Mf csbrp
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Mf csbrp
- 1. Myeloproliferative disordersMyeloproliferative disorders MyelofibrosisMyelofibrosis Dr.CSBR.Prasad, M.D.
- 3. Chronic myelofibrosis [Agnogenic myeloid metaplasia] Development of obliterative marrow fibrosis Extensive deposition of collagen in the marrow by non-neoplastic fibroblasts Results in: Cytopenias Extramedullary hematopoiesis - EMH
- 4. Chronic myelofibrosis [Agnogenic myeloid metaplasia] Clinical studies have proved FIBROSIS is a secondary phenomenon Marrow fibrosis may result from: –MPD –Exposure to chemicals (benzene, aniline dyes) –Lymphomas / myelomas
- 5. Marrow fibrosis: there is very little collagen in the normal marrow Proliferation of connective tissue in the marrow is a constant feature in MF • > Reticulin • > Collagen type-III • > Vascularity • New bone formation (Osteomyelosclerosis) Chronic myelofibrosis [Agnogenic myeloid metaplasia]
- 6. The culprit in inducing marrow fibrosis is Megakaryocyte Fibrosis is caused by the inappropriate release of fibrogenic factors from neoplastic Mkc It includes: • PDGF • TGF-ß • Both are mitogenic to fibroblasts • TGF-ß - Collagen deposition and angiogenesis Chronic myelofibrosis [Agnogenic myeloid metaplasia]
- 7. Molecular Pathogenesis • Activating JAK2 mutations 50% to 60% of cases • MPL mutations in an additional 1% to 5% of cases • ? Whether primary myelofibrosis is distinct from PCV and ET or merely spent stage
- 8. EMHEMH As marrow fibrosis progresses, circulating hematopoietic stem cells take up residence in niches in secondary hematopoietic organs, such as: • the spleen • the liver, and • the lymph nodes leading to the appearance of extramedullary hematopoiesis - EMH
- 9. Clinical features: – Middle age/elderly – Splenomegaly (pain in the left hypochondrium) – Ascitis – Portal HT – EMH – X-rays may show increased bone density Chronic myelofibrosis [Agnogenic myeloid metaplasia]
- 10. Peripheral blood smear: – Anemia – Leucoerythroblastic blood picture – LEBP – TLC >100k – PLT >1000k (abnormal morphology) – Tear drop cells (>3/oil immersion) Chronic myelofibrosis [Agnogenic myeloid metaplasia]
- 11. Myelofibrosis Teardrop poikilocytes (>3/oil immersion) in MF
- 12. Are “tear drop” cells diagnostic of MF?Are “tear drop” cells diagnostic of MF? • Characteristic of primary myelofibrosis are: –Leukoerythroblastosis and –Teardrop red cells • They are also seen in many infiltrative disorders of the marrow, including granulomatous diseases and metastatic tumors
- 14. Osteosclerosis: is not seen with other MPDs and helps, when present, in arriving at a correct diagnosis
- 15. Mkc are always abnormal with pleomorphic shapes and exhibit clustering. Note also the ‘streaming’ of other marrow elements due to reticulin fibrosis.
- 16. Mkc are always abnormal with pleomorphic shapes and exhibit clustering. Note also the ‘streaming’ of other marrow elements due to reticulin fibrosis.
- 18. A reticulin stain shows diffuse marked (3+) fibrosis in Primary myelofibrosis
- 20. Bone marrow: -Dry tap (biopsy is a reliable way to diagnose) Sequence of events: -hyperplastic with >reticulin -fibrocollagenous proliferation -MKc prominence -fibrosis -sclerosis Chronic myelofibrosis [Agnogenic myeloid metaplasia]
- 21. Massive splenomegaly with infarcts
- 22. PVSG definition of MF: • Splenomegaly • Fibrosis >1/3 of adequate biopsy • LEBP • no >Red cell mass • Absence of Ph’ • Exclusion of secondary causes for MF (TB, NHL, Mets, Leishmania) Chronic myelofibrosis [Agnogenic myeloid metaplasia]
- 23. Course & Prognosis • Primary MF is a more difficult to treat than PCV or ET • The course is variable • Median survival is in the range of 3 to 5 years – Intercurrent infections – Thrombotic episodes – Bleeding related to platelet abnormalities and – Transformation to AML [5% to 20% of cases] – AML sometimes arises at extramedullary sites • Bone marrow transplantation - younger patients • Kinase inhibitors - Targeted therapy
- 24. References • Clinical laboratory hematology by McKenzie 2nd Edition. • Robbin’s pathologic basis of disease 8th Edition.
- 25. E N D
Editor's Notes
- It is not clear whether primary myelofibrosis (particularly when associated with JAK2 or MPL mutations) is truly distinct from PCV and ET, or merely reflects unusually rapid progression of these MPDs to the spent phase.
- Two important features of MF is LEBP and Tear drop cells >3/oil immersion.
- Tear Drop Cells Morphology:Red cells shaped like a tear drop or pear Found in:Bone marrow fibrosisMegaloblastic anaemiaIron deficiencyThalassaemia
- Teardrop-shaped red cells (dacryocytes), cells that were probably damaged during the birthing process in the fibrotic marrow, are also often seen. Although characteristic of primary myelofibrosis, leukoerythroblastosis and teardrop red cells are seen in many infiltrative disorders of the marrow, including granulomatous diseases and metastatic tumors.
- This low power view of a blood film shows that both primitive red cells (nucleated rbc or erythroblasts) are present, together with primitive white blood cells (myelocytes). This usually (but not always) indicates that the bone marrow has been infiltrated or replaced by such things as secondary cancer or fibrosis.
- [PRIMARY MYELOFIBROSIS, FIBROTIC STAGE]. Primary myelofibrosis can have diffuse thickening of the bony trabeculae, the so-called ‘Osteosclerosis.’ However, no significant osteoblastic or osteoclastic activity is generally seen. Osteosclerosis is not seen with other chronic myeloproliferative disorders and helps, when present, in arriving at a correct diagnosis.
- [PRIMARY MYELOFIBROSIS, FIBROTIC STAGE]. Megakaryocytes are almost always abnormal looking with pleomorphic shapes that range from small to large and also exhibit clustering. Note also the ‘streaming’ of other marrow elements due to reticulin fibrosis.
- [PRIMARY MYELOFIBROSIS, FIBROTIC STAGE]. In the pre-fibrotic stage (cellular phase of IMF) distinction of Primary myelofibrosis from essential thrombocythemia may be difficult. However, even in the cellular phase megakaryocytes in IMF are pleomorphic whereas in essential thrombocythemia megakaryocytes are large and hyperlobated but not pleomorphic. In this fibrotic stage marrow, megakaryocytes are clearly pleomorphic with small and larger forms that also show clustering.
- [PRIMARY MYELOFIBROSIS, FIBROTIC STAGE]. A reticulin stain shows diffuse marked (3+) fibrosis in Primary myelofibrosis. A core biopsy is required for semi-quantitative estimation of marrow fibrosis. A three-tier grading system has been in use, which quantifies fibrosis as mild (1+), moderate (2+), and severe (3+). A trichrome stain for collagen fibrosis must also be performed on all cases of Primary myelofibrosis in the fibrotic stage. This is because drugs are available to halt or reverse marrow reticulin fibrosis but same cannot be done for collagen fibrosis.
- FIGURE 13-40 Splenic infarcts. Multiple well-circumscribed infarcts are present in this spleen, which is massively enlarged (2820 gm; normal: 150–200 gm) by extramedullary hematopoiesis secondary to a myeloproliferative disorder (myelofibrosis). Recent infarcts are hemorrhagic, whereas older, more fibrotic infarcts are a pale yellow-gray color.
- LEBP = Leucoerythroblastic blood picture.
- Primary myelofibrosis is a much more difficult disease to treat than PCV or ET. The course is variable, but the median survival is in the range of 3 to 5 years. Threats to life include intercurrent infections, thrombotic episodes, bleeding related to platelet abnormalities, and transformation to AML, which occurs in 5% to 20% of cases. When myelofibrosis is extensive, AML sometimes arises at extramedullary sites, including lymph nodes and soft tissues. Bone marrow transplantation is being used in some younger patients, and kinase inhibitors represent a future hope for targeted therapy.
- Q. I have a question about the Philadelphia chromosome. The Philadelphia chromosome is present in chronic myeloid leukemia. It’s also present in some case of precursor-B acute lymphoblastic leukemia. I guess I am assuming that the translocation will result in a similar gene product, but just in a different cell line. You mentioned that the Ph+ B-ALL in adults is a bad prognosis. I am wondering if this malignancy would be treated with imatinib, like CML, due to the drug targeting the specific protein that is formed (bcr-abl). If so, would there still be a bad prognosis? Thanks! A. Great question! You are correct: a t(9;22) translocation involving the bcr and abl genes occurs in both CML and rare cases of precursor-B ALL. In some of the cases of Ph+ ALL, the genetic mutation (and gene product) is exactly the same as it is in CML; in others the breakpoint is slightly different, and a slightly different fusion protein is produced (but it is still a mutant tyrosine kinase with presumably similar effects on the malignant cells). Most cases of Ph+ ALL occurring in children have this different fusion protein, whereas only half of the cases occurring in adults have this different fusion protein (the other half of the adult cases have exactly the same breakpoint and product as is present in CML). It doesn’t seem to have any effect on prognosis whether you have the same fusion protein as in CML or the slightly different one. You’re also correct that the genetic mutation occurs in different cell lines in each disease: in CML it is in the myeloid cell line, whereas in Ph+ ALL it is in the lymphoid cell line. One weird thing, though, is that in CML you can often find the Ph’ in lymphoid cells too. Strange. It indicates that the translocation between 9 and 22 occurs way back in a very early precursor stem cell, one that has not yet committed itself to the myeloid or lymphoid lineage. The occasional appearance of lymphoid blast crisis in CML indicates the same thing. We don’t see a similar picture in Ph+ ALL, though (there is no phase of the disease that involves myeloid cells). So perhaps in Ph+ ALL the translocation occurs in a lymphoid stem cell. As for the treatment, it appears that imatinib is useful in Ph+ ALL. It doesn’t appear to get the patients into a long-term remission like it does in CML, unfortunately. But it does help get the patient into at least a first remission so that they can go on to bone marrow transplant (the official way to say this is that it improves early event-free survival). So the prognosis has improved somewhat for Ph+ ALL – but the outcome is nothing like the miraculous outcome in CML. Prognosis for Ph+ ALL is still very poor, both for kids and adults – in fact, Ph+ ALL has the worst prognosis of all the types of ALL.