizing the same IGHV gene). In conclusion, continuous stimulation by antigen seems to be relevant not only for SMZL development but also for selection leading to clonal evolution, at least for a substantial proportion of cases. The extensive and distinctive ID observed in IGHV1–2*04 cases compared to cases utilizing other IGHV genes further supports the hypothesis that the former might constitute a distinct subgroup with important implications for both SMZL sub-classification and future clinical and biological research. Disclosures: No relevant conflicts of interest to declare.

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Ongoing Antigen Interactions In Splenic Marginal Zone Lymphoma: Revelations From The Analysis Of Intraclonal Diversification In Immunoglobulin Light Chain Genes

Blood ◽

10.1182/blood.v122.21.2999.2999 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2999-2999

Author(s):

Maria Karypidou ◽

Evangelia Stalika ◽

Panagiotis Baliakas ◽

Vasilis Bikos ◽

Zadie Davis ◽

...

Keyword(s):

Marginal Zone ◽

Conflicts Of Interest ◽

Marginal Zone Lymphoma ◽

Molecular Evidence ◽

Splenic Marginal Zone Lymphoma ◽

Gene Repertoire ◽

Nucleotide Substitutions ◽

Time Points ◽

Molecular Features ◽

Mutational Status

Abstract Immunogenetic studies have made seminal contributions towards understanding the pathogenesis of splenic marginal zone lymphoma (SMZL) by documenting a highly skewed immunoglobulin (IG) gene repertoire with molecular features strongly implicating selection by antigen(s) in disease ontogeny and evolution. Indeed, a major subset of SMZL, roughly 30% of the entire cohort, is defined by the expression of IG receptors with heavy variable domains (VH) utilizing the IGHV1-2*04 gene. These VH domains exhibit low-level, yet non-randomly targeted somatic hypermutation (SHM), carry long and often positively charged heavy complementarity-determining region 3 with restricted motifs, and also show biased associations with certain light IG genes, namely IGKV3-20, IGKV1-8 and IGLV2-14. We recently documented that the great majority of SMZL, especially IGHV1-2*04 cases, exhibit intraclonal diversification (ID) in IGHV genes, reflecting ongoing interactions with antigen(s). In this study we further extend the analysis of ID in SMZL focusing on IG light genes. To this end, we performed a comprehensive subcloning analysis of IGKV-IGKJ and IGLV-IGLJ gene rearrangements from 11 SMZL cases; two patients were studied at two different time-points. A total of 311 subcloned sequences (10-38/sample, median, 25) were obtained from 9 IGKV-IGKJ and 4 IGLV-IGLJ rearrangements. Multiple alignment of the subcloned sequences revealed that: (1) only one of 13 studied samples (7.8%) carried identical subclones (no ID); (2) 6/13 (46.1%) carried only unconfirmed mutations (UCMs, mutations in single subclones; unconfirmed ID); and, (3) 6/13 (46.1%) carried confirmed mutations (CMs, identical mutations in at least 2 subclones; confirmed ID). Both IGHV1-2*04 cases of the present series belonged to the confirmed ID category and both displayed intense ID with extensive subclone formation. Among cases positive for ID, the number of nucleotide substitutions introduced by ongoing SHM ranged from 1-21. A total of 66 unique substitutions were identified in 42 positions of the variable domain; 44 of these resulted in the replacement of the germline-encoded amino acid (R), while the remaining 22 were silent (S). The distribution of replacement and silent CMs and UCMs in CDRs and FRs was compatible with a canonical SHM process in that R/S ratios were higher in CDRs, except CDR2. In general, ID was more pronounced in IGKV-IGKJ versus IGLV-IGLJ rearrangements, regardless of the overall mutational load of each rearrangement. The analysis of the same rearrangement at different time-points revealed a consistent ID profile: one case carried only UCMs at both time-points, while the other (IGHV1-2*04 case) exhibited a dynamic pattern of appearing and disappearing CMs. Overall, the presence of mutations in the context of ID was independent of the mutational status, as ID was observed even in minimally mutated cases (98-99.9% germline identity). Moreover, in 3/6 cases with confirmed ID, subclones were classified in ≥2 main mutational groups, indicating early “branching” of the clonal population in subpopulations with distinct mutational profiles. In conclusion, the present study complements the immunogenetic profile of SMZL, offering novel molecular evidence for crosstalk with the microenvironment mediated through the clonotypic B-cell receptors. Furthermore, it underscores the significance of IG light chains in the immune pathogenesis of SMZL. Disclosures: No relevant conflicts of interest to declare.

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Acquired Angioedema due to C1 Inhibitor Deficiency Preceding Splenic Marginal Zone Lymphoma: Further Insights from Clinical Practice

International Archives of Allergy and Immunology ◽

10.1159/000509805 ◽

2020 ◽

Vol 181 (12) ◽

pp. 941-946

Author(s):

Mariana Paes Leme Ferriani ◽

Orlando Trevisan-Neto ◽

Julia S. Costa ◽

Janaina M.L. Melo ◽

Adriana S. Moreno ◽

...

Keyword(s):

Clinical Practice ◽

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Splenic Marginal Zone Lymphoma ◽

C1 Inhibitor ◽

C1 Inhibitor Deficiency ◽

Acquired Angioedema ◽

Risk Of Death ◽

Increased Risk

Background: Acquired angioedema due to C1 inhibitor deficiency (AAE-C1-INH) is a very rare disease. In clinical practice, it may be difficult to differentiate AAE-C1-INH from hereditary angioedema due to C1-INH deficiency (HAE-C1-INH). In both conditions, patients are at an increased risk of death from asphyxiation due to upper airway obstruction. The association of AAE-C1-INH with lymphoproliferative and autoimmune diseases, and with presence of anti-C1-INH antibodies has been well documented, and treatment of the underlying condition may result in complete remission of angioedema. Objectives: To discuss the clinical evaluation, diagnosis, and treatment outcomes of AAE-C1-INH in the context of the care of 2 patients with recurrent isolated angioedema. Methods: Two patients were followed up prospectively at our clinic. Measurements of C3, C4, C1-INH, and C1q levels were carried out by nephelometry, and the functional activity of C1-INH was determined by a chromogenic assay. Hematological investigation included morphological and immunophenotyping analysis of peripheral blood, bone marrow, and spleen histopathology. Sequencing of the 8 exons and adjacent intronic regions of the SERPING1 gene was performed using the Sanger method. Results: Two patients were diagnosed with AAE-C1-INH associated with splenic marginal zone lymphoma during follow-up. Conclusions: Close follow-up, including detailed clinical history, physical examination, and laboratory tests, of our patients with AAE-C1-INH was essential for the early diagnosis and successful treatment of the lymphoproliferative disease, leading to the resolution of the angioedema attacks.

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Increased Immunohistochemical CD138 Expression in Waldenström's Macroglobulinemia (WM) in Comparison with Splenic Marginal Zone Lymphoma (SMZL).

Blood ◽

10.1182/blood.v114.22.5008.5008 ◽

2009 ◽

Vol 114 (22) ◽

pp. 5008-5008

Author(s):

Tatiana K Tzenou ◽

G.A. Pangalis ◽

Georgia Levidou ◽

Christina Kalpadakis ◽

Spyros Siakavellas ◽

...

Keyword(s):

Bone Marrow ◽

B Lymphocytes ◽

Marginal Zone ◽

Plasma Cells ◽

Conflicts Of Interest ◽

Marginal Zone Lymphoma ◽

Lymphocytic Leukemia ◽

Splenic Marginal Zone Lymphoma ◽

Neoplastic Cells ◽

Bone Marrow Biopsies

Abstract Abstract 5008 Introduction Differentiating Waldenström's Macroglobulinemia (WM) from other lymphomas and especially Splenic Marginal Zone lymphoma (SMZL), which presents common features with WM, consists a challenge. There is no characteristic molecular abnormality neither for WM nor for SMZL, while in addition, serum IgM cut off is no longer used for the diagnosis of WM. Moreover, while paratrabecular and intrasinusoidal pattern of bone marrow infiltration are described as typical of WM and SMZL respectively, there is often overlap between them. B-lymphocytes' immunophenotype is usually CD5 and CD23 negative in both entities, although deviations from this pattern may be observed; CD38, a marker of lymphocyte activation, theoretically related to lymphoplasmacytic differentiation and adverse prognosis in Chronic Lymphocytic Leukemia, may be expressed. Both WM and SMZL are included among the least reproducible diagnoses of the WHO classification when the diagnosis is based only on clinical grounds, routine laboratory tests and bone marrow biopsy (absence of lymph node or spleen biopsy or typical leukemic picture). CD138 (Syndecan) is expressed in immature as well as in terminally differentiated B-lymphocytes, especially in plasma cells. A strong CD138 expression is observed in myeloma plasma cells. Aim To evaluate firstly whether CD138 is expressed in WM and SMZL and secondly if its expression may help in the differential diagnosis of these entities. Patients and methods 61 patients were studied at presentation, 40 with WM and 21 with SMZL. Among WM patients, 16 were females and 24 males with a median age of 64 years. 57% presented anemia with hemoglobin<12gr/lt, 12% lymphathenopathy and 5% splenomegaly. Among SMZL patients, there were 8 females and 13 males (median age 61 years). 70% presented anemia and 9% lymphathenopathy. In all 61 patients bone marrow was infiltrated by neoplastic cells. By definition, all WM patients had a monoclonal serum IgM paraprotein while 19% of SMZL patients secreted a serum monoclonal paraprotein, either IgM or IgG. Paraffin embedded sections of bone marrow biopsies performed at diagnosis, were stained with anti-CD138 monoclonal antibody, CD138 expression was evaluated in the bone marrow of all patients and comparison between the two patient groups was made. 10% CD 138 expression in bone marrow neoplastic cells was used as cut-off for the evaluation of positivity or negativity. Results 62% of WM patients presented CD138 expression in contrast with 14% of SMZL patients. Median percentage of total CD138 expression in neoplastic cells in WM was 26.5% (range 2-100%) while in SMZL it was 8% (range 0-30%). These differences were statistically significant (p<0.01). It is interesting to note that, 3 out of 4 SMZL patients who secreted IgM at low levels did not express CD138. Otherwise in WM patients CD138 expression correlated only with serum IgM levels. In addition it was observed that 68% of WM patients expressed CD38 by bone marrow lymphocyte flow cytometry compared to 5% of SMZL (p<0.01); however this finding was not related to CD138 immunohistochemical expression. Conclusions Patients with WM presented increased CD138 expression when compared to SMZL patients. If confirmed in larger series, CD138 expression could help differentiating the two entities. Disclosures No relevant conflicts of interest to declare.

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