Editor’s note: This issue’s Continuing Education section is comprised of two outstanding articles on different aspects of interest to the Hematology bench. The first explores the testing strategies and diagnostic challenges related to myelodysplastic syndrome. The second describes an interesting study that analyzes sample degeneration of blood components on days 2 through 6 after collection.
Myelodysplastic syndrome (MDS) is a group of complex, often deadly blood disorders in which the bone marrow no longer makes enough healthy blood cells. In about one-third of patients with MDS, the disease transforms into acute myelogenous leukemia (AML), usually within months to a few years. Patients who have MDS are frequently misdiagnosed or diagnosed when the disease is already in its late stages.
Challenges to diagnosis
MDS is a challenging diagnosis to make for a number of reasons. For one, it is not all that common. Between 2006 and 2010 there were an estimated 14,123 new cases of MDS in the United States per year.1 MDS predominantly affects the elderly. The median age of diagnosis is 70 years, though approximately 10 percent of cases affect people younger than 50 years of age. Individuals who have had chemotherapy or radiation therapy are also at a higher risk for developing therapy-related MDS. Clinicians who work in an academic institution that serves a large patient population are likely to see more specialized cases than their counterparts who work in a smaller, community-hospital setting.
Patients with MDS present with cytopenias, or low blood cell counts. Yet many people have cytopenias, which can be acquired from other medical conditions, such as deficiencies of vitamin B12 or folate and a variety of infections, and as a side effect of certain medications, among other causes. Many nonmalignant disorders mimic the symptoms of MDS, including megaloblastic anemia, parvovirus infection, and autoimmune disease. Also, morphology can have an element of subjectivity. Thus, even though guidelines exist for the diagnosis and treatment of MDS, its identification by a clinician can be difficult.
Making a diagnosis
MDS is considered a type of cancer. Normally, blood cells are produced in a controlled manner by the bone marrow. In MDS, the stem cells in the bone marrow acquire mutations and do not function normally. One or more types of blood cells that they produce do not mature and are abnormal. When the immature blood cells fill up the marrow, there is less room for healthy red or white blood cells or platelets to develop in the bone marrow. This can lead to anemia, easy bleeding, and infection.
MDS diagnosis requires clear communication among the entire healthcare team. A cooperative effort among pathologists, cytogeneticists, and hematologists/oncologists is best for accurate diagnosis, prognostication, and determination of the best therapeutic plan.
To make a diagnosis, first a complete blood count (CBC) is performed to see whether the numbers of various types of blood cells are within normal ranges. Abnormalities provide the first sign that someone may have MDS, and examination of a blood smear should be performed. A bone marrow biopsy and a bone marrow aspirate are needed to make the diagnosis of MDS when the blood tests do not show the reason for the abnormal blood counts. Tests performed on these samples will help confirm the diagnosis of MDS and help the clinician determine the most effective treatment and prognosis.
Tests that are performed on bone marrow samples include:
- Cytogenetic studies. Such studies help to determine whether there are chromosomal abnormalities in bone marrow cells.
- Morphologic studies. Physicians look at the bone marrow cells to determine whether the cells appear to be abnormal.
- Flow cytometry. Cells are passed through a laser beam for analysis to see whether the bone marrow cells are developing normally and to obtain an estimate of the blast (immature myeloid cell) count.
- Molecular genetic studies. Highly sensitive DNA and RNA tests are conducted to determine the specific genetic traits of the bone marrow cells.
When pathologists evaluate bone marrow samples and peripheral blood smear samples for evidence of MDS, they need to assess whether dysplasia is present in the samples and quantitate the number of blasts present. Dysplasia is present as morphologic abnormalities in the cells in the blood and bone marrow. More than 10 percent of all cells in a particular cell line (e.g. erythroid cells, granulocytic cells, megakaryocytes) have to show morphologic dysplasia before a diagnosis of MDS is typically made. The pathologist will also look at the blood and bone marrow samples and count the number of blasts that are present in each sample. This is important for classifying the type of MDS that a patient may have.
Determining the exact percentage of blasts is critical to making the correct diagnosis. It is recommended that the pathologist count 500 cells in the bone marrow to get an accurate “blast count.” The blast count is part of that International Prognostic Scoring System (IPSS) for MDS. Many physicians use the IPSS to determine the severity of a patient’s MDS. The following prognostic indicators are used by the IPSS to predict the progression of a patient’s disease:
- The percentage of leukemic blast cells in the marrow
- The type of chromosomal changes in the marrow cells
- The presence of one or more low blood cell counts.
Each category is given a numerical IPSS score. The patient’s IPSS risk category is determined by adding together all of the IPSS scores within the three disease factors.
Obtaining adequate specimens
Obtaining an adequate specimen is key to accurately diagnosing MDS. An adequate bone marrow aspirate smear must contain bone marrow particles to ensure that the bone marrow is properly sampled. An adequate bone marrow biopsy is generally at least 1 cm in length and should contain bone marrow. Challenges to getting a good specimen include operator experience, a patient’s tolerance of the procedure, and intrinsic factors of the specimen—for example, it will be difficult to obtain a good aspirate smear from a fibrotic sample. After that, the specimen has to be stained properly and properly evaluated. (There are anecdotal reports that some physicians are handicapping themselves by not following the guidelines to do a 500-cell blast count. This may be because some pathologists are improperly trained, or the specimen may be of poor quality, or there is insufficient sample to enumerate 500 cells.)
Another difficulty is deciding what dysplasia is. Years of training and clinical experience are required for a pathologist to confidently recognize morphologic dysplasia, and there are other conditions which can look similar to the dysplasia found in MDS. When pathologists suspect a condition that can mimic MDS, they have to contact the clinician and get additional information such as medications, prior history of malignancy or chemotherapy, recent infection, comorbidities, and nutritional deficiencies. The pathologist has to dig into the patient background to know whether there are findings that could explain abnormalities seen in the blood and bone marrow samples and how long a cytopenia has been persisting. This is why having a case presented at a Tumor Board is important. Tumor boards enable a multidisciplinary approach to patient care which includes pathologists, hematologists/oncologists, radiologists, and other members of the healthcare team.
Future of diagnosis and treatment
The Connect AML and MDS Registry, an observational registry sponsored by a global biopharmaceutical company, provides insights into diagnosis and treatment as they relate to clinical outcomes of patients with newly diagnosed MDS or AML in routine clinical practice. This is an opportunity to see how patients are diagnosed in regular practice, including what tests are or are not ordered and how hematologists and pathologists routinely practice in diagnosing patients. This also allows pathologists to evaluate molecular and cellular markers that may provide further prognostic classification and/or might be predictive of therapy outcomes. No medication is given as a part of this study, but one can observe what therapies patients receive. Initial observations show that diagnosing MDS and AML is challenging and that there are some areas where there is uniformity of practice, while other areas show much more variability.
Looking ahead, MDS diagnosis and treatment can be improved through education that addresses the challenges the disease poses for pathologists, hematologists, cytogeneticists, and other healthcare professionals. For pathologists, it is important to recognize morphologic dysplasia and also to recognize what is not dysplasia. Morphologic recognition of blasts is also key, and standardizing practices in counting blasts and what tests to perform is an area that needs to be improved. That has been addressed over the last two years through an educational program run by ASCP, ASH, and The France Foundation aimed at pathologists, hematologists/oncologists, and laboratory professionals involved in diagnosing and treating patients with MDS. The program addresses what should be done to model best practices.
Part of this commitment involves taking advantage of opportunities to come together with partners on the interdisciplinary team to discuss and discover innovative solutions to case-based problems. The aforementioned organizations also have collaborated to build a comprehensive, multi-disciplinary, case-based, MDS-directed educational curriculum that features live summits and online materials designed to address the complexities of MDS.
Such education is well-suited for physicians at all levels of training and for laboratory professionals. The effort continues to establish best practices and to improve diagnosis and treatment of patients with MDS.
- Fenaux P, Haase D, Sanz GF, Santini V, Buske C. Myelodysplastic Syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Ann Oncol. 2014;25 (suppl 3): iii57-iii69. DOI: https://doi.org/10.1093/annonc/mdu180.
Tracy I. George, MD, FASCP, is a Professor in the Department of Pathology, University of New Mexico School of Medicine. She also serves as Vice Chair of Clinical Affairs and Hematopathology Division Chief at the University of New Mexico Health Sciences Center, and as Medical Director of the Genetics and Cytometry Laboratories at TriCore Reference Laboratories in Albuquerque, NM. In 2015 and 2016, Dr. George chaired a national steering committee which implemented a new teaching curriculum and methods in myelodysplastic syndrome, a collaboration of the American Society for Clinical Pathology, the American Society of Hematology, and The France Foundation.