Since Dimitri Romanowski, in 1891, invented a staining technique that made intracellular structures visible, and Gustaaf Giemsa, in his studies of malaria detection, described a method to stabilize and standardize this technique, light microscopic examination and description of the cells on films of blood and bone marrow has been the most important tool in the diagnosis and classification of hematologic malignancies.21 Subsequently, in 1976, this morphological assessment formed the basis of the French-American-British (FAB) classification.3 To define the lymphatic, myeloid and monocytic character of the cells more specifically than the degree obtained using only morphology, cytochemical reactions for myeloperoxidase and non-specific esterase, also performed on the film, were included. Soon immunological methods were added to this classification for the detection of megakaryoblasts and those blasts that are negative both for myeloperoxydase and B- and T-lymphoid markers.54
The introduction of the immunophenotypic characterization of the cells for diagnostic purposes was further facilitated when monoclonal antibodies and flow cytometric reading techniques became available in the 1980s. In those days, the immunophenotypic characterization of hematologic malignancies was considered by many to generate much more objective results than morphology.
But a new development, starting with the discovery of the Philadelphia chromosome in 1960 and the underlying translocation (9;22) in 1973, led to the definition of the disease entity of chronic myeloid leukemia, primarily based on a genetic abnormality.76 Acute myeloid leukemias with recurrent cytogenetic abnormalities were to follow (WHO 2001) and also mutations themselves became the key defining criterion (WHO 2008).98 This development is expected to progress further when new generation sequencing will become daily diagnostic practice.10
Without a doubt, these developments have changed the role and significance of the morphological profile in the diagnosis of hematologic malignancies considerably, and will continue to do so in the future.
But should we, as clinical hematologists, sell our microscopes on eBay¿
Let us not be too quick to say “no”. Although the question is a painful one (because one of the most attractive aspects of hematology, and the reason why many physicians choose to become a clinical hematologist, has been the involvement in diagnostic procedures that is so uncommon in most other specialities) we have to be realistic. Also, besides the technical developments that have taken place, clinical hematologists are under such huge pressure in their working environment that they are forced to push morphological examination to the edge of the agenda, and there is a tendency to concentrate hematologic diagnostics in big centers, often commercial facilities. These are all additional factors to take into consideration.
To put the question in another way, can morphology offer any answers that other techniques cannot provide¿
First of all, the technique is quick and cheap, which makes it highly suitable for getting a first impression about what is behind an abnormality found at physical examination or in the blood cell count. Secondly, it can direct further diagnostic interventions if needed. Also, when further examinations are required, it can be used as a quality control: for example, are the cells of interest present in the sample, e.g. plasma cells when a myeloma is suspected or are there, in any case, enough cells for fluorescence in situ hybridization examination.
In the diagnosis and classification of hematologic malignant diseases, morphology is required by the WHO classification in the definition of blasts and monocytic lineage and in the description of myelodysplastic features.9 In both cases, immunophenotype may help, but is not considered to be sufficient. However, several of the acute leukemias are no longer defined by blast count, and it is to be expected that this will apply to more of them when next-generation sequencing techniques have become a more common procedure in diagnostics. Also, definition of dysplasia by immunophenotypic, genetic or epigenetic changes may become more common. The same is true for the definition of complete remission in acute leukemias, currently defined by morphological blast count, but increasingly by immunophenotype and PCR-based techniques.
Taken together, and in spite of new developments, there remains a niche for morphological examination of the blood film or the bone marrow aspirate that is not easily replaced by other, more advanced techniques. This being the case, a second, more difficult, question arises. Does the clinical hematologist need to be involved in the morphological assessment¿ Frankly speaking the answer is “no”. One example is those clinical oncologists who rely completely on the expertise of the pathologist for the diagnosis of the tumor. However, there are several arguments in favor of involving the clinical hematologist in the diagnostic process. The most important reason is the large diversity of the problems that may be hidden behind a putative minor abnormality, especially in the field of hematology. ‘Leukopenia’ can mean many things. A morphological examination will help ask the right questions to the right specialized laboratories or scientists who are used to starting with the destruction of the cells in order to make their own analysis. The final diagnosis and classification in hematologic malignancies is the product of the integration of many different results. Since, and not only according to the WHO classification, clinical data have to be included in this final classification, the clinical hematologist is the right person to combine the results from the different assessments and make an overall final conclusion. He is, after all, the person who initiated the diagnostic procedure and he is the one who can guide this process. And to do this efficiently and cost effectively, he may be the most suitable person to carry out the morphological screening.
The landscape of diagnostics in malignant hematology is changing towards a more high-tech approach and greater specialization, and the significance of morphology as part of this process is changing with it. So, what are the clinical hematologists going to do with their microscopes: use them or sell them¿
- Mars van ‘t Veer is a consultant hematologist at Addenbrooke’s University Hospital, Cambridge, UK.
- Torsten Haferlach works at the MLL Munich Leukemia Laboratory, Germany.
- Financial and other disclosures provided by the author using the ICMJE (www.icmje.org) Uniform Format for Disclosure of Competing Interests are available with the full text of this paper at www.haematologica.org.
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