Publications by authors named "Attilio Orazi"

174 Publications

A rare case of B cell lymphoblastic leukemia with inv(7)(p15q34) with review of literature.

Leuk Res Rep 2021 1;15:100250. Epub 2021 Jun 1.

Department of Pathology, Texas Tech Health Sciences Center at El Paso, TX.

The inv(7)(p15q34) chromosomal abnormality which juxtaposes part of the HOXA gene cluster on 7p15 to the TCRβ locus on 7q34, has been described in a subset of cases of T-cell lymphoblastic leukemia, but its presence in cases of B-cell lymphoblastic leukemia is virtually unknown. Herewith, we report a case of a B-cell lymphoblastic leukemia with inv(7)(p15q34). The patient received standard induction chemotherapy, which failed to produce remission. After treatment with blinatumomab, a bispecific T-cell engager, the follow-up bone marrow biopsy showed no evidence of persistent/ relapsed B-cell lymphoblastic leukemia. The unique cytogenetics of this case may have contributed to its resistance of standard induction chemotherapy.
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http://dx.doi.org/10.1016/j.lrr.2021.100250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192865PMC
June 2021

Myeloid/lymphoid neoplasms with FLT3 rearrangement.

Mod Pathol 2021 May 14. Epub 2021 May 14.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Myeloid/lymphoid neoplasms (M/LN) with 13q12/FLT3 rearrangement have been suggested as candidates for possible inclusion in the World Health Organization classification group of M/LN with eosinophilia (M/LN-eo). We report 12 patients with confirmed FLT3 rearrangement, six with t(12;13)/ETV6-FLT3; one with ins(13;22)/BCR-FLT3; and five with an unconfirmed partner gene located on chromosome bands 2p16, 3q27, 5q15, 5q35, and 7q36. Disease presentations were heterogeneous, including lymphoblastic leukemia/lymphoma, myeloid sarcoma, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, and myelodysplastic syndrome. However, some common features were observed, such as extramedullary involvement (n = 7, 58%), associated eosinophilia in blood, bone marrow, or tissue (n = 8, 67%), multilineage involvement, either as biphasic myeloid/lymphoid neoplasms (n = 2) or mixed phenotype acute leukemia (n = 2). Mutations were detected in 4/8 (50%) patients by next-generation sequencing. None (0/10) had FLT3 or KIT mutations. Eleven patients received disease-based chemotherapy or hypomethylating agents, three received FLT3 inhibitors, and five patients proceeded to hematopoietic stem cell transplant. Together with a review of 16 cases published in the literature, it is apparent that M/LNs with FLT3 rearrangement show disease features reminiscent of members in the category of M/LN-eo with PDGFRA, PDGFRB, FGFR1, and PCM1/JAK2 rearrangement, characterized by a specific gene rearrangement, frequent eosinophilia, multi-lineage involvement and therapeutic benefit from kinase inhibitors.
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http://dx.doi.org/10.1038/s41379-021-00817-7DOI Listing
May 2021

Ethnic and border differences on blood cancer presentation and outcomes: A Texas population-based study.

Cancer 2021 Apr 3;127(7):1068-1079. Epub 2020 Dec 3.

Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas.

Background: The Texas/Chihuahua (US/Mexico) border is a medically underserved region with many reported barriers for health care access. Although Hispanic ethnicity is associated with health disparities for many different diseases, the population-based estimates of incidence and survival for patients with blood cancer along the border are unknown. The authors hypothesized that Hispanic ethnicity and border proximity is associated with poor blood cancer outcomes.

Methods: Data from the Texas Cancer Registry (1995-2016) were used to investigate the primary exposures of patient ethnicity (Hispanic vs non-Hispanic) and geographic location (border vs non-border). Other confounders and covariates included sex, age, year of diagnosis, rurality, insurance status, poverty indicators, and comorbidities. The Mantel-Haenszel method and Cox regression analyses were used to determine adjusted effects of ethnicity and border proximity on the relative risk (RR) and survival of patients with different blood cancer types.

Results: Hispanic patients were diagnosed at a younger age than non-Hispanic patients and presented with increased comorbidities. Whereas non-Hispanics had a higher incidence of developing blood cancer compared with Hispanics overall, Hispanics demonstrated a higher incidence of acute lymphoblastic leukemia (RR, 1.92; 95% CI, 1.79-2.08; P < .001) with worse outcomes. Hispanics from the Texas/Chihuahua border demonstrated a higher incidence of chronic myeloid leukemia (RR, 1.28; 95% CI, 1.07-1.51; P = .02) and acute myeloid leukemia (RR, 1.17; 95% CI, 1.04-1.33; P = .0009) compared with Hispanics living elsewhere in Texas.

Conclusions: Hispanic ethnicity and border proximity were associated with a poor presentation and an adverse prognosis despite the younger age of diagnosis. Future studies should explore differences in disease biology and treatment strategies that could drive these regional disparities.
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http://dx.doi.org/10.1002/cncr.33347DOI Listing
April 2021

Primary pancreatic diffuse large B-cell lymphoma, activated B-cell subtype, diagnosed by endoscopic ultrasound-guided fine needle aspiration-A case report and review of the literature.

Clin Case Rep 2021 Feb 4;9(2):669-672. Epub 2020 Dec 4.

Paul L. Foster School of Medicine Texas Tech University Health Sciences Center El Paso El Paso TX USA.

Although primary pancreatic lymphoma is a rare cause of pancreatic mass, this diagnosis should be considered during work-up. Furthermore, when adequate diagnostic material is available from biopsy, complete workup of the lymphoma, including not only type but also subtype when applicable, should be performed.
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http://dx.doi.org/10.1002/ccr3.3605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869370PMC
February 2021

Clinical, immunophenotypic and genomic findings of NK lymphoblastic leukemia: a study from the Bone Marrow Pathology Group.

Mod Pathol 2021 Jul 1;34(7):1358-1366. Epub 2021 Feb 1.

Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

Natural killer (NK) cells are lymphocytes of the native immune system that play a pivotal role in host defense and immune surveillance. While the conceptual view of NK-neoplasms is evolving, little is known about the rare NK lymphoblastic leukemia (NK-LL), which remains as a provisional entity in the 2016 WHO Classification. The goal of this study is to characterize NK-LL cases and compare with other CD56 co-expressing acute leukemias. We identified 105 cases, diagnosed as NK-LL (6), CD56+ acute undifferentiated leukemia (AUL) (6), CD56+ T-lymphoblastic leukemia (T-LL) (51), and CD56+ acute myeloid leukemia (AML) (42). Compared to AUL patients, NK-LL patients were significantly younger (p = 0.021) and presented with higher white blood cell (WBC) (p = 0.037) and platelet counts (p = 0.041). Flow cytometry showed more frequent expression of cytoplasmic CD3 (cCD3, p = 0.064) and CD33, (p = 0.065), while HLA-DR was significantly absent from NK-LL (p = 0.035) compared to AUL. Compared to T-ALL, NK-LL cases showed less frequent cCD3 (p = 0.002), CD4 (p = 0.051), and CD10 expression (p = 0.06). The frequency of abnormal karyotypes was similar between NK-LL, AUL, and T-ALL. The mutational profile differed in four leukemia groups, with a significance enrichment of NOTCH1 (p = 0.002), ETV6 (p = 0.002) and JAK3 (p = 0.02) mutations in NK-LL as compared to AML. As compared to T-ALL, NK-LL cases showed a higher number of total mutations (p = 0.04) and significantly more frequent ETV6 mutations (p = 0.004). Clinical outcome data showed differences in overall survival between all four groups (p = 0.0175), but no difference in event free survival (p = 0.246). In this largest study to date, we find that that NK-LL shows clinical presentation, immunophenotypic and molecular characteristics distinct from AUL, T-ALL, and AML. Our findings suggest NK-LL is a distinct acute leukemia entity and should be considered in the clinical diagnosis of acute leukemias of ambiguous lineage.
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http://dx.doi.org/10.1038/s41379-021-00739-4DOI Listing
July 2021

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

Am J Clin Pathol 2021 02;155(2):179-210

Division of Hematopathology, Mayo Clinic, Rochester, MN.

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.
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http://dx.doi.org/10.1093/ajcp/aqaa244DOI Listing
February 2021

Myeloid/Lymphoid Neoplasms Associated With Eosinophilia and Rearrangements of PDGFRA, PDGFRB, or FGFR1 or With PCM1-JAK2.

Am J Clin Pathol 2021 02;155(2):160-178

MD Anderson Cancer Center, Houston, TX.

Objectives: To summarize cases submitted to the 2019 Society for Hematopathology/European Association for Haematopathology Workshop under the category of myeloid/lymphoid neoplasms with eosinophilia and PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2 rearrangements, focusing on recent updates and relevant practice findings.

Methods: The cases were summarized according to their respective gene rearrangement to illustrate the spectrum of clinical, laboratory, and histopathology manifestations and to explore the appropriate molecular genetic tests.

Results: Disease presentations were heterogeneous, including myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDSs), MDS/MPN, acute myeloid leukemia, acute B- or T-lymphoblastic lymphoma/acute lymphoblastic lymphoma (ALL/LBL), or mixed-lineage neoplasms. Frequent extramedullary involvement occurred. Eosinophilia was common but not invariably present. With the advancement of RNA sequencing, cryptic rearrangements were recognized in genes other than PDGFRA. Additional somatic mutations were more frequent in the FGFR1-rearranged cases. Cases with B-ALL presentations differed from Philadelphia-like B-ALL by the presence of an underlying MPN. Cases with FLT3 and ABL1 rearrangements could be potential candidates for future inclusion in this category.

Conclusions: Accurate diagnosis and classification of this category of myeloid/lymphoid neoplasms has important therapeutic implications. With the large number of submitted cases, we expand our understanding of these rare neoplasms and improve our ability to diagnose these genetically defined disorders.
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http://dx.doi.org/10.1093/ajcp/aqaa208DOI Listing
February 2021

Reactive Eosinophil Proliferations in Tissue and the Lymphocytic Variant of Hypereosinophilic Syndrome.

Am J Clin Pathol 2021 02;155(2):211-238

Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany.

Objectives: The 2019 Society for Hematopathology and European Association for Haematopathology Workshop reviewed the spectrum of neoplastic, nonneoplastic, and borderline entities associated with reactive eosinophilia in tissue.

Methods: The workshop panel reviewed 46 cases covered in 2 workshop sessions.

Results: The 46 cases were presented with their consensus diagnoses during the workshop. Reactive eosinophilia in lymph nodes and other tissues may be accompanied by or be distinct from peripheral blood eosinophilia. Reactive etiologies included inflammatory disorders such as Kimura disease and IgG4-related disease, which may show overlapping pathologic features and reactions to infectious agents and hypersensitivity (covered in a separate review). Hodgkin, T-cell, and B-cell lymphomas and histiocytic neoplasms can result in reactive eosinophilia. The spectrum of these diseases is discussed and illustrated through representative cases.

Conclusions: Reactive eosinophilia in lymph nodes and tissues may be related to both nonneoplastic and neoplastic lymphoid proliferations and histiocytic and nonhematolymphoid processes. Understanding the differential diagnosis of reactive eosinophilia and the potential for overlapping clinical and pathologic findings is critical in reaching the correct diagnosis so that patients can be treated appropriately.
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http://dx.doi.org/10.1093/ajcp/aqaa227DOI Listing
February 2021

GATA1 downregulation in prefibrotic and fibrotic stages of primary myelofibrosis and in the myelofibrotic progression of other myeloproliferative neoplasms.

Leuk Res 2021 01 15;100:106495. Epub 2020 Dec 15.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, NY, USA. Electronic address:

GATA binding protein 1 (GATA1) is a transcription factor essential for effective erythropoiesis and megakaryopoiesis. Two isoforms of GATA1 exist, derived from alternative splicing. "GATA1" is the full length and functionally active protein; "GATA1s" is the truncated isoform devoid of the activation domain, the function of which has not been fully elucidated. Reduced megakaryocytic expression of GATA1 has been linked to impaired hematopoiesis and bone marrow fibrosis in murine models and in vivo in patients affected by primary myelofibrosis (PMF). However, data is limited regarding GATA1 expression in other myeloproliferative neoplasms (MPN) such as pre-fibrotic PMF (pre-PMF), polycythemia vera (PV) and essential thrombocythemia (ET) and in their respective fibrotic progression. To assess whether an immunohistologic approach can be of help in separating different MPN, we have performed a comprehensive immunohistochemical evaluation of GATA1 expression in megakaryocytes within a cohort of BCR-ABL1 negative MPN. In order to highlight any potential differences between the two isoforms we tested two clones, one staining the sum of GATA1 and GATA1s ("clone 1"), the other staining GATA1 full length alone ("clone 2"). At the chronic phase, a significant reduction preferentially of GATA1 full length was seen in pre-fibrotic PMF, particularly compared to ET and PV; no significant differences were observed between PV and ET. The fibrotic progression of both PV and ET was associated with a significant reduction in GATA1, particularly affecting the GATA1 full length isoform. The fibrotic progression of pre-PMF to PMF was associated with a significant reduction of the overall GATA1 protein and a trend in reduction of GATA1s. Our findings support a role of GATA1 in the pathogenesis of BCR-ABL1 negative MPN, particularly in their fibrotic progression and suggest that the immunohistochemical evaluation of GATA1 may be of use in the differential diagnosis of these neoplasms.
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http://dx.doi.org/10.1016/j.leukres.2020.106495DOI Listing
January 2021

Acute aleukemic mast cell leukemia: Report of a case and review of the literature.

Leuk Res Rep 2020 26;14:100230. Epub 2020 Nov 26.

Department of Pathology, Texas Tech University Health Sciences Center El Paso, Texas, United States.

Mast Cell Leukemia (MCL) is the rarest form of systemic mastocytosis, a rare group of neoplastic disease that result from clonal proliferation of mast cells and their accumulation in one or more organ systems. The diagnosis of MCL is made by meeting the World Health Organization (WHO) 2017 criteria. MCL is further subclassified as leukemic or aleukemic based on presence or absence of circulating mast cells in the peripheral blood and acute versus chronic based on presence or absence of findings indicative of impaired organ function due to mast cell infiltration. A 64-year-old Hispanic male presented with myalgia, diarrhea, urticarial rash, back pain, and fulminant disseminated intravascular coagulation. Bone marrow examination, supplemented by immunohistochemistry results, fulfilled the WHO criteria for the diagnosis of MCL. To the best of our knowledge, this is the first documented case of aleukemic acute MCL in a Hispanic patient.
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http://dx.doi.org/10.1016/j.lrr.2020.100230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725938PMC
November 2020

Mastocytosis.

Am J Clin Pathol 2021 02;155(2):239-266

Department of Pathology, University of Utah School of Medicine, Salt Lake City.

Objectives: The 2019 Workshop of the Society for Hematopathology/European Association for Haematopathology received and reviewed cases covering the spectrum of mastocytosis and related diseases, including morphologic mimics, focusing on recent updates and relevant findings for pathologists.

Methods: The workshop panel reviewed 99 cases of cutaneous and systemic mastocytosis (SM) and SM and associated hematologic neoplasms (SM-AHN).

Results: Despite a common theme of KIT mutation (particularly D816V), mastocytosis is a heterogeneous neoplasm with a wide variety of presentations. This spectrum, including rare subtypes and extramedullary organ involvement, is discussed and illustrated by representative cases.

Conclusions: In the age of targeted treatment aimed at KIT, the accurate diagnosis and classification of mastocytosis has major implications for therapy and further interventions. Understanding the clinical, pathologic, and genetic findings of mastocytosis is crucial for selecting the proper tests to perform and subsequent arrival at a correct diagnosis in this rare disease.
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http://dx.doi.org/10.1093/ajcp/aqaa183DOI Listing
February 2021

Progression, transformation, and unusual manifestations of myelodysplastic syndromes and myelodysplastic-myeloproliferative neoplasms: lessons learned from the XIV European Bone Marrow Working Group Course 2019.

Ann Hematol 2021 Jan 31;100(1):117-133. Epub 2020 Oct 31.

Institute of Medical Genetics and Pathology, University Hospital of Basel, Schoenbeinstrasse 40, CH-4031, Basel, Switzerland.

Disease progression in myelodysplastic syndromes (MDS) and myelodysplastic-myeloproliferative neoplasms (MDS/MPN) is a major source of mortality. The European Bone Marrow Working Group organized a dedicated workshop to address MDS and MDS/MPN progression, and myeloid neoplasms with histiocytic and lymphoblastic outgrowths in 2019 in Frankfurt, Germany. In this report, we summarize clinical, histopathological, and molecular features of 28 cases. Most cases illustrate that prognostic mutational profiles change during follow-up due to accumulation of high-risk mutations in the trunk clone, and that results from repeated molecular testing can often explain the clinical progression, suggesting that regular genetic testing may predict transformation by early detection of aggressive clones. Importantly, identical mutations can be linked to different clinical behaviors or risks of fibrotic progression and/or transformation in a context-dependent manner, i.e., MDS or MDS/MPN. Moreover, the order of mutational acquisition and the involved cell lineages matter. Several cases exemplify that histiocytic outgrowths in myeloid neoplasms are usually accompanied by a more aggressive clinical course and may be considered harbinger of disease progression. Exceptionally, lymphoblastic transformations can be seen. As best estimable, the histiocytic and lymphoblastic compounds in all occasions were clonally related to the myeloid compound and-where studied-displayed genomic alterations of, e.g., transcription factor genes or genes involved in MAPK signaling that might be mechanistically linked to the respective type of non-myeloid outgrowth.
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http://dx.doi.org/10.1007/s00277-020-04307-9DOI Listing
January 2021

Pathology of the spleen: INTRODUCTION.

Semin Diagn Pathol 2021 Mar 25;38(2):111. Epub 2020 Aug 25.

Department of Pathology, University of Chicago, Chicago, IL, USA.

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http://dx.doi.org/10.1053/j.semdp.2020.08.001DOI Listing
March 2021

B-cell neoplasms and Hodgkin lymphoma in the spleen.

Semin Diagn Pathol 2021 Mar 10;38(2):125-134. Epub 2020 Aug 10.

Texas Tech University Health Sciences Center, PL Foster School of Medicine, Department of Pathology, MSC 41022, 5001 El Paso Drive, El Paso, TX 79905, United States.

B-cell lymphoma of spleen may be primary (most commonly splenic diffuse large B-cell lymphoma) or secondary (typically low-grade non-Hodgkin lymphoma). Depending on the specific lymphoma subtype, there may be a predominantly white pulp pattern of involvement, a predominantly red pulp pattern or a focal nodular pattern. Splenectomy is the ideal specimen for a multiparametric integrative diagnosis of splenic lymphoma, as it allows for a combined study of morphology, immunohistology, flow cytometry, cytogenetics, and molecular genetic techniques. This review article describes the clinicopathologic characteristics of all the relevant B-cell neoplasms that may be encountered in a splenic biopsy or a splenectomy specimen.
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http://dx.doi.org/10.1053/j.semdp.2020.08.002DOI Listing
March 2021

Chronic myeloid neoplasms harboring concomitant mutations in myeloproliferative neoplasm driver genes (JAK2/MPL/CALR) and SF3B1.

Mod Pathol 2021 01 21;34(1):20-31. Epub 2020 Jul 21.

Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

JAK2, CALR, and MPL are myeloproliferative neoplasm (MPN)-driver mutations, whereas SF3B1 is strongly associated with ring sideroblasts (RS) in myelodysplastic syndrome (MDS). Concomitant mutations of SF3B1 and MPN-driver mutations out of the context of MDS/MPN with RS and thrombocytosis (MDS/MPN-RS-T) are not well-studied. From the cases (<5% blasts) tested by NGS panels interrogating at least 42 myeloid neoplasm-related genes, we identified 18 MDS/MPN-RS-T, 42 MPN, 10 MDS, and 6 MDS/MPN-U cases with an SF3B1 and an MPN-driver mutation. Using a 10% VAF difference to define "SF3B1-dominant," "MPN-mutation dominant," and "no dominance," the majority of MDS/MPN-RS-T clustered in "SF3B1-dominant" and "no dominance" regions. Aside from parameters as thrombocytosis and ≥15% RS required for RS-T, MDS also differed in frequent neutropenia, multilineage dysplasia, and notably more cases with <10% VAF of MPN-driver mutations (60%, p = 0.0346); MPN differed in more frequent splenomegaly, myelofibrosis, and higher VAF of "MPN-driver mutations." "Gray zone" cases with features overlapping MDS/MPN-RS-T were observed in over one-thirds of non-RS-T cases. This study shows that concomitant SF3B1 and MPN-driver mutations can be observed in MDS, MPN, and MDS/MPN-U, each showing overlapping but also distinctively different clinicopathological features. Clonal hierarchy, cytogenetic abnormalities, and additional somatic mutations may in part contribute to different disease phenotypes, which may help in the classification of "gray zone" cases.
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http://dx.doi.org/10.1038/s41379-020-0624-yDOI Listing
January 2021

Concordance among hematopathologists in classifying blasts plus promonocytes: A bone marrow pathology group study.

Int J Lab Hematol 2020 Aug 16;42(4):418-422. Epub 2020 Apr 16.

Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Enumeration of blasts and promonocytes is essential for World Health Organization (WHO) classification of myelomonocytic neoplasms. The accuracy of distinguishing blasts, promonocytes and monocytes, including normal vs abnormal monocytes, remains controversial. The objective of this analysis is to assess concordances between experienced hematopathologists in classifying cells as blasts, promonocytes, and monocytes according to WHO criteria. Each of 11 hematopathologists assessed glass slides from 20 patients [12 with chronic myelomonocytic leukemia (CMML) and 8 with acute myeloid leukemia (AML)] including blood and BM aspirate smears, and limited nonspecific esterase (NSE) stains. All cases were blindly reviewed. Fleiss' extension of Cohen's kappa for multiple raters was used on these variables, separately for peripheral blood (PB) and bone marrow (BM). Spearman's rank correlation was used to assess correlations between each pair of hematopathologists for each measurement. For the classification based on the sum of blasts and promonocytes in the BM, Fleiss' kappa was estimated as 0.744. For PB, categorizing patients according to the sum of blasts and promonocytes, Fleiss' kappa was estimated as 0.949. Distinction of abnormal monocytes from normal monocytes in PB did not achieve a good concordance and showed strong evidence of differences between hematopathologists (P < .0001). The hematopathologists achieved a good concordance rate of 74% in CMML vs AML classification and a high k rate, confirming that criteria for defining the blasts equivalents (blasts plus promonocytes) could be applied consistently. Identification of monocyte subtypes (abnormal vs normal) was not concordant. Our results support the practice of combining blasts/promonocytes into a single category.
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http://dx.doi.org/10.1111/ijlh.13212DOI Listing
August 2020

Comparison of therapy-related and de novo core binding factor acute myeloid leukemia: A bone marrow pathology group study.

Am J Hematol 2020 07 20;95(7):799-808. Epub 2020 Apr 20.

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.

This multi-institutional study retrospectively evaluated clinicopathologic and genetic characteristics in 351 patients with core-binding-factor acute myeloid leukemia (CBF-AML), comprising 69 therapy-related (t-CBF-AML) and 282 de novo cases. The T-CBF-AML patients were older, had lower WBC counts, and slightly higher hemoglobin than patients with de novo disease. Secondary cytogenetic abnormalities were more frequent in patients with de novo disease than t-CBF-AML (57.1% vs 41.1%, P = .026). Patients with secondary cytogenetic abnormalities had longer overall survival (OS) than those without abnormalities (median 190 vs 87 months, P = .021); trisomy 8, trisomy 22, and loss of the X or Y chromosome were associated with longer OS. In the 165 cases performed of targeted gene sequencing, pathogenic mutations were detected in 75.7% of cases, and were more frequent in de novo than in therapy-related disease (P = .013). Mutations were found in N/KRAS (37.0%), FLT3 (27.8%), KIT (17.2%), TET2 (4.9%), and ASXL1 (3.9%). The TET2 mutations were associated with shorter OS (P = .012) while N/KRAS mutation was associated with longer OS in t(8;21) AML patients (P = .001). The KIT mutation did not show prognostic significance in this cohort. Although they received similar therapy, t-CBF-AML patients had shorter OS than de novo patients (median 69 vs 190 months, P = .038). In multivariate analysis of all patients, older age and absence of any secondary cytogenetic abnormalities were significant predictors of shorter OS. Among the t-CBF-AML subset, age and hemoglobin were significant on multivariate analysis. This study demonstrated that although de novo and t-CBF-AML patients share many features, t-CBF-AML patients have worse clinical outcome than de novo patients.
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http://dx.doi.org/10.1002/ajh.25814DOI Listing
July 2020

How I investigate chronic myelomonocytic leukemia.

Int J Lab Hematol 2020 Apr 16;42(2):101-108. Epub 2019 Dec 16.

Department of Pathology, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA.

The 2016 revised 4th edition of the World Health Organization classification of hematopoietic neoplasms updated the diagnostic criteria for chronic myelomonocytic leukemia (CMML). Persistent peripheral blood monocytosis of at least 1 × 10 /L and a percentage of monocytes ≥10% of the circulating white blood cell count (WBC) are both prerequisite criteria for this diagnosis. CMML represents the prototype of "overlapping" myeloid neoplasms with concurrent myeloproliferative and myelodysplastic features. However, clinical presentation is heterogeneous, with cases showing prevailing "dysplastic" features and others a predominant "proliferative" phenotype. Accounting for this diversity, two variants of CMML are recognized: "dysplastic" CMML defined by WBC < 13 × 10 /L and "proliferative" CMML with WBC ≥ 13 × 10 /L often showing features mimicking a myeloproliferative neoplasm. Although not an official WHO category, the "oligomonocytic" variant of CMML is defined by relative monocytosis with an absolute monocyte count of 0.5-0.9 × 10 /L. It can be considered a "pre-phase," as it frequently anticipates the development of an overt, classic CMML. In an attempt at improving disease prognostication, the blast count based grading system for CMML of the WHO 2008 Classification has been expanded in 2016 to include a new "CMML-0" category. Lastly, the large body of knowledge on the molecular events occurring in CMML has been used to assist diagnosis and assess prognosis. Despite the step forwards, diagnosis of CMML still remains one of exclusion as no clinical, pathologic or molecular findings are specific for this disease. The current review brings insight into the spectrum of CMML and provides practical advice to approach suspected cases of CMML.
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http://dx.doi.org/10.1111/ijlh.13145DOI Listing
April 2020

The Spectrum of Aggressive Mastocytosis: A Workshop Report and Literature Review.

Pathobiology 2020 4;87(1):2-19. Epub 2019 Dec 4.

Department of Pathology, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA.

Most cases of mastocytosis are indolent, usually cutaneous mastocytosis or indolent systemic mastocytosis (SM). Aggressive mast cell (MC) diseases are very rare and often fatal. They can develop de novo or due to progression of indolent forms and can present in different ways; either as MC sarcoma or as advanced SM which includes aggressive SM, MC leukemia, and SM with an associated hematological neoplasm. This review will describe these different aggressive forms of mastocytosis, illustrated by cases submitted to the workshop of the 18th Meeting of the European Association for Haematopathology, Basel 2016, organized by the European Bone Marrow Working Group. In addition, the diagnostic criteria for identifying myelomastocytic leukemia, an aggressive myeloid neoplasm with partial MC differentiation that falls short of the criteria for SM, and disease progression in patients with established mastocytosis are discussed.
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http://dx.doi.org/10.1159/000504099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158230PMC
October 2020

Myeloid neoplasms with isolated del(5q) and V617F mutation: a "grey zone" combination of myelodysplastic and myeloproliferative features?

Haematologica 2020 06 26;105(6):e276-e279. Epub 2019 Sep 26.

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY, USA.

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http://dx.doi.org/10.3324/haematol.2019.227686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271604PMC
June 2020

Chronic lymphocytic leukemia with TP53 gene alterations: a detailed clinicopathologic analysis.

Mod Pathol 2020 03 2;33(3):344-353. Epub 2019 Sep 2.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.

TP53 alteration in chronic lymphocytic leukemia indicates a high-risk disease that is usually refractory to chemotherapy. It may be caused by deletion of 17p involving the loss of TP53 gene, which occurs in low percentage of patients at diagnosis but can be acquired as the disease progresses. Since patients may harbor TP53 mutation without chromosome 17p deletion, consensus recommendations call for both cytogenetic and PCR mutation analysis of TP53 in chronic lymphocytic leukemia. We conducted a single-institution retrospective study to investigate the clinicopathologic features of chronic lymphocytic leukemia with TP53 alterations as well as the utility of different diagnostic modalities to identify p53 alterations. Forty percent of chronic lymphocytic leukemia patients with TP53 alterations demonstrated atypical lymphocytes with cleaved/irregularly shaped nuclei and/or large atypical lymphoid cells with abundant cytoplasm in the peripheral blood. Progression was also observed in lymph node and bone marrow samples (21% with Richter transformation; 33% with findings suggestive of "accelerated phase" of chronic lymphocytic leukemia including prominent proliferation centers and/or increased numbers of prolymphocytes). However, the presence of the morphologic features suggestive of "accelerated phase" had no effect on overall survival within the chronic lymphocytic leukemia group with TP53 abnormalities (p > 0.05). As previously reported by others, a subset of patients with TP53 alterations were only identified by either PCR mutation analysis (12%) or cytogenetic studies (14%). p53 immunostain positivity was only identified in approximately half of the patients with TP53 alterations identified by either method, and it failed to identify any additional patients with p53 abnormalities. In summary, chronic lymphocytic leukemia patients with TP53 alterations frequently show atypical morphologic features. Use of multiple modalities to identify p53 abnormalities is recommended to ensure optimal sensitivity and specificity.
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http://dx.doi.org/10.1038/s41379-019-0356-zDOI Listing
March 2020

A rare case of acute myeloid leukemia with der(1)t(1;19)(p13;p13.1).

Leuk Res Rep 2019 8;12:100175. Epub 2019 Jun 8.

Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, TX, United States.

We present a case of acute myeloid leukemia with der(1)t(1;19)(p13;p13.1) translocation and mutation. A literature review summarizing the clinical, pathological, and molecular features of the published cases is also presented.
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http://dx.doi.org/10.1016/j.lrr.2019.100175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581877PMC
June 2019

Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions.

Haematologica 2019 10 2;104(10):1935-1949. Epub 2019 May 2.

Department of Pathology, Hematopathology Unit and James P Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.

Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by dysplasia, abnormal production and accumulation of monocytic cells and an elevated risk of transforming into acute leukemia. Over the past two decades, our knowledge about the pathogenesis and molecular mechanisms in CMML has increased substantially. In parallel, better diagnostic criteria and therapeutic strategies have been developed. However, many questions remain regarding prognostication and optimal therapy. In addition, there is a need to define potential pre-phases of CMML and special CMML variants, and to separate these entities from each other and from conditions mimicking CMML. To address these unmet needs, an international consensus group met in a Working Conference in August 2018 and discussed open questions and issues around CMML, its variants, and pre-CMML conditions. The outcomes of this meeting are summarized herein and include diag nostic criteria and a proposed classification of pre-CMML conditions as well as refined minimal diagnostic criteria for classical CMML and special CMML variants, including oligomonocytic CMML and CMML associated with systemic mastocytosis. Moreover, we propose diagnostic standards and tools to distinguish between 'normal', pre-CMML and CMML entities. These criteria and standards should facilitate diagnostic and prognostic evaluations in daily practice and clinical studies in applied hematology.
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http://dx.doi.org/10.3324/haematol.2019.222059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886439PMC
October 2019

Clinical, immunophenotypic, and genomic findings of acute undifferentiated leukemia and comparison to acute myeloid leukemia with minimal differentiation: a study from the bone marrow pathology group.

Mod Pathol 2019 09 18;32(9):1373-1385. Epub 2019 Apr 18.

Department of Pathology and Laboratory Medicine, University of Chicago, Chicago, IL, USA.

Acute undifferentiated leukemia is a rare type of acute leukemia that shows no evidence of differentiation along any lineage. Clinical, immunophenotypic and genetic data is limited and it is uncertain if acute undifferentiated leukemia is biologically distinct from acute myeloid leukemia with minimal differentiation, which also shows limited myeloid marker expression and has been reported to have a poor prognosis. We identified 92 cases initially diagnosed as acute undifferentiated leukemia or acute myeloid leukemia with minimal differentiation from pathology databases of nine academic institutions with available diagnostic flow cytometric data, cytogenetic findings, mutational and clinical data. Outcome analysis was performed using Kaplan Meier test for the 53 patients who received induction chemotherapy. Based on cytogenetic abnormalities (N = 30) or history of myelodysplastic syndrome (N = 2), 32 cases were re-classified as acute myeloid leukemia with myelodysplasia related changes. The remaining 24 acute undifferentiated leukemia patients presented with similar age, blood counts, bone marrow cellularity, and blast percentage as the remaining 30 acute myeloid leukemia with minimal differentiation patients. Compared to acute myeloid leukemia with minimal differentiation, acute undifferentiated leukemia cases were characterized by more frequent mutations in PHF6 (5/15 vs 0/19, p = 0.016) and more frequent expression of TdT on blasts (p = 0.003) while acute myeloid leukemia with minimal differentiation cases had more frequent CD123 expression (p = 0.042). Outcome data showed no difference in overall survival, relapse free survival, or rates of complete remission between acute undifferentiated leukemia and acute myeloid leukemia with minimal differentiation groups (p > 0.05). Acute myeloid leukemia with myelodysplasia-related changes patients showed shorter survival when censoring for bone marrow transplant as compared to acute undifferentiated leukemia (p = 0.03) and acute myeloid leukemia with minimal differentiation (p = 0.002). In this largest series to date, the acute undifferentiated leukemia group shows distinct characteristics from acute myeloid leukemia with minimal differentiation, including more frequent PHF6 mutations and expression of TdT.
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http://dx.doi.org/10.1038/s41379-019-0263-3DOI Listing
September 2019

Update on the pathologic diagnosis of chronic myelomonocytic leukemia.

Mod Pathol 2019 06 5;32(6):732-740. Epub 2019 Feb 5.

Department of Pathology, Texas Tech Health Sciences Center, El Paso, TX, USA.

The diagnostic criteria for chronic myelomonocytic leukemia were recently revised in the 2016 World Health Organization classification update and include new and revised subtypes. In addition, molecular genetic studies have provided new insights into the prognosis and diagnosis of this myeloid neoplasm. This review summarizes the 2016 changes to the diagnostic criteria, discusses potential future changes that may impact diagnosis and provides an overview of recent advances in the diagnosis and prognosis determination of chronic myelomonocytic leukemia.
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http://dx.doi.org/10.1038/s41379-019-0215-yDOI Listing
June 2019

Hematopoietic neoplasms with 9p24/JAK2 rearrangement: a multicenter study.

Mod Pathol 2019 04 6;32(4):490-498. Epub 2018 Nov 6.

Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

The purpose of this study is to examine hematopoietic neoplasms with 9p24/JAK2 rearrangement including neoplasms associated with t(8;9)(p22;p24)/PCM1-JAK2 fusion neoplasm as well as cases with translocations involving 9p24/JAK2 and other partner genes. From seven large medical centers, we identified ten patients with t(8;9)(p22;p24) /PCM1-JAK2 and 3 with t(9p24;v)/JAK2 at diagnosis. Majority of the cases showed myeloproliferative neoplasm (MPN) associated features (n = 7) characterized by variable degrees of eosinophilia, myelofibrosis, frequent proliferations of early erythroblasts in bone marrow and extramedullary sites, and infrequent/absent somatic mutations. Other less common presentations included myelodysplastic syndromes (MDS) or MDS/MPN (one each). Four patients presented with B-lymphoblastic leukemia (B-ALL), and of them, two patients with t(8;9)(p22;p24.1) were proven to be B-lymphoblastic crisis of MPN; and the other two cases with t(9p24;v) both were de novo B-ALL, BCR-ABL1-like (Ph-like). We show that the hematopoietic neoplasms with 9p24/JAK2 rearrangement are extremely rare, and most of them are associated with t(8;9)(p22;p24)/PCM1-JAK2, a recent provisional World Health Organization entity under "myeloid/lymphoid neoplasm with a specific gene rearrangement". Cases of t(8;9)(p22;p24)/PCM1-JAK2, though heterogeneous, do exhibit some common clinicopathological characteristic features. Cases with t(9p24;v)/JAK2 are extremely rare; while such cases with a MPN presentation may resemble t(8;9)(p22;p24.1)/PCM1-JAK2, B-ALL cases presenting de novo B-ALL might belong to Ph-like B-ALL.
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http://dx.doi.org/10.1038/s41379-018-0165-9DOI Listing
April 2019

A multimodality work-up of patients with Hypereosinophilia.

Am J Hematol 2018 11 26;93(11):1337-1346. Epub 2018 Sep 26.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

The work-up of patients with hypereosinophilia (HE) is complex. Following the recently revised World Health Organization criteria, we retrospectively reviewed 125 patients who were referred to us to exclude a neoplastic cause of HE (2003-2016). The clinical laboratory work-up confirmed secondary HE in 25 (20%) patients; myeloid/lymphoid neoplasms with rearrangements of PDGFRA (n = 9) or PDGFRB (n = 2) (9%); HE associated with a well-defined myeloid neoplasm in 8 (6%); and abnormal bone marrow and/or molecular genetic abnormalities consistent with chronic eosinophilic leukemia (CEL), not otherwise specified (NOS) in 21 (17%) patients. For the remaining 60 (48%) patients, a specific diagnosis was not identified, and 56 patients had HE related findings consistent with idiopathic hypereosinophilic syndrome (HES), while 4 patients who were asymptomatic. With a median follow up of 35.3 months (range, <1-104), patients with CEL, not otherwise specified (NOS) had a median OS of 26.1 months, significantly inferior to patients with idiopathic HES (not reached, P < .01). Thus, our experience in a single tertiary cancer center shows that the work-up of HE following WHO recommendations requires a multimodality-based approach; and a correct diagnosis determines risk stratification and proper patient management. However, the causes of HE remain unknown in approximately half of referred patients, indicating the need for further studies.
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http://dx.doi.org/10.1002/ajh.25247DOI Listing
November 2018