We are fortunate to live in unprecedented times, when rapid progress in molecular diagnostic techniques and computational biology has allowed tremendous advances in scientific research of numerous human conditions, including in the field of bone marrow pathology, leading to a more granular understanding of myeloid neoplasms than ever before. It is therefore not surprising that the exponential proliferation of scientific reports, the sheer volume and the variable quality of the new information have led to significant new questions and unresolved concerns. One of the great challenges we now face is to how best summarize and make sense of the abundant and occasionally conflicting scientific data. The field of hematopathology in particular had an unfortunate recent fracturing where most of the editors and authors of the 3rd, 4th, and the updated 4th edition of the World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues have organized a new classification – the International Consensus Classification (ICC) [1], while the upcoming 5th edition of the WHO is led by a different group of expert hematopathologists [2]. The two classifications are generally in agreement, but there are occasional significant differences, especially in the area of bone marrow pathology to which this issue is dedicated. Thus, this very timely special issue in Pathobiology has been sponsored by the European Bone Marrow Working Group and is dedicated to updates and current challenges in the diagnosis of myeloid neoplasms.

Artificial intelligence is an extremely timely topic with prominent coverage in the international news cycle. In particular, advances in digital pathology continue to revolutionize the practice of pathology. As more and more pathology departments undergo the process of digitalization of routine diagnostic slides, there is much interest in applying machine learning techniques to the daily clinical practice. Can these methods be applied to bone marrow pathology? Drs van Eekelen, Litjens, and Hebeda from the Radboud University Medical Center in Nijmegen, Netherlands expand on their prior work and share their experience and insights with artificial intelligence in bone marrow histology interpretation as well as the challenges and future perspectives of this potentially practice-changing technology [3].

As far as advances in molecular biology and diagnostics, the Weill Cornell Medicine molecular hematopathology group led by Dr. Michael Kluk [4] has published the internal experience of validation and subsequent clinical utilization of an RNA-based NGS assay that enables detection of hybrid fusion transcripts including rare and novel gene partners and hotspot variants in certain high-use genes. This test has since been used clinically on the majority of cases of new and recurrent myeloid neoplasms. Through several interactive examples, the authors show how using this test has the potential to transform and improve the clinical practice in hematology-oncology of myeloid neoplasms.

TP53 mutated myeloid neoplasms are a broad new category of bone marrow neoplasms recognized by both the ICC and the upcoming 5th edition WHO. It is clear that TP53 status is an important prognostic indicator in MDS and AML, correlating with dismal patient outcomes. Better therapies, specifically geared toward this high-risk patient group are urgently needed. However, numerous controversies remain, including whether having a TP53 mutation is sufficient to define specific types of myeloid neoplasms. While the ICC recognizes both MDS and AML with mutated TP53 as distinct disease subtypes, the new WHO classification acknowledges TP53 mutated MDS, but not AML as discrete entities. In this special issue, Drs. Venugopal and Loghavi describe the biology of TP53 in myeloid neoplasms, the different approaches taken by the WHO and the ICC, and how this knowledge translates into current management of the patients, including a comprehensive discussion of several ongoing clinical trials [5].

NPM1 mutated AML is a well-characterized group of AML with recurrent genetic abnormalities. Both the ICC and the 5th edition WHO now consider NPM1 mutation as an AML-defining event, although at different blast count thresholds. Dr. Sanjay Patel discusses the pathophysiology of NPM1 mutation in myeloid neoplasia and the controversies in the disease classification [6]. He describes in detail the advances in minimal/measurable residual disease detection both by multiparameter flow cytometry and the molecular techniques (PCR, NGS). The review also summarizes the current advances in therapy directed toward this very common acute leukemia subtype, as well as the future therapeutic directions.

Advances in the molecular diagnostics including the widespread use of NGS and the emergence of gene expression profiling (RNA-seq) technology have revolutionized the diagnostic workup for hematologic disorders and led to the identification of new disease subgroups as well as prognostic information that impacts the clinical treatment. These advances seem especially significant in the pediatric hematologic malignancies group, which has been shown to have genetic features distinct from their adult counterparts. As an example, the updated 4th edition of the WHO has 14 subtypes of ALL including 4 provisional subtypes. The ICC now proposes 39 subtypes of ALL, including 14 provisional ones, based on the seminal work with whole-transcriptome analysis and gene expression clustering studies of thousands of ALL samples. In addition to ALL, the review by Drs. Liu and Geyer discusses the recent advances in juvenile myelomonocytic leukemia, pediatric AML, germline predisposition variants to MDS/AML, and pediatric MDS [7]. This review also includes a brief discussion of the updated classifications as it pertains to these disease entities.

Following on the theme of pediatric hematologic neoplasms, a multi-institutional study of five large academic centers in the USA including two children’s hospitals has examined 40 Down syndrome patients with myeloid proliferations, either transient abnormal myelopoiesis (TAM) or MDS/AML [8]. TAM is known to present with clinical, morphologic findings that are indistinguishable from MDS/AML. Both groups of children have the pathognomonic GATA1 mutation. The differentiation is imperative since as opposed to MDS/AML, TAM is a self-limited transient process that only requires supportive treatment. By careful examination of clinical presentation and outcome, morphology, flow cytometry, and molecular characteristics of the patients, the group finds significant differences between TAM and MDS/AML and provides concrete recommendations on achieving the differential diagnosis. The role and diagnostic strategies to identify the GATA1 mutation in this patient subgroup are also discussed.

Finally, progression in myeloid neoplasms is a challenging diagnostic area that is generally not discussed in the ICC or the WHO classifications since the provided diagnostic criteria are for patients with a new diagnosis of a myeloid neoplasm. Disease evolution and post-therapy modifications are not currently addressed, with the exception of myelofibrotic progression of polycythemia vera and essential thrombocythemia. Therefore, the various pathways for disease progression can cause considerable difficulties in the diagnostic clinical approach. Drs. Faria and Tzankov provide a comprehensive analysis of the current knowledge and experience in disease evolution in myeloid neoplasms, including the rare and poorly understood phenomena of acquisition of MPN features in MDS and, vice versa, acquired MDS characteristics in MPN, development of persistent monocytosis in MDS/MPN, lymphoblastic and histiocytic/dendritic transformation [9]. Detailed molecular analysis is provided to explain the current understanding of the phenotype-genotype associations.

The author would like to kindly thank the co-editors of this special issue: Dr. Alexandar Tzankov and Dr. Michael Kluk who greatly contributed to the scientific design and execution of this collection. The author and the co-editors would like to acknowledge the European Bone Marrow Working Group which has supported the publication of this special issue.

The author has no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

J.T.G. has written the editorial.

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