ABSTRACT
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by a chronic inflammatory state that plays a relevant role in the disease pathogenesis (as proven by high levels of inflammatory cytokines with prognostic significance and by a persistent oxidative stress) and by extensive neoangiogenesis in bone marrow (BM) and spleen. Myeloid-derived suppressor cells (MDSCs) are immature cells that expand in patients with cancer, sepsis or chronic inflammation, favoring tumor onset and progression mainly through the decrease in immune surveillance and the promotion of neoangiogenesis. In this paper, we evaluated the presence of circulating MDSCs in PMF patients, the plasmatic factors involved in their mobilization/expansion and the correlations with laboratory, genetic and clinical parameters. The data indicated that MDSCs could have a relevant role in PMF as a new pathogenic mechanism contributing to explaining the phenotypic diversity observed during the clinical course of the disease, or a potential new target for personalized treatment.
ABSTRACT
Hereditary thrombocytosis (HT) is a rare inherited disorder with clinical features resembling those of sporadic essential thrombocythemia. This study included 933 patients with persistent isolated thrombocytosis for whom secondary reactive causes were excluded. Of 933 patients screened, 567 were JAK2-mutated, 255 CALR-mutated, 41 MPL-mutated, 2 double-mutated, and 68 were triple-negative. Two patients carried germline non-canonical mutations in exon 10: MPL W515* and MPL V501A. One triple-negative patient carried another germline non-canonical MPL mutation outside exon 10: MPL R102P. As germline MPL mutations may be underlying causes of HT, we recommend screening patients with triple-negative isolated thrombocytosis for non-canonical MPL mutations. Although clear evidence concerning HT treatment is still lacking, individuals with HT should probably be excluded from cytoreductive treatment. Thus, an accurate diagnosis is pivotal in avoiding unnecessary treatments.
Subject(s)
Receptors, Thrombopoietin , Thrombocytosis , Humans , Receptors, Thrombopoietin/genetics , Receptors, Thrombopoietin/metabolism , Calreticulin/genetics , Thrombocytosis/genetics , Mutation , Janus Kinase 2/genetics , Germ Cells/metabolismSubject(s)
Mastocytosis, Systemic , Ultraviolet Therapy , Humans , Child , Mastocytosis, Systemic/radiotherapy , Treatment Outcome , PhototherapyABSTRACT
Systematic studies of germ line genetic predisposition to myeloid neoplasms in adult patients are still limited. In this work, we performed germ line and somatic targeted sequencing in a cohort of adult patients with hypoplastic bone marrow (BM) to study germ line predisposition variants and their clinical correlates. The study population included 402 consecutive adult patients investigated for unexplained cytopenia and reduced age-adjusted BM cellularity. Germ line mutation analysis was performed using a panel of 60 genes, and variants were interpreted per the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines; somatic mutation analysis was performed using a panel of 54 genes. Of the 402 patients, 27 (6.7%) carried germ line variants that caused a predisposition syndrome/disorder. The most frequent disorders were DDX41-associated predisposition, Fanconi anemia, GATA2-deficiency syndrome, severe congenital neutropenia, RASopathy, and Diamond-Blackfan anemia. Eighteen of 27 patients (67%) with causative germ line genotype were diagnosed with myeloid neoplasm, and the remaining with cytopenia of undetermined significance. Patients with a predisposition syndrome/disorder were younger than the remaining patients and had a higher risk of severe or multiple cytopenias and advanced myeloid malignancy. In patients with myeloid neoplasm, causative germ line mutations were associated with increased risk of progression into acute myeloid leukemia. Family or personal history of cancer did not show significant association with a predisposition syndrome/disorder. The findings of this study unveil the spectrum, clinical expressivity, and prevalence of germ line predisposition mutations in an unselected cohort of adult patients with cytopenia and hypoplastic BM.
Subject(s)
Anemia, Aplastic , Genetic Predisposition to Disease , Germ Cells , Leukemia, Myeloid , Humans , Leukemia, Myeloid/genetics , Clonal Hematopoiesis , Male , Female , Middle Aged , Anemia, Aplastic/genetics , Penetrance , DNA Mutational AnalysisABSTRACT
INTRODUCTION: Philadelphia-negative myeloproliferative neoplasms (MPN) are clonal myeloid proliferative disorders characterized by sustained systemic inflammation. Despite its renowned importance, the knowledge concerning the inflammatory pathophysiology of these conditions is currently limited to studies on serum cytokines, while cellular immunity has rarely been investigated. METHODS: In the present study, we targeted Arginase-1 immunosuppressive myeloid cells in the bone marrow of MPN patients and healthy controls and investigated their clinical and prognostic significance. We demonstrated that MPN are characterized by a significant reduction of bone marrow immunosuppressive cells and that the number of these cells significantly correlates with several clinical and histopathological features of diagnostic and prognostic importance. Moreover, we identified an unreported correlation between a reduction of Arginase-1+ bone marrow cells and the presence of CALR mutations, linking tumor-promoting immunity and molecular drivers. Finally, we postulate that the reduction of bone marrow Arginase-1+ immunosuppressive cells may be due to the migration of these cells to the spleen, where they may exert systemic immunomodulatory function. CONCLUSION: Altogether, this study preliminary investigated the contribution of cellular immunity in the pathogenesis of myeloproliferative neoplasms and identified a possible interesting therapeutic target as well as a set of new links that may contribute to unraveling the biological mechanisms behind these interesting hematological neoplasms.
Subject(s)
Hematologic Neoplasms , Myeloproliferative Disorders , Humans , Bone Marrow/pathology , Arginase/genetics , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/pathology , Myeloid Cells , Fibrosis , MutationABSTRACT
Clonal cytopenia of undetermined significance (CCUS) is associated with an increased risk of developing a myeloid neoplasm with myelodysplasia (MN). To identify the features of the mutant clone(s) that is associated with clinical phenotype and progression, we studied the following cohorts of individuals: 311 patients with idiopathic cytopenia of undetermined significance (ICUS), 532 community-dwelling individuals without hematologic phenotype (n = 355) or with unexplained anemia (n = 177), and 592 patients with overt MN. Ninety-two of 311 (30%) patients with ICUS carried a somatic genetic lesion that signaled CCUS. Clonal hematopoiesis (CH) was detected in 19.7% and 27.7% of nonanemic and anemic community-dwelling individuals, respectively. Different mutation patterns and variant allele frequencies (VAFs) (clone metrics parameters) were observed in the conditions studied. Recurrent mutation patterns exhibited different VAFs associated with marrow dysplasia (0.17-0.48), indicating variable clinical expressivity of mutant clones. Unsupervised clustering analysis based on mutation profiles identified 2 major clusters, characterized by isolated DNMT3A mutations (CH-like cluster) or combinatorial mutation patterns (MN-like cluster), and showing different overall survival (HR, 1.8). In patients with CCUS, the 2 clusters had different risk of progression to MN (HR, 2.7). Within the MN-like cluster, distinct subsets with different risk of progression to MN were identified based on clone metrics. These findings unveil marked variability in the clinical expressivity of myeloid driver genes and underline the limitations of morphologic dysplasia for clinical staging of mutant hematopoietic clones. Clone metrics appears to be critical for informing clinical decision-making in patients with clonal cytopenia.
Subject(s)
Clonal Hematopoiesis , Adult , Aged , Aged, 80 and over , Cohort Studies , DNA Methyltransferase 3A/genetics , Female , Gene Frequency , Humans , Male , Middle Aged , Mutation , Young AdultSubject(s)
COVID-19 , Vasculitis , COVID-19 Vaccines , Humans , RNA, Messenger , SARS-CoV-2 , Vasculitis/chemically induced , Vasculitis/diagnosisSubject(s)
Down Syndrome , GATA1 Transcription Factor , Leukemia, Megakaryoblastic, Acute , Down Syndrome/complications , Down Syndrome/diagnosis , Down Syndrome/genetics , Female , Fetus , GATA1 Transcription Factor/genetics , Humans , Leukemia, Megakaryoblastic, Acute/diagnosis , Leukemia, Megakaryoblastic, Acute/genetics , Mutation , Pregnancy , Pregnancy Trimester, Second , Stillbirth , TrisomyABSTRACT
PURPOSE: Breast lesions classified as of "uncertain malignant potential" represent a heterogeneous group of abnormalities with an increased risk of associated malignancy. Clinical management of B3 lesions diagnosed on vacuum-assisted breast biopsy (VABB) is still challenging: surgical excision is no longer the only available treatment and VABB may be sufficient for therapeutic excision. The aim of the present study is to evaluate the positive predictive value (PPV) for malignancy in B3 lesions that underwent surgical excision, identifying possible upgrading predictive factors and characterizing the malignant lesions eventually diagnosed. These results are compared with a subset of patients with B3 lesions who underwent follow-up. METHODS: A total of 1250 VABBs were performed between January 2006 and December 2017 at our center. In total, 150 B3 cases were diagnosed and 68 of them underwent surgical excision. VABB findings were correlated with excision histology. A PPV for malignancy for each B3 subtype was derived. RESULTS: The overall PPV rate was 28%, with the highest upgrade rate for atypical ductal hyperplasia (41%), followed by classical lobular neoplasia (29%) and flat epithelial atypia (11%). Only two cases of carcinoma were detected in the follow-up cohort, both associated with atypical ductal hyperplasia at VABB. CONCLUSION: Open surgery is recommended in case of atypical ductal hyperplasia while, for other B3 lesions, excision with VABB only may be an acceptable alternative if radio-pathological correlation is assessed, if all microcalcifications have been removed by VABB, and if the lesion lacks high-risk cytological features. KEY POINTS: ⢠Surgical treatment is strongly recommended in case of ADH, while the upgrade rate in case of pure FEA, especially following complete microcalcification removal by VABB, may be sufficiently low to advice surveillance as a management strategy. ⢠The use of 11-G- or 8-G-needle VABB, resulting in possible complete diagnostic excision of the lesion, can be an acceptable alternative in case of RS, considering open surgery only for selected high-risk patients. ⢠LN management is more controversial: surgical excision may be recommended following classical LN diagnosis on breast biopsy if an additional B3 lesion is concurrently detected while in the presence of isolated LN with adequate radiological-pathological correlation follow-up alone could be an acceptable option.
Subject(s)
Breast Neoplasms , Carcinoma, Intraductal, Noninfiltrating , Breast/diagnostic imaging , Breast/surgery , Breast Neoplasms/surgery , Humans , Image-Guided Biopsy , Mammography , Predictive Value of Tests , Retrospective StudiesABSTRACT
Impaired immune responses have been hypothesised to be a possible trigger of unfavourable outcomes in coronavirus disease 2019 (COVID-19). We aimed to characterise IgM memory B cells in patients with COVID-19 admitted to an internal medicine ward in Northern Italy. Overall, 66 COVID-19 patients (mean age 74 ± 16.6 years; 29 females) were enrolled. Three patients (4.5%; 1 female) had been splenectomised and were excluded from further analyses. Fifty-five patients (87.3%) had IgM memory B cell depletion, and 18 (28.6%) died during hospitalisation (cumulative incidence rate 9.26/100 person-week; 5.8-14.7 95% CI). All patients who died had IgM memory B cell depletion. A superimposed infection was found in 6 patients (9.5%), all of them having IgM memory B cell depletion (cumulative incidence rate 3.08/100 person-week; 1.3-6.8 95% CI). At bivariable analyses, older age, sex, number of comorbidities, and peripheral blood lymphocyte count < 1500/µl were not correlated with IgM memory B cell depletion. A discrete-to-marked reduction of the B-cell compartment was also noticed in autoptic spleen specimens of two COVID-19 patients. We conclude that IgM memory B cells are commonly depleted in COVID-19 patients and this correlates with increased mortality and superimposed infections.
Subject(s)
B-Lymphocytes/cytology , COVID-19/mortality , Hospital Mortality , Immunologic Memory/immunology , Lymphocyte Depletion , Adult , Aged , Aged, 80 and over , B-Lymphocyte Subsets/cytology , B-Lymphocyte Subsets/immunology , B-Lymphocytes/immunology , COVID-19/pathology , Female , Humans , Immunoglobulin M/blood , Longitudinal Studies , Lymphocyte Count , Male , Middle Aged , Prospective Studies , SARS-CoV-2/immunology , Spleen/cytology , Spleen/immunologyABSTRACT
Non-chronic lymphocytic leukemia (non-CLL) clonal B-cell lymphocytosis (CBL) encompasses a heterogeneous group of hematologic disorders that are still poorly understood. To shed light on their biological aspects, we retrospectively analyzed a highly selected series of 28 patients, who had a clonal B-cell population in the peripheral blood and in the bone marrow, without evidence of lymphoma. Extended targeted next-generation sequencing revealed wide molecular heterogeneity with MYD88 (14%), PDE4DIP (14%), BIRC3 (11%), CCND3 (11%), NOTCH1 (11%), and TNFAIP3 (11%) as the most mutated genes. Mutations of MYD88 were "nonclassic" in most cases. Although some genetic lesions were overlapping with indolent lymphomas, mainly splenic B-cell lymphomas of marginal zone origin and splenic diffuse red pulp small B-cell lymphoma, the genetic profile of our non-CLL CBL series seemed to suggest that various pathways could be involved in the pathogenesis of these disorders, not mirroring any specific lymphoma entity. These data better enlighten the molecular characteristics of non-CLL CBL; however, more efforts are needed in order to improve the diagnostic process, prognostication, and clinical management.
Subject(s)
Biomarkers, Tumor , Genetic Heterogeneity , High-Throughput Nucleotide Sequencing , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Aged , Alleles , Disease Susceptibility , Female , Gene Expression , Genetic Predisposition to Disease , Humans , Immunoglobulin Heavy Chains/genetics , Immunohistochemistry , Immunophenotyping , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Male , Middle Aged , MutationABSTRACT
Lymphoplasmacytic lymphoma (LPL) is usually associated with a serum IgM paraprotein, corresponding to Waldenström's Macroglobulinemia (WM). Cases presenting with IgG or IgA, or without a monoclonal protein are extremely rare. We analyzed clinical characteristics, frontline treatment, and the outcome of 45 patients with non-IgM LPL, and compared them with a control group of WM patients. The median age was similar, with significantly higher prevalence of females in non-IgM LPL, than in WM patients (60% vs 39%, P = .016). Patients with non-IgM LPL more frequently presented with lymphadenopathies (53% vs 15%, P < .001), splenomegaly (22% vs 8%, P = .015) or extranodal involvement (20% vs 8%, P = .05). In non-IgM LPL a serum monoclonal protein and bone marrow infiltration were less common than in WM patients (69% and 84% of cases respectively, P < .001 for both comparisons). The MYD88 (L265P) mutation was found in 8/19 patients using allele-specific polymerase chain reaction. A CXCR4 mutation was found in 4/17 cases using Sanger. In 16 patients we performed targeted next-generation sequencing of genes MYD88, CXCR4, ARID1-A, KMT2D, NOTCH2, TP53, PRDM1, CD79B, TRAF3, MYBBP1A, TNFAIP3. Seven patients (44%) had a MYD88 mutation (S219C in one), four (25%) a CXCR4 mutation, three (19%) a KMT2D mutation, one (6%) a TP53 mutation and one (6%) a TRAF3 mutation. With a median follow-up of 55.7 months, 36 non-IgM LPL patients (80%) were treated. Non-IgM LPL patients received more frequently anthracycline-containing regimens, as compared with WM patients, who mainly received alkylating-based therapies. Five-year overall survival (OS) was 84%, similar to that of WM patients.
Subject(s)
Paraproteins/analysis , Waldenstrom Macroglobulinemia/epidemiology , Adult , Aged , Aged, 80 and over , Anthracyclines/administration & dosage , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow/pathology , Female , Follow-Up Studies , Humans , Italy/epidemiology , Kaplan-Meier Estimate , Lymph Nodes/pathology , Male , Middle Aged , Mutation , Myeloid Differentiation Factor 88/genetics , Neoplasm Proteins/genetics , Progression-Free Survival , Receptors, CXCR4/genetics , Sex Distribution , Waldenstrom Macroglobulinemia/blood , Waldenstrom Macroglobulinemia/drug therapy , Waldenstrom Macroglobulinemia/geneticsABSTRACT
IgM monoclonal gammopathies of undetermined significance (IgM MGUS) are associated with a risk of progression to Waldenström macroglobulinaemia (WM) or other lymphoproliferative disorders (LPD) of 1-2% per year. We analysed 176 consecutive patients with IgM MGUS to evaluate risk factors for progression. With a median follow-up of 83 months (1214 person-years), 15 patients (8·5%) progressed to WM (n = 14) or marginal zone lymphoma (n = 1). The rate of progression was 1·32% per year (95% confidence interval [CI] 0·80-2·20). The serum monoclonal protein concentration and the MYD88 mutation were independent risk factors for progression (Hazard ratio [HR] 23·3, 95% CI 2·0-273·3, P = 0·012 and HR 24·4, 95% CI 2·2-275·3, P = 0·010, respectively). The cumulative incidence of progression, while considering death as a competing event, was 11·6% at 5 years and 38·0% at 10 years in MYD88-mutated patients with a serum monoclonal protein of 10 g/l or higher, as compared with 0% at 5 years and 1·1% at 10 years for patients with none or one risk factor. This risk-stratification model is able to identify a subset of patients with IgM MGUS at high risk of progression to WM or LPD who deserve a lifelong follow-up.
Subject(s)
Disease Progression , Lymphoproliferative Disorders/etiology , Monoclonal Gammopathy of Undetermined Significance/diagnosis , Myeloid Differentiation Factor 88/genetics , Myeloma Proteins/analysis , Waldenstrom Macroglobulinemia/etiology , Adult , Aged , Female , Humans , Immunoglobulin M , Male , Middle Aged , Monoclonal Gammopathy of Undetermined Significance/blood , Monoclonal Gammopathy of Undetermined Significance/pathology , Mutation , Risk Assessment/methods , Risk FactorsABSTRACT
Diagnostic criteria for hypoplastic myelodysplasic syndrome (h-MDS) have not been clearly established, making the differential diagnosis from other bone marrow failure syndromes (BMF) challenging. In this study, we aimed to delineate clinical, histopathological, and molecular features of h-MDS, based on a large and well-annotated cohort of patients with bone marrow (BM) hypocellularity. The study included 534 consecutive adult patients with hypocellular BM (278 h-MDS and 136 aplastic anemia), and 727 with normo- or hypercellular MDS (n-MDS). Comparison of clinical features of patients with h-MDS as defined by BM cellularity ≤25% (n = 204) or reduced age-adjusted cellularity (n = 74) did not reveal significant differences. We developed a diagnostic score to discriminate h-MDS from non-malignant BMF based on histological and cytological variables with the highest specificity for MDS (h-score). The information from chromosomal abnormalities and somatic mutation patterns was then integrated into a cyto-histological/genetic score (hg-score). This score was able to segregate two groups of h-MDS with a significantly different risk of blast progression (P < 0.001). The integration of cyto-histological and genetic features in adult patients with hypocellular BM facilitated segregation into two distinct groups, one with clinical and genetic features highly consistent with myeloid neoplasm, and one with features more consistent with non-malignant BMF.
Subject(s)
Myelodysplastic Syndromes/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Anemia, Aplastic/pathology , Bone Marrow/pathology , Chromosome Aberrations , Cohort Studies , Diagnosis, Differential , Female , Humans , Karyotyping , Male , Middle Aged , Young AdultSubject(s)
Lymphoma, B-Cell , Myeloproliferative Disorders , Pyrazoles/administration & dosage , Female , Follow-Up Studies , Humans , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/mortality , Male , Myeloproliferative Disorders/drug therapy , Myeloproliferative Disorders/mortality , Nitriles , Pyrimidines , Risk FactorsABSTRACT
Telangiectasia macularis eruptiva perstans (TMEP) is a rare form of cutaneous mastocytosis (CM). Although TMEP has been traditionally thought to be restricted to the skin, a recent retrospective multicentric study established a diagnosis with systemic involvement of mastocytosis in 47% patients affected by TMEP and aggressive systemic mastocytosis in 9%. To evaluate systemic involvement in patients affected by TMEP. We conducted a retrospective monocentric study among patients affected by TMEP visited in our dermatology clinic. Data regarding gender, age at diagnosis, duration of the disease before diagnosis, topography, clinical features, presence of extra-cutaneous symptoms, serum tryptase levels, and histopathological and bone marrow biopsy features were analysed. Among 119 patients classified with mastocytosis, eight patients (six males, two females) with TMEP and one female patient affected by mastocytosis in the skin, a TMEP variant, were retrospectively studied. The mean diagnostic delay was two years (range: 8-26 months). In two patients (25%), bone marrow involvement was identified and osteoporosis and hepatosplenomegaly were also found. The two patients with systemic involvement exhibited a statistically significant increase in serum tryptase levels (p < 0.05). The detection of KIT gene mutation in skin specimens revealed a somatic mutation, KITD816 V, only in these two patients. TMEP is a rare form of CM, often neglected. A correct and early diagnosis of TMEP is important to rule out systemic involvement of the disease. Detection of serum tryptase levels may be a useful, rapid, and non-invasive marker of systemic involvement.
Subject(s)
Mastocytosis, Cutaneous/pathology , Telangiectasis/pathology , Adult , Aged , Biopsy , Female , Humans , Male , Mastocytosis, Systemic/pathology , Middle Aged , Retrospective StudiesABSTRACT
AIM: We collected 'real-life' data on the management of patients with mastocytosis in the Italian Mastocytosis Registry. METHODS: Six hundred patients diagnosed with mastocytosis between 1974 and 2014 were included from 19 centers. RESULTS: Among adults (n = 401); 156 (38.9%) patients were diagnosed with systemic mastocytosis. In 212 adults, no bone marrow studies were performed resulting in a provisional diagnosis of mastocytosis of the skin. This diagnosis was most frequently established in nonhematologic centers. In total, 182/184 pediatric patients had cutaneous mastocytosis. We confirmed that in the most patients with systemic mastocytosis, serum tryptase levels were >20 ng/ml and KIT D816V was detectable. CONCLUSION: The Italian Mastocytosis Registry revealed some center-specific approaches for diagnosis and therapy. Epidemiological evidence on this condition is provided.