How the disease subclassifications differ
Amy Carpenter
April 2025—Speakers in a CAP24 session last fall spotlighted the differences between the WHO fifth edition of hematolymphoid tumors and the International Consensus Classification and set forth a framework for how to approach myeloid malignancy cases.
While the differences in the two classifications for myeloid malignancies can be confusing, “the basic understanding of how to diagnose myeloid malignancies remains the same,” said Kamran M. Mirza, MD, PhD, professor of pathology (hematopathology) and the Godfrey D. Stobbe professor of pathology education, University of Michigan. “We synthesize the blast count, the morphology, cytogenetics, and molecular genetics.”
“All the ingredients are the same, but how you cook the meal is a little different,” he said.
Dr. Mirza was a co-presenter with Sanam Loghavi, MD, associate professor of pathology and laboratory medicine, Department of Hematopathology, University of Texas MD Anderson Cancer Center. We report Dr. Mirza’s comments and cases here and will report the same for Dr. Loghavi in a subsequent article.
Understanding the framework of normal hematopoiesis and how the transition to myeloid neoplasia occurs enables an understanding of the driver mutations that give rise to malignant myeloid clones, Dr. Mirza said.
Under normal circumstances, highly prolific stem cells “will give us what we typically want to see: a normal cellular bone marrow for age and no abnormalities in the peripheral blood,” he said. However, if there is a clonal hematopoietic change in one of those stem cells and if that change is at a sufficiently high variant allele frequency, “this could lead to a clonal proliferation or a subclonal proliferation of those stem cells.”
Early on in this process, no changes can be identified morphologically in the bone marrow, and quantitative changes may not be able to be seen in the blood or the differential of the marrow cells. However, “a perfect storm of mutations” and/or cytogenetic or other molecular genetic abnormalities could lead to a clonal hematopoietic event, which leads to myeloid neoplasia, he said. Epigenetic factors and the microenvironment are among the many things that can play a role.
“Ultimately, in myeloid neoplasia what we’re looking for or trying to assess is ineffective hematopoiesis, where typically we will see highly cellular marrows,” Dr. Mirza said, but the hematopoietic response is ineffective and patients will usually present with cytopenias. “The framework hasn’t changed.”
Unchanged in the premyeloid neoplasms is the concept of clonal hematopoiesis of indeterminate potential (CHIP), clonal cytopenia of undetermined significance (CCUS), and idiopathic cytopenia of undetermined significance (ICUS). “That lays the foundation for the framework.”
In individuals with normal blood cell counts, there should be no detectable somatic mutations, though “all of us may have a ubiquitous low level of a mutation and we live without symptoms or changes in our hematopoietic system,” Dr. Mirza said.
The group with no CHIP can continue on and is prone, like the general population, to having nonhematological sequelae, such as cardiovascular disease, and can progress to de novo acute myeloid leukemia, myelodysplastic neoplasm/syndrome, or myeloid neoplasms (MN).
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There will be a population of individuals who will get those mutations at a higher level, he said, noting the prevalence is 10 to 40 percent. And given a variety of factors—inflammation, genetics, smoking, and other environmental risks—they will be in the CHIP category where the hematopoiesis is clonal and clonality can be detected by molecular genetics. Overall their blood counts remain normal. “This is the first category of premyeloid neoplasms.”
Those with CHIP have a 0.5 to one percent risk of progression to myeloid neoplasia.
The other population consists of patients who present with unexplained cytopenias and have clonal hematopoiesis at a variant allele frequency of more than two percent. “We have to make sure that the cytopenias are not due to reactive causes,” Dr. Mirza said, and once that has been done, “Ultimately, we realize they can have clonal or nonclonal hematopoiesis.”
Patients who present with cytopenia but for whom no mutation is detected in the bone marrow examination, in the karyotype analysis and/or by FISH, or by next-generation sequencing are in the ICUS category, and non-neoplastic causes have to be reconsidered. In contrast, patients who present with cytopenia and who have genetic abnormalities or mutations above the two percent VAF level and no morphologic dysplasia will be in the CCUS category, “basically CHIP with evidence of clonal disease and cytopenia,” he said. These patients have a risk of up to 10 to 20 percent per year of progressing to acute myeloid leukemia, myelodysplastic syndrome/neoplasm, or other hematological disorders.
“With this framework, we have an understanding that with all our stem cells constantly proliferating, some become clonal. There could be low-level ubiquitous mutations in the population, but after they hit a threshold of VAF, you will have to think about whether they fall under clonal cytopenia of undetermined significance or clonal hematopoiesis of indeterminate potential.”
All that said, “to establish the diagnosis of myeloid malignancy,” Dr. Mirza said, “you still need the same three things we’ve needed for decades”—blood count, morphology, and genetics.
The blood count is important to confirm that hematopoiesis is ineffective. Genetics can confirm whether hematopoiesis is clonal. Morphology confirms the hematopoietic cells are functionally abnormal. “And while the classification system has moved around about how much importance to give to morphology in certain subclassifications, it remains one of the pillars of diagnosing myeloid malignancy,” Dr. Mirza said.
“With this framework, you need to take a look at these three events, along with the patient’s history, to make a diagnosis.”