An introduction and brief historical perspective
Attilio Orazi | | Longer Read
Prior to the 1970s, we lacked a uniform system for classification and nomenclature of the leukemic diseases. In fact, most of the terminology used to describe diseases represented the work of one or a few individuals. An international effort led to the French-American-British (FAB) classification of acute leukemias originally published in 1976 (1,2,3,4), which became the first universally adopted classification of these neoplasms. Additionally, the FAB group published several other papers over the next quarter-century providing guidelines for the classification of both acute and chronic hematologic neoplasms (5,6,7). FAB schemes were based largely on the morphologic characteristics used to distinguish various myeloid neoplasms.
The 2001 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues reflected a paradigm shift in our approach. Classification was based on consensus among many hematopathologists from around the world, as well as input from a clinical advisory committee of international expert hematologists and oncologists. For the first time, genetic information was incorporated into the diagnostic algorithms provided. Subsequent editions and revisions (8,9,10)incorporated new genetic data that have become available since the publication of the third edition.
The revised fourth edition follows the philosophy of its predecessors – integrating clinical features, morphology, immunophenotyping, cytogenetics, and molecular genetics to define disease entities of clinical significance. The most recent revision explicitly acknowledges that recurrent genetic abnormalities not only provide objective criteria for recognition of specific entities, but are also vital for the identification of abnormal gene products and pathways that can be used as therapeutic targets. Several disease subgroups and sets of defining criteria now include the presence of gene mutations with or without a cytogenetic correlate. However, the importance of a careful clinical, morphological, and immunophenotypic characterization of every myeloid neoplasm – and correlation with genetic findings – cannot be overemphasized.
Myeloproliferative neoplasms (MPN)
Since the 1980s, chronic myeloid leukemia (CML) has been recognized as a molecularly defined entity based on the presence of the BCR-ABL1 gene fusion. The discoveries of activating JAK2 mutations and mutations in CALR, MPL, and CSF3R have revolutionized the diagnostic approach to myeloproliferative neoplasms (11,12,13,14,15,16). However, these mutations are not specific to any single clinical or morphological MPN phenotype and some are also reported in certain cases of myelodysplastic syndromes (MDS), MDS/MPN, and acute myeloid leukemia (AML). Therefore, we need an integrated multimodality for the classification of these myeloid neoplasms. Early MPN can be difficult to identify. Polycythemia vera, for instance, is often missed by relying only on CBC data; bone marrow morphology represents a critical criterion for diagnosis. Essential thrombocythemia must be distinguished from prefibrotic or early primary myelofibrosis (pre-PMF) – achieved by applying standardized morphologic criteria (10).
Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and myeloid/lymphoid neoplasms with eosinophilia
The MDS/MPN neoplasms category was introduced in 2002 to include myeloid neoplasms with clinical, laboratory, and morphologic features that overlap between MDS and MPN. Chronic myelomonocytic leukemia (CMML) – considered a variant of MDS by the FAB system – became a separate entity within this new disease group. In 2016, based on accumulated scientific evidence, MDS/MPN with ring sideroblasts and thrombocytosis was moved from provisional to full status (9,10). The approach for diagnosing MDS/MPN is strictly multiparametric. An important point is the separation of CMML from PMF with monocytosis in patients with JAK2 V617F mutation, which requires careful consideration of clinical and genetic results (17).
The presence of specific gene rearrangements is key to the classification of myeloid/lymphoid neoplasms with eosinophilia, a group of truly molecularly defined diseases. In 2016, the myeloid neoplasm with t(8;9)(p22;p24.1);PCM1-JAK2 became a new provisional entity (18).
Myelodysplastic syndromes (MDS)
Persistent cytopenia is required for diagnosing a myelodysplastic syndrome (MDS). The cytopenia levels that should trigger an investigation were redefined in 2017 (19). MDS classification still incorporates morphologic elements of the FAB classification originally proposed in 1982 (3). Cytogenetics was added in 2001 and expanded in 2008. Targeted sequencing of myeloid neoplasm-associated genes can detect mutations in a vast majority of MDS patients (20,21) and selected gene mutations are integrated into several diagnostic algorithms. SF3B1 mutation is now a defining criterion for MDS with single or multilineage dysplasia and ring sideroblasts in cases with less than 15 percent ring sideroblasts. Evaluation for TP53 mutation, a negative prognostic marker, is particularly relevant in cases of MDS with isolated del(5q), which identifies a clinically adverse subgroup. Importantly, acquired clonal mutations identical to those seen in MDS can occur in the hematopoietic cells of apparently healthy older individuals (22,23) – so-called “clonal hematopoiesis of indeterminate potential” (CHIP). Although a minority of patients with CHIP subsequently develop MDS, the presence of MDS-associated somatic mutations alone is not considered diagnostic of MDS.
Acute myeloid leukemias (AML)
The WHO continues to define specific AML disease entities by focusing on significant cytogenetic and molecular genetic subgroups. Many recurring, balanced cytogenetic abnormalities are recognized in AML; most that are not formally recognized by the classification are rare (9,10,24), often occurring in pediatric patients. Although important to recognize, they do not represent separate disease categories. The realization that the improved prognosis seen in AML with mutated CEBPA is only associated with the presence of a biallelic mutation of the gene has modified the disease definition. Additionally, the presence of NPM1 or biallelic CEBPA mutation now supersedes the presence of multilineage dysplasia in the classification. Finally, a provisional category of AML with mutated RUNX1 has been added for cases of de novo AML with RAS mutation that are not associated with MDS-related cytogenetic abnormalities.
Myeloid neoplasms with germline predisposition
Cases of MDS or acute leukemia can be associated with germline mutations. A major change to the 2016 revision of the WHO classification was the addition of a new section on myeloid neoplasms with germline predisposition, which includes cases of MDS, MDS/ MPN, and AML that occur on the background of those mutations (9,10). The presence of germline genetic aberrations should indicate a need to screen family members for these aberrations and healthy family members diagnosed with a leukemia predisposition syndrome should be counseled regarding appropriate cancer surveillance (25).
The development of a globally adopted classification system crafted both by hematopathologists and clinicians has been of great benefit to the field of hematologic malignancies in general and of myeloid neoplasm in particular. Its flexible approach allows for the seamless integration of new data into a sound diagnostic scaffold. It remains an effective instrument for daily therapeutic decision-making and clinical trial design and will inform any future classification scheme.
Read on to discover our four myeloid cases...
Case 1: Clonal Cytopenia of Uncertain Significance or Myelodysplastic Syndrome?
Case 2: SF3B1-Mutant Chronic Myelomonocytic Leukemia
Case 3: Myelodysplastic Syndrome with Excess Blasts and Fibrosis
Case 4: Elevating the Treatment Standard in Older Patients with AML
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