An Autopsy Case of Severe COVID-19 Pneumonia Complicated by Intrapulmonary Thrombosis in Myelodysplastic/Myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosis.

Patients with coronavirus disease 2019 (COVID-19) pneumonia are prone to intrapulmonary thrombosis owing to excessive inflammation and platelet activation. Myelodysplastic/myeloproliferative neoplasm (MDS/MPN) with ring sideroblasts and thrombocytosis (RS-T) is a rare disease in MDS/MPN overlap entities. Patients with MDS/MPN RS-T are known to be at a high risk of thrombosis, and platelet count control with drug therapy does not necessarily reduce this risk. Here, we report the autopsy case of an older male patient with MDS/MPN RS-T and severe COVID-19 pneumonia complicated by intrapulmonary thrombosis. His platelet count had been controlled in the normal range after treatment with hydroxyurea and 5-aza-2'-deoxycytidine. On admission day, he rapidly developed respiratory distress and tested positive on a polymerase chain reaction test for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). After admission, he received supplemental oxygen and was administered remdesivir and dexamethasone; however, his respiratory and circulatory status did not improve. The patient died on day 4 of illness. Autopsy findings revealed massive thrombi within blood vessels and diffuse alveolar damage in both lungs, which were determined to be the cause of death. In patients with MDS/MPN RS-T combined with COVID-19 pneumonia, clinicians may need to pay close attention to the risk of pulmonary thrombosis.

Adrenal infarction with latent myelodysplastic/myeloproliferative neoplasm, unclassifiable with JAK2V617F mutation.

Key Clinical Message: Hematopoietic neoplasms can cause adrenal infarction. In cases of thrombosis occurring at uncommon sites, it is necessary to consider evaluating for the JAK2V617F mutation, even in the absence of notable abnormalities in blood counts. Abstract: Adrenal infarction, a rare ailment, has been sporadically linked to hematopoietic neoplasms. A 46-year-old male encountered left adrenal infarction, which coincided with a progressive rise in platelet counts. Subsequent diagnosis revealed myelodysplastic/myeloproliferative neoplasm-unclassifiable, featuring a JAK2V617F mutation. Simultaneously, the patient manifested multiple arteriovenous thromboses, necessitating treatment with edoxaban, aspirin, and hydroxyurea. Following thrombosis resolution, he was transferred to a transplantation center. This report delves into the thrombogenicity linked to the JAK2V617F mutation, while also examining documented instances of adrenal infarction in myeloid neoplasms. We should consider evaluating for JAK2V617F mutation even in cases of thrombosis at unusual sites, including adrenal infarction, even if there are no considerable abnormalities in blood counts.

Cytogenetics in the management of myeloproliferative neoplasms, mastocytosis and myelodysplastic/myeloproliferative neoplasms: Guidelines from the Group Francophone de Cytogénétique Hématologique (GFCH).

Myeloproliferative neoplasms, mastocytosis, myeloid/lymphoid neoplasms with hypereosinophilia and tyrosine kinase gene fusions, and myelodysplastic/myeloproliferative neoplasms are clonal hematopoietic cancers that, with the exception of certain entities, have an indolent course. In addition to their increasingly important role in the diagnosis of these entities, as shown by the recent classification of hematolymphoid tumors in the 5th edition of the World Health Organization and the International Consensus Classification of myeloid neoplasms and acute leukemias, identification of the profile of acquired genetic abnormalities is essential for adapting patient management and early detection of patients at high risk of progression. Alongside molecular abnormalities, cytogenetic abnormalities play an important role in the diagnosis, prognosis and follow-up of these diseases. Here, we review the recent literature on the impact of chromosomal abnormalities in these different entities and provide updated cytogenetic recommendations and guidelines for their management.

Differential diagnoses and the mutational landscape of myelodysplastic/myeloproliferative neoplasm with neutrophilia: A case report.

Myelodysplastic/myeloproliferative neoplasm with neutrophilia (MDS/MPN-N; previously referred to as atypical chronic myeloid leukemia) is a type of myelodysplastic syndrome/myeloproliferative neoplasm. A molecular genetic precondition for diagnosis is BCR::ABL negativity; further diagnostic criteria include clinicopathological assessments, such as peripheral blood leukocyte counts, the number of neutrophils and their precursors, and the presence of dysgranulopoiesis. The present case report highlights the importance of differential diagnoses with a stringent diagnostic workup according to the 5th Edition of the World Health Organization Classification of Hematolymphoid Tumors. A systematic review of the literature from 2013 to 2022 covering the mutational landscape of MDS/MPN-N was also performed to highlight recent improvements in the molecular genetic diagnostics of this disease.

Recurrent bilateral adrenal infarction with myelodysplastic/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U): a case report.

BACKGROUND: Bilateral adrenal infarction is rare and only a small number of cases have been reported so far. Adrenal infarction is usually caused by thrombophilia or a hypercoagulable state, such as antiphospholipid antibody syndrome, pregnancy, and coronavirus disease 2019. However, adrenal infarction with myelodysplastic/myeloproliferative neoplasm (MDS/MPN) has not been reported. CASE PRESENTATION: An 81-year-old man with a sudden severe bilateral backache presented to our hospital. Contrast-enhanced computed tomography (CT) led to the diagnosis of bilateral adrenal infarction. Previously reported causes of adrenal infarction were all excluded and a diagnosis of MDS/MPN-unclassifiable (MDS/MPN-U) was reached, which was considered to be attributed to adrenal infarction. He developed a relapse of bilateral adrenal infarction, and aspirin administration was initiated. Partial primary adrenal insufficiency was suspected as the serum adrenocorticotropic hormone level was persistently high after the second bilateral adrenal infarction. CONCLUSION: This is the first case of bilateral adrenal infarction with MDS/MPN-U encountered. MDS/MPN has the clinical characteristics of MPN. It is reasonable to assume that MDS/MPN-U may have influenced bilateral adrenal infarction development, considering the absence of thrombosis history and a current comorbid hypercoagulable disease. This is also the first case of recurrent bilateral adrenal infarction. It is important to carefully investigate the underlying cause of adrenal infarction once adrenal infarction is diagnosed, as well as to assess adrenocortical function.

Myelodysplastic Syndromes/Myeloproliferative Overlap Neoplasms and Differential Diagnosis in the WHO and ICC 2022 Era: A Focused Review.

The myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) category comprises a varied group of myeloid neoplastic diseases characterized by clinical and pathologic overlapping features of both myelodysplastic and myeloproliferative neoplasms. For these reasons, these tumors are challenging in terms of diagnosis. The recent World Health Organization (WHO) 2022 classification and the International Consensus Classification (ICC) made changes in the classification of MDS/MPN compared to the previous 2016 WHO classification and improved the diagnostic criteria of these entities. The aim of this review is to describe the main entities reported in the more recent classifications, focusing on chronic myelomonocytic leukemia (CMML), MDS/MPN with neutrophilia (or atypical CML [aCML]), and MDS/MPN with SF3B1 mutation and thrombocytosis/MDS/MPN with ring sideroblasts and thrombocytosis. A particular emphasis is given to the differential diagnosis and analysis of subtle divergences and semantic differences between the WHO classification and the ICC for these entities.

Extramedullary T-lymphoblastic Crisis in a Myelodysplastic/Myeloproliferative Neoplasm with a t(12;22)/MN1::ETV6 Translocation.

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are not a single disease, but rather a heterogenous group of entities which are increasingly subclassified according to recurrent genetic abnormalities. Chromosomal translocations involving meningioma 1 (MN1) and ETS variant 6 (ETV6) genes are extremely rare, but recurrent in myeloid neoplasms. We describe the case of a patient with a myelodysplastic/myeloproliferative neoplasm with neutrophilia, who developed an extramedullary T-lymphoblastic crisis with the t(12;22)(p13;q12) translocation as the only cytogenetic abnormality. This case shares several clinical and molecular features with myeloid/lymphoid neoplasms with eosinophilia. The treatment of this patient was challenging, as the disease proved to be highly refractory to chemotherapy, with allogenic stem cell transplantation as the only curative option. This clinical presentation has not been reported in association with these genetic alterations and supports the concept of a hematopoietic neoplasm originating in an early uncommitted precursor cell. Additionally, it stresses the importance of molecular characterization in the classification and prognostic stratification of these entities.

Venetoclax in combination with hypomethylating agent for the treatment of advanced myeloproliferative neoplasms and acute myeloid leukemia with extramedullary disease.

The combination of venetoclax and hypomethylating agent (HMA/venetoclax) has emerged as a treatment option for patients with de novo acute myeloid leukemia (AML) who are unfit to receive intensive chemotherapy. In this single-center retrospective study, we evaluated clinical outcomes following treatment with HMA/venetoclax in 35 patients with advanced myeloproliferative neoplasms, myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes or AML with extramedullary disease. The composite complete remission (CR) rate (including confirmed/presumed complete cytogenetic response, acute leukemia response-complete, CR and CR with incomplete hematologic recovery) was 42.9% with median overall survival (OS) of 9.7 months. Complex karyotype was associated with inferior median OS (3.7 versus 12.2 months; p = 0.0002) and composite CR rate (22% versus 50.0%; p = 0.2444). Although SRSF2 mutations were associated with higher composite CR rate (80.0% versus 28.0%; p = 0.0082), this was not associated with longer median OS (10.9 versus 8.0 months; p = 0.2269). Future studies should include these patient subgroups.

Dasatinib for chronic myelomonocytic leukemia with ZMIZ1-ABL1 fusion gene: a case report.

The fusion gene ZMIZ1-ABL1 is rare, with only one known case reported in lymphatic system malignancies, and none reported in a myeloid tumor. Here, we report the case of a patient with chronic myelomonocytic leukemia with the ZMIZ1-ABL1 fusion gene. Elevated leukocytes and splenomegaly were the main manifestations. Remission was achieved with the second-generation tyrosine kinase inhibitor (TKI) dasatinib, and the response has been sustained for 10 months. The treatment results in this case suggest that dasatinib is effective in treating ZMIZ1-ABL1 fusion gene-positive disease.

Advances in myelodysplastic/myeloproliferative neoplasms.

The myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) category includes a heterogeneous group of diseases characterized by the co-occurrence of clinical and pathologic features of both myelodysplastic and myeloproliferative neoplasms. The recently published International Consensus Classification of myeloid neoplasms revised the entities included in the MDS/MPN category as well as criteria for their diagnosis. In addition to the presence of one or more increased peripheral blood cell counts as evidence of myeloproliferative features, concomitant cytopenia as evidence of ineffective hematopoiesis is now an explicit requirement to diagnose the diseases included in this category. The increasing availability of modern gene sequencing has allowed better understanding of the biologic characteristics of these myeloid neoplasms. The presence of specific mutations in the appropriate clinicopathologic context is now included in the diagnostic criteria for some of MDS/MPN entities. In this review, we highlight what has changed in the diagnostic criteria of MDS/MPN from the WHO 2016 classification while providing practical guidance in diagnosing these diseases.

ETNK1 mutation occurs in a wide spectrum of myeloid neoplasms and is not specific for atypical chronic myeloid leukemia.

BACKGROUND: ETNK1 mutation has been suggested as a useful tool to support the diagnosis of atypical chronic myeloid leukemia. ETNK1 mutations, however, occur in other myeloid neoplasms. METHODS: The authors assessed the clinicopathologic and molecular genetic features of 80 ETNK1-mutated myeloid neoplasms. RESULTS: Thirty-seven neoplasms (46%) were classified as myelodysplastic syndrome, 17 (21%) were classified as myelodysplastic/myeloproliferative neoplasm, 14 (18%) were classified as acute myeloid leukemia, and 12 (15%) were classified as myeloproliferative neoplasm. ETNK1 mutations were detected at the first test in 96% of patients, suggesting that ETNK1 mutation is an early event in pathogenesis. ETNK1 mutations represented the dominant clone in 63% of patients and was persistently dominant in 93%. The variant allele frequencies were usually higher in acute myeloid leukemia and increased upon leukemic transformation. ETNK1 mutation was accompanied by coexisting mutations in all patients, with ASXL1 (50%), TET2 (25%), EZH2 (24%), RUNX1 (24%), and SRSF2 (24%) mutations being the most common. Neoplasms with ETNK1 mutations were associated with morphologic dysplasia, increased blasts, myelofibrosis, and noncomplex karyotypes. With a median follow-up of 16.5 months, 30 patients died, 44 had persistent disease, and four achieved complete remission after stem cell transplantation. CONCLUSIONS: ETNK1 mutation is present in various myeloid neoplasms, often as an early event and a dominant clone and always with concurrent mutations. It may play an important role in the pathogenesis and progression of myeloid neoplasms by causing DNA damage and inducing other mutations and genomic instability, and it may serve as a potential therapeutic target. ETNK1 mutation is not disease-specific and should be interpreted with caution to classify myeloid neoplasms.

CSF3R T618I mutant myelodysplastic/myeloproliferative neoplasm in the elderly: An age-related disease with unfavorable prognosis.

We reported two MDS/MPN-U and one CMML patients with CSF3R T618I mutation. There were two males and one female, with a median age of 84 years. Three patients presented with leukocytosis and anemia, two with thrombocytopenia, and one with monocytosis. In all the patients, bone marrow showed hypercellularity with myeloid or erythroid predominant trilineage hematopoiesis and dysplasia. Two cases carried -7/-7q abnormalities. In addition to CSF3R T618/I mutation, each case carried 3-5 additional somatic mutations. The median survival was only 2 months. These rare patients were characterized by old age, high mutation rates, clonal hematopoiesis-associated mutations, clonal evolution, and unfavorable prognosis.

Acute leukemia arising from myeloproliferative or myelodysplastic/myeloproliferative neoplasms: A series of 372 patients from the PETHEMA AML registry.

Treatment of acute myeloid leukemia (AML) evolving from myeloproliferative (MPN) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) is challenging. We evaluated disease characteristics, treatment patterns and outcomes in 372 patients diagnosed with AML after MPN or MDS/MPN over a 27-year period. Frontline treatment was intensive chemotherapy (38%), hypomethylating agents [HMAs] (17%), non-intensive chemotherapy (14%), and supportive care (31%). Median overall survival was 4.8 months, with a 5-year survival rate of 4%. Median survival was 2.8, 3.9 and 8.3 months for the 1992-2010, 2011-2015 and 2016-2019 periods, respectively (test for trend p < 0.001). Complete response (CR) rate was higher with intensive chemotherapy (43%) than with non-intensive chemotherapy (12%) or HMAs (8.5%) [p < 0.001], but responses were short-lived without allogeneic hematopoietic cell transplantation. Patients treated with intensive chemotherapy or HMAs had superior survival than those receiving non-intensive chemotherapy (median: 8.5 vs. 8.6 vs. 4.2 months, respectively). No differences in treatment response or survival were observed according to prior disease subtypes. Patients undergoing transplantation in CR had better survival than those transplanted in other response categories (3-year survival rate of 64% vs. 22%, p = 0.002). Our results support the use of intensive chemotherapy followed by transplant whenever possible, and the preferential use of HMAs over attenuated chemotherapy regimens in unfit patients. In spite of the survival improvement in recent years, this subset of AML constitutes an unmet medical need and deserves systematic incorporation in clinical trials.

Molecular Progression of Myeloproliferative and Myelodysplastic/Myeloproliferative Neoplasms: A Study on Sequential Bone Marrow Biopsies.

Myeloproliferative neoplasms (MPN) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) both harbor the potential to undergo myelodysplastic progression or acceleration and can transform into blast-phase MPN or MDS/MPN, a form of secondary acute myeloid leukemia (AML). Although the initiating transforming events are yet to be determined, current concepts suggest a stepwise acquisition of (additional) somatic mutations-apart from the initial driver mutations-that trigger disease evolution. In this study we molecularly analyzed paired bone marrow samples of MPN and MDS/MPN patients with known progression and compared them to a control cohort of patients with stable disease course. Cases with progression displayed from the very beginning a higher number of mutations compared to stable ones, of which mutations in five (ASXL1, DNMT3A, NRAS, SRSF2 and TP53) strongly correlated with progression and/or transformation, even if only one of these genes was mutated, and this particularly applied to MPN. TET2 mutations were found to have a higher allelic frequency than the putative driver mutation in three progressing cases ("TET2-first"), whereas two stable cases displayed a TET2-positive subclone ("TET2-second"), supporting the hypothesis that not only the sum of mutations but also their order of appearance matters in the course of disease. Our data emphasize the importance of genetic testing in MPN and MDS/MPN patients in terms of risk stratification and identification of imminent disease progression.

The utility of a myeloid mutation panel for the diagnosis of myelodysplastic syndrome and myelodysplastic/myeloproliferative neoplasm.

INTRODUCTION: The diagnosis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) is based on morphology and cytogenetics/FISH findings per 2017 WHO classification. With rare exceptions, somatic mutations have not been incorporated as the diagnostic criteria. METHODS: We analyzed the utility of mutational analysis with a targeted 54-gene or 40-gene next-generation sequencing (NGS) panel in the diagnosis of MDS and MDS/MPN. RESULTS: We retrospectively collected 92 patients who presented with unexplained cytopenia with or without cytosis, including 32 low-grade MDS (MDS-L), 18 high-grade MDS (MDS-H), 5 therapy-related MDS (MDS-TR), 19 MDS/MPN, and 18 negative cases. Of 92 patients, 197 somatic mutations involving 38 genes were detected and had variant allele frequency (VAF) ranging from 3% to 99%. The most common mutated genes were TET2, ASXL1, RUNX1, TP53, SRSF2, and SF3B1. MDS-L, MDS-H, MDS-TR, and MDS/MPN showed an average number of somatic mutations with a mean VAF of 1.9/33%, 2.6/30%, 2/36%, and 4/41%, respectively. SF3B1 mutations were exclusively observed in MDS-L and MDS/MPN. TP53 gene mutations were more frequently seen in MDS-H and MDS-TR. Among 34 patients with a diagnosis of MDS or MDS/MPN with normal cytogenetics, 31 patients (91%) had at least 1 mutation and 24 patients (71%) had ≥2 mutations with ≥10% VAF. CONCLUSION: A myeloid mutational panel provides additional evidence of clonality besides cytogenetics/FISH studies in the diagnosis of cytopenia with or without cytosis. Two or more mutations with ≥10% VAF highly predicts MDS and MDS/MPN with a positive predictive value of 100%.

Development of a myelodysplastic/myeloproliferative neoplasm-unclassifiable in a patient with acute myeloid leukemia: a case report and literature review.

Myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are a heterogeneous group of hematologic malignancies characterized by dysplastic and myeloproliferative overlapping features in the bone marrow and blood. The occurrence of the disease is related to age, prior history of MPN or MDS, and recent cytotoxic or growth factor therapy, but it rarely develops after acute myeloid leukemia (AML). We report a rare case of a patient diagnosed with AML with t(8; 21)(q22; q22) who received systematic chemotherapy. After 4 years of follow-up, MDS/MPN-unclassifiable occurred without signs of primary AML recurrence.

Eosinophilia/Hypereosinophilia in the Setting of Reactive and Idiopathic Causes, Well-Defined Myeloid or Lymphoid Leukemias, or Germline Disorders.

OBJECTIVES: To report the findings of the 2019 Society for Hematopathology/European Association for Haematopathology Workshop within the categories of reactive eosinophilia, hypereosinophilic syndrome (HES), germline disorders with eosinophilia (GDE), and myeloid and lymphoid neoplasms associated with eosinophilia (excluding entities covered by other studies in this series). METHODS: The workshop panel reviewed 109 cases, assigned consensus diagnosis, and created diagnosis-specific sessions. RESULTS: The most frequent diagnosis was reactive eosinophilia (35), followed by acute leukemia (24). Myeloproliferative neoplasms (MPNs) received 17 submissions, including chronic eosinophilic leukemia, not otherwise specified (CEL, NOS). Myelodysplastic syndrome (MDS), MDS/MPN, and therapy-related myeloid neoplasms received 11, while GDE and HES received 12 and 11 submissions, respectively. CONCLUSIONS: Hypereosinophilia and HES are defined by specific clinical and laboratory criteria. Eosinophilia is commonly reactive. An acute leukemic onset with eosinophilia may suggest core-binding factor acute myeloid leukemia, blast phase of chronic myeloid leukemia, BCR-ABL1-positive leukemia, or t(5;14) B-lymphoblastic leukemia. Eosinophilia is rare in MDS but common in MDS/MPN. CEL, NOS is a clinically aggressive MPN with eosinophilia as the dominant feature. Bone marrow morphology and cytogenetic and/or molecular clonality may distinguish CEL from HES. Molecular testing helps to better subclassify myeloid neoplasms with eosinophilia and to identify patients for targeted treatments.

Efficacy of ruxolitinib in a patient with myelodysplastic/myeloproliferative neoplasm unclassifiable and co-mutated JAK2, SF3B1 and TP53.

Myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U) is a rare but heterogeneous subtype of MDS/MPN, with no specific genetic alterations and standard treatments. ASXL1, SRSF2, TET2, JAK2 and NRAS are commonly mutated in MDS/MPN-U. Double gene mutations could be detected in MDS/MPN-U, however, co-mutations of 3 and more genes in this disease entity are very rare. Here, we present a case of MDS/MPN-U with triple mutations involving JAK2, SF3B1, and TP53. After failure of traditional therapy including hydroxyurea and interferon-α, the patient received ruxolitinib monotherapy and achieved hematological response quickly. Though mutations in TP53 implied a poor prognosis in myeloid malignancies, this patient has maintained no AML transformation for 26 months since diagnosis. Further research on complex mutations in the pathogenesis and prognosis of MDS/MPN-U is warranted.

Molecular genetics of MDS/MPN overlap syndromes.

The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are a heterogenous group of myeloid malignancies hallmarked by clinicopathologic features that overlap with myelodysplastic syndromes and myeloproliferative neoplasms. Formally recognized by the World Health Organization, this group includes the entities chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, MDS/MPN with ring sideroblasts and thrombocytosis and MDS/MPN, unclassifiable. Advancements in next generation sequencing have begun to unravel the molecular underpinnings of these diseases, identifying an array of recurrently mutated genes involved in epigenetic regulation, RNA splicing, transcription, and cell signaling. Despite molecular overlap with other myeloid malignancies, each entity displays a unique spectrum of somatic mutations supporting their unique pathobiology and clinical features. Importantly, molecular profiling is becoming an integral tool utilized in routine clinical practice. This review summarizes our current understanding of the molecular pathogenesis of overlap syndromes and details the impact of somatic mutations in diagnostic, prognostic, and therapeutic decision-making.

[Myelodysplastic/myeloproliferative neoplasm: a histopathological review].

Myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) is a type of myeloid neoplasm where at least one hematopoietic lineage exhibiting cytopenia clinically coexists with other (s) exhibiting hypercytosis. There is ineffective erythropoiesis and bone marrow coexistence of at least one hematopoietic lineage morphologically characterized by dysplasia of blood cells and other (s) characterized by pronounced proliferation. At a molecular level, various abnormalities have been identified that overlap with related diseases, and a prerequisite for MDS/MPN diagnosis includes ruling out various hematopoietic tumors and reactive conditions. Therefore, a multilateral approach involving clinical findings, morphology, and molecular biology is needed. Herein, we introduce the pathological features of MDS/MPN and the relationship between molecular abnormalities and morphological characteristics.