Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs ...of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes.
The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases.
In front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p < 0.0001) and progression-free survival (PFS, p < 0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes (p < 0.0001 for OS and p = 0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort.
The outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL.
Summary Poly(ADP-ribose) polymerase-1 (PARP-1) and Bcl-2 are emerging as therapeutic targets in various cancers. The former is a DNA repair protein associated with genomic stability and apoptosis, ...whereas the latter is an antiapoptotic protein having a DNA repair function through inhibition of PARP-1. Because genomic stability is critical for prognosis in B-lymphoblastic leukemia/lymphoma (B-ALL), we studied the expression of PARP-1 and Bcl-2 proteins in patients with B-ALL of different ages and compared the results with cytogenetic data. The PARP-1 protein was overexpressed in about two-thirds (61%) of patients with B-ALL. It had a nuclear location, whereas Bcl-2 protein was cytosolic. Expression of the 2 proteins showed a highly positive correlation ( ρ = 0.367; P < .001). Overexpression of PARP-1 correlated with a complex karyotype ( P = .030), and this correlation remained significant for coexpression of PARP-1 and Bcl-2 proteins ( χ2 = 7.498; P = .024) as well as after exclusion of pediatric patients (n = 9, P = .042). Overexpression of PARP-1 was not significantly more common in diploid versus aneuploid karyotypes (50% versus 59%, P = .610). The PARP-1 protein showed no correlation with specific chromosomal abnormalities associated with prognosis in B-ALL, as defined by the World Health Organization. In conclusion, high expression of the PARP-1 protein among patients with B-ALL is related to a complex karyotype and Bcl-2 positivity. Although these findings require validation in a larger population, the observations will be valuable in planning therapeutic trials (such as of PARP inhibitors and BH3 mimetics).
Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of non-Hodgkin lymphoma that shares features with diffuse large B-cell lymphoma (DLBCL). While significant progress has been made in ...treating DLBCL, the prognosis for PBL remains poor, highlighting the need to identify new therapeutic targets. Using RNA expression analysis, we compared the expression of genes involved in the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways between PBL and DLBCL. We used critical PI3K (n = 201) and MAPK (n = 57) signaling probe sets to achieve this objective. Our results demonstrate unique molecular mechanisms underlying PBL pathogenesis compared to DLBCL, particularly within the PI3K and MAPK signaling pathways. We found that elevated STAT3 expression in PBL correlates with hyperactive MAPK and PI3K pathways, unlike DLBCL. Additionally, the hyperactivation of the PI3K signaling axis in PBL is unrelated to B-cell receptor or phosphatase and tensin homolog activity, indicating a distinct mechanism compared to DLBCL. Furthermore, we observed unique activation patterns in MAPK pathways between PBL and DLBCL, with PBL exhibiting high expression of the neurotrophic tyrosine kinase receptor (NTKR) family, specifically NTRK1 and NTRK2 genes, which have therapeutic potential. We also found that neither human immunodeficiency virus nor Epstein–Barr virus infection influences gene expression profiles linked to PI3K and MAPK signaling in PBL. These findings could lead to adapting targeted therapies developed for DLBCL to address the specific needs of PBL patients better and contribute to developing novel, targeted therapeutic strategies to improve patient outcomes.
•Plasmablastic lymphoma (PBL) has dismal prognosis with limited therapeutic options.•PI3K / MAPK genomic mutations in PBL are linked with poor clinical outcome.•RNA expression analysis of PI3K and MAPK molecules defined unique molecular patterns.•Our findings contribute to developing novel, targeted therapeutic strategies for PBL patients.
In situ follicular B-cell neoplasm (ISFN) is a variant of follicular lymphoma, presenting as an incidental histologic finding in lymph node biopsy or excisional specimens. ISFN presents with a B-cell ...population that strongly expresses BCL2 and CD10 within the germinal centers of a lymph node or extranodal site. Genetic analysis shows t(14;18) translocation. Herein, we report a case of ISFN presenting as military and agminated facial papules in a young woman, which resolved spontaneously in the postpartum period. To our knowledge, this is the only report of a cutaneous site of involvement of this rare entity.
Background: Red blood cell (RBC) analysis is a key feature in the evaluation of hematological disorders. The gold standard light microscopy technique has high sensitivity, but is a relativity ...time-consuming and labor intensive procedure. This study tested the sensitivity and specificity of gold standard light microscopy manual differential to the CellaVision® DM96 (CCS; CellaVision, Lund, Sweden) automated image analysis system, which takes digital images of samples at high magnification and compares these images with an artificial neural network based on a database of cells and preclassified according to RBC morphology. Methods: In this study, 212 abnormal peripheral blood smears within the Calgary Laboratory Services network of hospital laboratories were selected and assessed for 15 different RBC morphologic abnormalities by manual microscopy. The same samples were reassessed as a manual addition from the instrument screen using the CellaVision® DM96 system with 8 microscope high power fields (×100 objective and a 22 mm ocular). The results of the investigation were then used to calculate the sensitivity and specificity of the CellaVision® DM96 system in reference to light microscopy. Results: The sensitivity ranged from a low of 33% (RBC agglutination) to a high of 100% (sickle cells, stomatocytes). The remainder of the RBC abnormalities tested somewhere between these two extremes. The specificity ranged from 84% (schistocytes) to 99.5% (sickle cells, stomatocytes). Conclusions: Our results showed generally high specificities but variable sensitivities for RBC morphologic abnormalities.
Summary We describe 3 unusual B-cell non–Hodgkin's lymphomas in which the entire tumors histologically mimicked marginal zone B-cell lymphoma. All patients were male (mean age, 65 years). Excisional ...biopsy from lymph node (2 of 3) and parotid gland (1 of 3) showed proliferation of monocytoid B-cells with plasmacytoid features (2 of 3) and conspicuous absence of large lymphoma cells (3 of 3). By immunohistochemistry, cyclin D1 was positive (3 of 3), CD23 was negative (3 of 3), and aberrant expression of CD5/CD43 was present in 1 case. Ki67 labeling was greater than 50% in 1 case and 10% to 25% in the other 2 cases. Evidence of the t(11;14) was detectable in all by molecular techniques. One patient died within 15 months, and the other 2 patients had widely disseminated diseases at the last follow-up (8 months). Based on these features, we believed that the best classification for these lesions is the marginal zone B-cell lymphoma–like mantle cell lymphoma.
Familial Hodgkin Lymphoma (HL) accounts for 4.5% of HL. Both genetic susceptibility and shared environmental factors can play a role. The usual presentation of HL is cervical lymphadenopathy/ ...mediastinal mass. Subdiaphragmatic presentation is rare and hepatosplenomegaly is associated with advanced HL.
Adenosine deaminase 2 (ADA2) act as an outside extracellular growth factor for integrity of endothelial cells and in the development of certain immune cells. Deficiency of ADA2 (DADA2) is a recently described inborn error of immunity caused by biallelic mutations in adenosine deaminase 2 (ADA2) gene (formerly known as CECR1). It is an auto-inflammatory disorder with a spectrum of vascular, inflammatory, hematological and immunodeficiency phenotypes. The condition is inherited in an autosomal recessive pattern.The association of DADA2 with lymphoproliferation such asT-LGL like condition and ALPS like disease have been reported, however, HL has not previously been reported in DADA2.
Herein we describe two siblings with DADA2 who presented with Hodgkin Lymphoma. The first patient is the third child of Saudi first degree related parents. He is known to have bronchial asthma on bronchodilators. At the age of 5 years, he was referred from primary care clinic for investigation of hepatosplenomegaly. He was otherwise well with growth along the fifth centile. His complete blood count (CBC) showed mild lymphopenia, other lab results including liver function tests were within normal. Few months later, he developed non-tender mobile cervical lymph nodes enlargement. Viral serology including EBV was negative based on PCR testing. Lymph node biopsy revealed the diagnosis of HL, mixed cellularity type, EBV negative (Figure 1). Whole exome analysis sequencing identified a homozygous variant in ADA2 gene c.1447_1451del. This variant has been confirmed by Sanger sequencing. Plasma assay of ADA2 enzyme activity revealed undetectable levels compatible with ADA2 deficiency.
The patient started on prednisone 2 mg/kg/day, which showed good response in the form of being off blood support and regression of splenomegaly. Few months later, the course was complicated by recurrent infections. The patient remained stable for three years on small dose of prednisone, monthly IVIG due to hypogammaglobulinemia. Recently, etanercept was started to control disease progression.
Nine months after the diagnosis of first patient, his younger brother who is known to have mild bronchial asthma on bronchodilators presented at the age of five years with hepatosplenomegaly and generalized lymphadenopathy. Lymph node biopsy revealed the diagnosis of classical HL, lymphocyte-rich subtype. Similar to his sibling, whole exome analysis identified the same mutation (a homozygous variant in ADA2 gene c.1447_1451del). This variant has been confirmed by Sanger sequencing and plasma level of ADA2 enzyme activity was undetectable. After the diagnosis of DADA2, screening for serum immunoglobulin levels showed hypogammaglobulinemia. The patient continues to be off treatment. Both patients were treated with chemotherapy with or without radiotherapy showing good response and they remained in remission at respectively and months after cessation of chemotherapy.
This study is important for several reasons. First, this is the first report of HL in the context of DADA2. This again widens the clinical spectrum of DADA2. Interestingly, the boys presented two different forms of HL at the cellular level with no evidence of viral infection. The reported siblings presented with subdiaphragmatic diseases, which is uncommon in HL but in line with the sites of lymphoproliferation in DADA2. In addition, the age of presentation in the two siblings is uncommon in HL (less than 10 years).
Second, we report an novel mutation in ADA2 gene. It creates a shift in the reading frame starting at codon Ser483. The new reading frame ends in a stop codon 4 positions downstream. This description and the description of the HL occurrence further expands the spectrum of DADA2. Our data, call for judicious exclusion of ADA2 deficiency in the HL patient with an aberrant course and additional symptoms / signs.
In summary, we report familial HL in two patients with a novel deleterious mutation in ADA2 gene. This expands the spectrum of this disease to include cancer and should alert the hemato-oncologist to the possibility of DADA2 as an underlying diagnosis in HL.
No relevant conflicts of interest to declare.
Context: Many hematology laboratories have adopted semi-automated digital platforms for routine use and the evidence supporting their use is increasing. Aims: The CellaVision platforms are among the ...most thoroughly studied digital hematology platforms; we wished to determine the accuracy of CellaVision for reticulocyte counting. Design, Materials and Methods: We compared reticulocyte counts performed manually, using the Beckman Coulter LH750 automated analyzer and with the CellaVision DM96 platform. We analyzed the results for pair-wise correlation and bias, and precision. Statistical Analyses Used: Analyses were performed using Statistical Package for the Social Sciences software (SPSS), including Spearman’s rho correlation coefficient, Friedman’s two-way Analysis Of Variance (ANOVA) for comparison of distributions; bias was compared by way of mean and standard deviation. Results: The CellaVision reticulocyte counts correlated most strongly with those of the analyzer (often considered the benchmark test); the reticulocyte count distributions were noted not to be significantly different from each other across all three methods. The mean and standard deviation of bias were lowest in the comparison of CellaVision and LH750 counts. Conclusions: Our data provide additional support for the accuracy of digital hematology applications using the CellaVision DM96 platform.
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