Laryngeal Involvement of Multiple Myeloma

The objectives of this paper are to discuss a rare cause of laryngeal multiple myeloma, to review unique pathologic findings associated with plasma cell neoplasms, to discuss epidemiology, differential diagnosis, and treatment options for plasma cell neoplasms of the larynx. Laryngeal multiple myeloma, also noted in the literature as “metastatic” multiple myeloma, presenting as a de novo laryngeal mass is extremely rare with few reported cases. Laryngeal involvement of extramedullary tumors is reported to be between 6% and 18% with the epiglottis, glottis, false vocal folds, aryepiglottic folds, and subglottis involved in decreasing the order of frequency. We present the case of a 58-year-old male with a history of IgA smoldering myeloma who presented to a tertiary care laryngological practice with a two-month history of dysphonia, which was found to be laryngeal involvement of multiple myeloma. We review the classification of and differentiation between different plasma cell neoplasms, disease workups, pathologic findings, and treatment options

Gestión del conocimiento. Perspectiva multidisciplinaria. Volumen 17

El libro “Gestión del Conocimiento. Perspectiva Multidisciplinaria”, Volumen 17 de la Colección Unión Global, es resultado de investigaciones. Los capítulos del libro, son resultados de investigaciones desarrolladas por sus autores. El libro es una publicación internacional, seriada, continua, arbitrada, de acceso abierto a todas las áreas del conocimiento, orientada a contribuir con procesos de gestión del conocimiento científico, tecnológico y humanístico. Con esta colección, se aspira contribuir con el cultivo, la comprensión, la recopilación y la apropiación social del conocimiento en cuanto a patrimonio intangible de la humanidad, con el propósito de hacer aportes con la transformación de las relaciones socioculturales que sustentan la construcción social de los saberes y su reconocimiento como bien público

CD30 Expression in Diffuse Large B-Cell Lymphoma and Its Relation to Important Clinical and Biological Disease Features

Abstract Abstract 1592 Background: CD30 is a well-known diagnostic marker in both anaplastic large cell lymphoma (ALCL) and classical Hodgkin's lymphoma (CHL). Recently the chimeric drug brentuximab vedotin that combines an anti-CD30 monoclonal antibody with the anti-tubulin agent monomethyl auristatin E demonstrated activity in patients with relapsed ALCL and CHL. Previous observational studies have suggested that CD30 may be expressed in 10 to 20% of DLBCLs. It is possible that CD30+ DLBCLs may show different biologic behavior and be amenable to anti-CD30 therapy. The aim of this study was to determine the prevalence of CD30 expression in DLBCL by immunohistochemistry and explore possible relationships with important clinical and biologic variables of DLBCL. Methods: We retrospectively identified cases of DLBCL diagnosed between July 2003 and July 2012 at our institution. Eligible cases included patients with diagnosis of DLBCL irrespective of anatomic site or tumor stage. The diagnosis of DLBCL was based on the current WHO 2008 criteria. The following large B cell lymphoma subtypes were excluded from this analysis: post-transplant lymphoproliferative disorders with DLBCL morphology, Primary Mediastinal large cell lymphoma and the unclassifiable lymphomas with features intermediate between either DLBCL and Burkitt's lymphoma or between DLBCL and Hodgkin's lymphoma. Immunohistochemistry was performed as part of the routine workup of the cases (Monoclonal Mouse Anti-Human CD30, Dako) and CD30 was considered positive when ≥30% of neoplastic cells stained positive. DLBCLs were classified into germinal center (GC) or non-GC subtypes applying the Hans algorithm. Logistic regression analysis was performed to assess association between selected variables and CD30 expression. Results: A total of 333 cases of DLBCL were eligible for this study and of these 148 cases (44.4%) had CD30 results available. Selected demographic, clinical and histological characteristics were similar between cases on which CD30 IHC was performed compared to those in which CD30 IHC was not performed (data not shown), arguing against a selection bias in the performance of CD30 immunohistochemistry in these cases. Twenty-three percent (95% CI: 16.2% – 29.8%) of DLBCL tumors expressed CD30. CD30 expression was not significantly different between females and males (27.6% and 20.0% respectively, p = 0.28). The patients with CD30+ DLBCLs were 11.6 years younger than those with CD30- DLBCLs (95% CI: 5.3 – 17.9 years). The optimal cutoff age for CD30 expression was 47 years (ROC area under the curve: 0.70, p < 0.001). CD30 expression was more frequent in nodal and BCL2+ DLBCLs (Table 1). There was a non-significant difference between the expression of CD30 in non-GC type compared to GC type DLBCL with a pronounced trend for higher proportion of CD30 positivity in non-GC DLBCL (Table 1). CD30 expression was not significantly different in Epstein-Barr virus positive (EBV) compared to EBV negative DLBCLs (Table 1). Conclusions: CD30 is expressed in approximately 20% of all DLBCL and is more frequently expressed in younger patients and in BCL2+ DLBCLs. Although statistical significance was not reached, a trend towards more frequent CD30 expression in non-GC DLBCLs was observed. The increased expression of CD30 in the younger age group is intriguing, as other CD30+ neoplasms (CD30+ ALCL, CHL, and embryonal carcinoma) are also commonly observed in younger patients. The development of brentuximab vedotin and its well established effectiveness in other types of relapsed lymphomas opens the possibility of its applicability in CD30+ DLBCLs. Disclosures: No relevant conflicts of interest to declare

Clinical Features, Treatment Outcome, and Predictive Biomarkers In Adult T-Cell Leukemia/Lymphoma: University Of Miami Experience

Abstract Introduction Adult T-cell leukemia/lymphoma (ATLL) is a rare aggressive malignancy with a poor prognosis caused by HTLV-1. Miami is proximal to the Caribbean where HTLV-I is endemic, and we encounter a relatively high number of ATLL cases. Herein, we have performed the largest single institution retrospective analysis of ATLL patients (pts) to date in the U.S. We studied ATLL patient characteristics, treatment patterns, and disease outcome. In addition, we investigated the expression of IRF-4/MUM-1 in available specimens. Previously, our group demonstrated an association between lack of IRF-4/MUM-1 and response to AZT-interferon-alpha (AZT/IFNa) therapy in a small ATLL cohort. IRF-4/MUM-1 is a putative NF-kB target gene that encodes a transcription factor. IRF-4/MUM-1 expression has been associated with interferon resistance in preclinical studies, and is a poor prognostic marker in some lymphomas. One of our objectives is evaluate and validate IRF-4/MUM-1 as a potential biomarker for treatment selection and outcome in ATLL. Methods We analyzed 125 pts diagnosed with ATLL in UM/JMH between 1987 and 2013. We evaluated MUM-1 protein expression using immunohistochemistry (IHC) on either tissue sections, or cytospins prepared from CD4+-enriched peripheral blood leukemic specimens using 30% nuclear staining as a cut-off positive value, or by western blot (WB) analysis in some cases where fresh or DMSO preserved ATLL cells were not available. Kaplan-Meier survival curves, log-rank test where used for survival analysis. Mann-Whitney's U test was used to compare non-normally distributed continuous variables. Pearson's chi-squared or Fischer's exact tests were used to compare categorical variables. Results ATLL pts were 45% male and 55% female with a median age of 51 (17-91). The great majority of pts were Afro-Caribbean (82%), followed by U.S. African American (12%) and South American (6%). A total of 109 pts have been analyzed for treatment response so far, including 51 acute, 50 lymphomatous (L), 6 chronic (5 unfavorable), and 2 smoldering types. The median overall survival (OS) for acute and L was 6 and 10 months respectively, and not reached for chronic and smoldering types (figure 1). Fifty-six pts (34 acute, 14 L, 5 unfavorable chronic, 1 chronic, and 2 smoldering) were treated with high-dose AZT/IFNa as first line therapy. The complete and overall response rates (CR and ORR) after AZT/IFNa for acute/unfavorable chronic (A/UC) vs. L types were 25% vs. 0.7%, and 54% vs. 21% respectively. Seventy-seven pts received chemotherapy at some point during their treatment. The CR rate and ORR for A/UC vs. L-type pts treated with chemotherapy-based regimens were 40 % vs. 21%, and 70% vs. 77% respectively. However, we observed a significantly longer median progression-free survival (PFS) and sustained responses in pts with A/UC ATLL who achieved a CR with AZT/IFNa (168.1 wks), as compared to chemotherapy (61.1 wks), which translated into an overall survival benefit. Next, in order to determine whether IRF-4/MUM-1 predicted response to AZT/IFNa, 66 ATLL cases were analyzed by IHC and/or WB. The results showed that 38.5% of A/UC were IRF-4/MUM-1+ as compared to 82.1% in the L type (<P.0001). Evaluable pts for AZT/IFNa response demonstrated that 55% of A/UC MUM-1(-) cases had a CR as compared to 0% in MUM-1+ pts (P=.009). In the L group, AZT/IFNa responses were minimal and were mainly limited to stable disease. Subgroup analysis showed that median OS for MUM-1(-) vs. MUM-1+ in A/UC subtype was 38.4 wks vs. 27.6 wks (P=0.275) (figure 2), respectively. In the L subtype, median OS for MUM-1(-) vs. MUM-1+ was 25.7 wks vs. 60.3 wks (P=0.02) (figure 3), respectively. Finally, the median PFS in AZT/IFNa-treated A/UC pts favored the MUM-1(-) as compared to MUM-1+ cases. Conclusion Our data demonstrate that AZT/IFNa therapy is beneficial in leukemic type (A/UC) lacking IRF-4/MUM-1 expression, while L type is generally resistant to this treatment. On the other hand, IRF-4/MUM-1 expression is associated with a favorable outcome in L subtype. We have identified IRF-4/MUM-1 expression as a predictive marker that could be used in deciding upfront therapy (i.e. AZT/IFNa vs. standard chemotherapy) in leukemic ATLL subtypes. Our study findings must be confirmed and validated in a larger ATLL cohort. Disclosures: No relevant conflicts of interest to declare

CD30 Expression Is Associated With Decreased Survival In Patients With Acute and Unfavorable Chronic Types Of Adult T-Cell Leukemia-Lymphoma

Abstract Background Adult T-cell leukemia-lymphoma (ATLL) is a rare malignancy caused by the human T-lymphotropic virus type-1 (HTLV-I) which has a dismal prognosis, urging development of new therapeutic strategies. ATLL is commonly encountered in Miami due to its proximity to the Caribbean, where HTLV-I is endemic. CD30, a well-known marker of activated T-cells that participates in regulating memory cells, has been reported to be positively expressed at variable frequencies in ATLL cells, with positive expression rates ranging from 21- 50% of cases. The variation in reported CD30 expression rates is likely due to the heterogeneous nature of this neoplasm and inclusion of different ATLL subtypes within previous study populations. We hypothesized that the CD30 expression in ATLL was likely to differ based on the subtype of ATLL. Additionally, because CD30 is a molecule involved in multiple cell regulation and activation functions, predominantly through the NFKB signaling pathway, we predicted that CD30 could be a potential marker for prognosis and disease behavior in ATLL. We have conducted this study to evaluate the association that CD30 expression may have with ATLL disease subtype and survival in our population. The availability of targeted therapy (anti-CD30-monomethyl-auristatin-E conjugate brentuximab vedotin) makes identification of the role of CD30 expression in ATLL an important one, particularly as clinical trials using these therapies are currently underway. Design We conducted a historic cohort study of CD30 expression in cases of ATLL including patients of any age and at initial diagnosis. Cases were retrieved from our clinical and pathology information systems (UM/JMH). CD30 expression was evaluated by either immunohistochemistry (IHC) using antihuman CD30 monoclonal mouse antibody, clone Ber-H2, (Dako, Carpinteria, CA; IR602, Dilution: 1:30) performed on formalin-fixed paraffin-embedded tissue sections or on cytospins prepared from CD4+-enriched peripheral blood leukemic specimens, using 30% expression as a cut-off positive value. We analyzed overall CD30 expression, CD30 expression by sub-type and survival outcome according to CD30 expression. Kaplan-Meier survival curves, log-rank test and Cox proportional hazards regression where used for survival analysis. An alpha value of 0.1 was used for all statistical tests. Results Sixty-eight ATLL cases (lymphomatous n= 31, acute n=33, unfavorable chronic n=3, smoldering n=1) met inclusion criteria, and had CD30 status and complete clinical data available. The overall proportion of CD30+ ATLLs was 22.1% (95% CI 13.8% – 30.3%). The frequency of CD30 expression for each group is as follows: lymphomatous: 25.8%, acute: 21.2%, unfavorable chronic: 0%, smoldering: 0%. There was no significant difference for CD30 expression between the combined acute/unfavorable chronic (A/UC) subgroup and the lymphomatous subgroup (proportion difference 6.4%; CI 90% -10.52% – 23.24%). Within the A/UC subgroup the median survival for CD30+ patients was 10.1 weeks compared to 33.7 weeks for CD30- patients (P=0.071). CD30 expression was associated with a higher risk of death in patients within the A/UC subgroup (hazard ratio [HR]: 2.6, 90% CI: 1.1 – 6.2) (Figure 1A). Within the lymphomatous subgroup the median survival for CD30+ patients was 63.1 weeks compared to 60.3 weeks for CD30- patients (P=0.260) and there no association of CD30 status with the risk of death in the lymphomatous subgroup (HR: 0.6, 90% CI: 0.2 – 1.3) (Figure 1B). Conclusions Our data show that 22.1% of ATLL is CD30+ and that expression is similar amongst aggressive ATLL subtypes. CD30 could be a marker of prognosis in cases of acute or unfavorable chronic ATLL. CD30+ cases of any subtype are potentially amenable to anti-CD30 therapy. Targeted anti-CD30 therapy may be especially useful in CD30+ acute type ATLL, which carry the worst prognosis. Given the sample size, these results must be validated in a larger cohort. Disclosures: No relevant conflicts of interest to declare

Anaphylactic reaction to platelet transfusion as the initial symptom of an undiagnosed systemic mastocytosis: a case report and review of the literature

INTRODUCTION: The association between anaphylactic reactions and systemic mastocytosis is well documented. However, platelet transfusion has not previously been reported as a potential elicitor of anaphylaxis in the context of systemic mastocytosis. CASE PRESENTATION: We describe the clinicopathological findings of a 59-year-old Latin American man who presented to the emergency room with fatigue, leukocytosis, thrombocytopenia and mild hepatosplenomegaly. He developed two separate, temporally associated and severe anaphylactic reactions after receiving platelet transfusions. The result of a laboratory investigation for clerical errors and Coombs test was negative. Pre- and post-transfusion urine samples were negative for hemolysis. Bone marrow biopsy and aspirate smears performed demonstrated involvement by systemic mastocytosis, which had been previously undiagnosed. CONCLUSIONS: We posit the transfusion reaction to be an anaphylactic reaction to transfused products as a result of heightened allergic sensitivity due to the underlying systemic mastocytosis. To the best of our knowledge, this is the first reported case of a severe anaphylactic-type reaction to blood products occurring in the setting of a previously undiagnosed systemic mastocytosis. Furthermore, it seems there are no published studies closely examining the relationship between hematopoietic neoplasms and transfusion reactions in general

Early Detection of Myelodysplastic Syndromes: Maximizing the Utility of Automated Hematology

Abstract Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal myeloid disorders, affecting primarily older individuals and characterized by abnormal hematopoiesis, varying degrees of bone marrow failure, and an increased risk for transformation to acute myeloid leukemia (AML). Despite recent technical advances in diagnostic hematology, accurate diagnosis and staging of MDS still relies heavily on morphologic assessment of peripheral blood and bone marrow cells, usually by an experienced hematopathologist. Peripheral cytopenias and the presence of dysplastic changes are required in all cases, to consider a diagnosis of MDS. However, the initial assessment of dysplasia in peripheral blood cells by manual differential can often be subjective. Furthermore, important components of the CBC generated by modern analyzers and relevant to the morphologic properties of blood cells, are often overlooked. These factors may contribute to why the true incidence of MDS is under-estimated. We undertook a retrospective case-control study to evaluate MDS relevant parameters generated by automated cell counters at our institution, to fully exploit the potential for modern analyzers to assist in the diagnosis of MDS, and to assist in the diagnostic yield for these important and usually fatal diseases. Methods: We identified patients with MDS who had peripheral blood counts reported by theSysmexXN-3000 automated analyzer over a one year period (from 6/2015 to 6/2016). The modern Sysmex cell counter generates several parameters directly relevant to the morphologic properties of blood cells including standard deviation of red cell distribution width (RDW-SD), mean platelet volume (MPV), immature platelet fraction (IPF), reticulocyte hemoglobin (RET-HE), immature granulocytes (IG) and immature reticulocyte fraction (IRF). A control group was selected consisting of patients with normal blood counts reported by the same analyzer and generated during the study period. The study and control groups were matched in age, gender and ethnicity to reduce bias. All parameters generated by automated hematology testing were statistically compared between the two groups and significant differences were used to develop a predictive model. Statistical analysis was largely descriptive for patient demographics (age, gender, and race/ethnicity) and complete blood count (CBC) parameters. Counts and percentages were used to summarize the distribution of categorical variables and median, range, mean, and standard deviation were used for continuous variables. CBC parameters were compared by treatment group (MDS vs. Control) using two sample tests (t-test or binomial exact test). Results: Of a sample size of over 200 patients during the study period, there were 80 evaluable patients for this interim analysis and results are presented in tabulated form (see table below). In our sample, we confirmed what has been previously reported in the literature, as statistically significant parameters in correctly predicting an MDS diagnosis (iereduced hemoglobin [Hgb, p<0.0001], hematocrit [Hct, p<0.0001] , white cell [WBC, p<0.0001] and platelet counts [Plts, p<0.0001]; increased mean corpuscular volume [MCV, p<0.001], mean corpuscular hemoglobin [MCH, p<0.0001] and red cell distribution width [RDW p<0.0001]. In addition to these parameters, we also found that decreased red blood cell counts (RBC, p<0.0001), neutrophils (ANC, p<0.0001) and lymphocytes (ANL, p<0.0001) were important predictive abnormalities. The performance of a predictive model incorporating the parameters listed in addition to RDW-SD, MPV, IPF, RET-HE, IG and IRF will be presented. Conclusion: Maximizing the utility of new and improved automated hematology analyzer technologies for early detection of MDS will greatly benefit both clinicians and patients by facilitating earlier diagnosis of MDS, eliminating subjectivity in the initial assessment of dysplasia and promoting better use of results from minimally invasive peripheral blood collection. Table Statistical correlation between CBC parameters and their diagnostic utility in correcting predicting patients with MDS Table. Statistical correlation between CBC parameters and their diagnostic utility in correcting predicting patients with MDS Disclosures No relevant conflicts of interest to declare

Abstract LB-160: HDAC9 expression is deregulated in malignant B-cell lymphomas in particular in diffuse large B-cell lymphoma and mantle cell lymphoma.

Histone Deacetylase 9 (HDAC9) is a class IIa chromatin-modifying enzyme that, within the hematopoietic system, is preferentially expressed in the B-cell lineage. In our previous works, in order to identify HDAC9 function in the B cell lineage we developed mice that constitutively expressed human HDAC9 from early stages of B-cell development, under the control of the immunoglobulin heavy chain (IgH) enhancer. These mice developed lymphoproliferative disorders, including indolent Marginal Zone Lymphoma (MZL) and more aggressive post-Germinal Center (GC) lymphomas, demonstrating an oncogenic role for HDAC9 in B-cells. In order to examine the relationship between diseases observed in the mouse model and human primary lymphoma, we have examined, using immunohistochemistry (IHC) the expression of full length HDAC9 isoform in a panel of various B-cell malignancies from human tumor samples. The study group included 59 non-Hodgkin lymphomas (NHL), and 3 classical HL. Non-HL consisted of 34 diffuse large B cell lymphoma (DLBCL), 9 follicular lymphoma (FL), 5 marginal zone lymphoma (MZL), 6 mantle cell lymphoma (MCL), and 2 small lymphocytic lymphomas (SLL). HDAC9 expression was assessed by IHC using tissue microarray and/or routine tissue sections. Protein expression was scored as negative (0), low (1), or high (2) depending on the staining signal intensity. Expression of HDAC9 in the nuclei of the tumor cells was compared with that seen in adenocarcinoma cells; if equal or higher, then expression of HDAC9 was considered high and if lower, then expression of HDAC9 was considered low. Five reactive lymph nodes were studied to assess the baseline expression of HDAC9. Rectal adenocarcinomas were used as positive controls. In reactive lymph nodes, HDAC9 was weakly expressed in a subset of germinal center cells, a subset of lymphoid cells in the paracortex as well as in endothelial cells. HDAC9 expression was detected in all subsets of B-cell lymphomas analyzed and in most cases with a level of expression higher than those seen in reactive lymph nodes. DLBCL and MCL tumors had the highest frequency of high HDAC9 expression among the B-cell lymphomas analyzed, 77 and 83% (Fisher's exact test P = 1.0), respectively. No differences in HDAC9 expression were detected in DLBCL of GC and non-GC type. In contrast, most (69%) of the low-grade B cell lymphomas showed no or lower expression of HDAC9 (Fisher's exact test P = 0.004; as compared to DLBCL). Classical HL showed frequently low-expression of HDAC9 in the tumor cells. In summary, HDAC9 is frequently expressed in B-cell lymphomas with the highest level of expression found in the most aggressive lymphomas such as DLBCL and MCL. These findings support the biological role of HDAC9 in the pathobiology of aggressive B cell neoplasms and highlight the need to further study HDAC9 function in these malignancies as well as its importance as a therapeutic target