The peripheral blood of chronic myeloid leukemia (CML) cells is characterized by leukocytosis due to the outpouring of immature and mature myeloid cells with peaks of myelocytes and neutrophils. Megakaryocytic series, including micromegakaryocytes, are rarely mentioned as standard PB findings in textbooks and other accounts from the West, reflecting a rare occurrence in CML as seen in the West. The occasional texts that do mention circulating micromegakaryocytes, state that they may be seen in the chronic phase, be associated with, or increase, in the course of acceleration, and when present in abundance in blast crisis, provide evidence of megakaryocytic lineage of the blasts.
Overall, accounts from the West are not representative of what is quite apparent from even a casual examination of the peripheral blood of our CML patients - that circulating Mk cells are far from rare or inconsequential findings and hence represent an unstudied population. In the present study we evaluated the morphology of peripheral blood Mk cells in 324 (235 chronic, 65 accelerated and 24 blastic phases) untreated CML patients, to systematically document megakaryocytic maturation in the peripheral blood, a milieu not native to megakaryocytes.
Observations and discussion: Over 40% of our chronic phase patients and 2/3 of those who were in accelerated phase had, respectively, up to 4.5% and 8.5% circulating micromegakaryocytes in the peripheral blood smear. Circulating Mk cells, up to approx.15%, were present also in 1/3 of our blast crisis patients, higher percentages merging imperceptibly with pure megakaryocytic blast crisis.
The main findings, reflecting two possibly inter-related themes of megakaroypoiesis in the peripheral blood, were as follows:
- Attempt at platelet production by megakaryoblasts – precocious and unsuccessful. First, megakaryocytic blasts, especially in some cases of blast crisis, precociously make a foray into platelet formation and end up producing not normal platelets, but huge agranular or poorly granular cytoplasmic lobulated masses, that break off and come to lie in the circulation. Though obvious from morphology alone, these are demonstrable also by CD41 immunocytochemistry. This attempt at platelet formation continues unabated even as the blasts mature further, as evidenced by increasing condensation of nuclear chromatin and appearance of granules in cytoplasm (Figure, top two panels). This evidence of unsuccessful effort may exist, in a considerably attenuated form in chronic phase as well.
- Production of mature platelets by unilobate mature micromegakaryocytes. The platelet-producing micromegakaryocyte is the central character in the second theme of peripheral blood Mk maturation. Seen in all phases of CML it is often the only type of circulating Mk cell in the chronic, and sometimes the accelerated phase. Circulating micromegakaryocytes have been accorded emphasis mostly as part of myelodysplastic syndrome and acute myeloid leukemia in the Western literature. We, however, find them more commonly in CML.
We find it surprising that neither these observations, nor the frequency of circulating Mk cells in as many as 2/3 of CML cases recorded by Minot, has been mentioned in reports or accounts of Mk cells in CML that have ensued since, including those that have cited Minot’s paper. Quite clearly, circulating Mk cells have been seen more as findings rather than as clues that when pieced together provide a perspective of Mk maturation distinct from that based on observations on the BM. The suggestion that they are dyspoietic, evidently based on their appearance that is different from the normal, is premature; it has never been investigated and proven.
Conclusion: We conclude that circulating Mk cells abound in our CML patients and afford a setting in which megakaryocytic maturation in the peripheral blood can be studied. Two themes of maturation, possibly interrelated, and quite distinct from what happens in the marrow, play out to variable extents in individual patients. One centered around blast cells prematurely attempting platelet formation, delivers to the circulation, in a wasted effort, large cytoplasmic fragments rather than normal platelets. The other has the well described micromegakaryocyte at its center, and yields morphologically normal platelets. The former is floridly dysplastic. The latter, differing from normal in not being polyploid, is presumed dysplastic; the possibility, however, that it may just be an alternative path of effective platelet formation that megakaryocytes follow when in circulation, has not been ruled out. Both these are exciting possibilities that need to be investigated. Quite fortuitously our observations are but a revisit of the perceptive exposition of George Minot on the subject, presented nearly a century ago.
Written by: Anita Chopra and Rajive Kumar
- Minot GR. Megacaryocytes in the peripheral circulation. J Exp Med 1922;361: 1-7.
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