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MYELOID DISEASES 2 - Coggle Diagram

- - - - the bone marrow is partly or wholly replaced by the clonal progeny of a neoplastic multipotent stem cell
        
        forms
        
        primary --> idiopathic
        
        secondary --> genotoxic drug or radiation therapy
        
        2-8y after the genotoxic exposure
    - - epigenetic factors
        
        RNA splicing factors
        
        transcription factors
        
        classic chromosomal rearrangements that are seen in de novo AML, such as the t(8;21), inv(16) and t(15;17) are not seen in MDS, instead, most of the mutations are loss-of-function mutations in genes such as RUNX1
        
        roughly 10% of MDS cases have loss-of-function mutations in TP53
        
        recurrent chromosomal abnormalities: monosomies 5 and 7; deletions of 5q, 7q and 20q, trisomy 8
        
        subtle increases in the oncoprotein MYC chr 8
        
        the region that is commonly lost on chromosome 5q contains a gene encoding the ribosomal protein RPS14
        
        MDS appears to frequently arise from an asymptomatic state called clonal hematopoiesis of indeterminate potential (CHIP)
        
        one or more pathogenic mutations associated with MDS, in an individual with normal blood counts
    - - hypercellular marrow (sometimes normo- or hypocellular)
        
        disordered differentiation and maturation of cells
        
        typical findings:
        
        ring sideroblasts with iron-laden mitochondria visible as perinuclear granules when stained with prussian blue on smears
        
        megaloblastic maturation and nuclear budding abnormalities (nuclei with misshapen outlines)
        
        other alterations:
        
        neutrophils containing decreased numbers of secondary granules
        
        megakaryocytes with single nuclear lobes or multiple separated nuclei (pawn ball megakaryocytes)
        
        myeloid blasts may be increased (<20% of the overall marrow cellularity)
        
        blood often contains giant platelets, macrocytes and poikilocytes, accompanied by a relative or absolute monocytosis
    - - predominantly a disease of older adults (mean age: 70y); half of the cases being diagnosed incidentally
      - symptoms: weakness, infections and hemorrhages
    - - in younger patients: allogeneic HSCT
        
        older patients: supportive treatment with antibiotics and blood transfusions
        
        thalidomide-like drugs and DNA methylation inhibitors improve effectiveness of hematopoiesis and peripheral blood counts
  - - - most myeloproliferative neoplasms originate in multipotent mueloid progenitors, whereas others arise in pluripotent stem cells
        
        it all depends on where the block is
    - - increased proliferation in the bone marrow, meaning hypercellularity or the BM
        
        homing of the neoplastic stem cells to secondary hematopoietic organs, producing extramedullary hematopoiesis
        
        variable transformation to a spent phase, characterized by marrow fibrosis and periphral blood cytopenias (BM is completely substituted by fibrosis)
        
        variable transformation to acute leukemia
    - - CHRONIC MYELOID LEUKEMIA
        
        chimeric BCR-ABL TK hyperactivation, due to t(9;22)
        
        in more than 90% of cases: (9;22)(q34;q11) --> Philadelphia chromosome
        
        morphology
        
        marrow
        
        hypercellular: increased numbers of maturing granulocytic precursors
        
        megakaryocytes in small and dysplastic forms
        
        erythroid progenitors are present in normal or decreased functions
        
        presence of scattered macrophages with aboundant wrinkled, green-blue cytoplasm (SEA-BLUE HISTIOCYTES)
        
        increased deposition of reticulin
        
        blood
        
        leukocytosis, consisting predominantly of mature granulocytes
        
        blasts make up <10% of the circulating cells
        
        platelets are usually increased
        
        the spleen is often greatly enlarged as a result of extensive extramedullary hematopoiesis
        
        clinical features
        
        primarily a disease of adults, but it may also occur in children and adolescents
        
        peak incidence: 5th-6th decades
        
        insidious onset
        
        signs and symptoms: mild-to-moderate anemia and hypermetabolism due to increased cell turnover (fatigue, weakness, weight loss and anorexia)
        
        sometimes the first symptoms is a dragging sensation in the abdomen, caused by splenomegaly, or the acute onset of LUQ pain
        
        natural history
        
        slow progression: survival of around 3 years
        
        accelerated phase (after 3y): marked anemia and thrombocytopenia
        
        blast crisis (within 6-12 months) --> this phase may happen in 50% of cases without the previous phases
        
        treatment
        
        target therapies against
        BCR-ABL fusion gene
        
        sustained hematologic remission in >90% of patients; no extinction of the CML stem cell
      - POLYCYTHEMIA VERA
        
        characterized by pan-myelosis
        
        the increase in RBCs is responsible for the symptoms
        
        DD: hemoconcentration
        
        pathogenesis
        
        the transformed progenitor cells have markedly decreased requirements for erythropoietin and other hematopoietic growth factors
        
        due to JAK2 activating mutations
        
        most commonly V617F
        
        serum erythropoietin levels in PCV are low
        
        elevated hematocrit leads to increased blood viscosity
        
        hemodynamic factors, together with thrombocytosis and abnormal platelet function, make patients with PCV prone to both thrombosis and bleeding
        
        morphology
        
        marrow is hypercellular, but some residual fat is usually present
        
        increase in red cell progenitors is subtle, and it is usually accompanied by an increase in granulocytic precursors and megakaryocytes as well
        
        early in the diagnosis: moderate/marked increase in reticulin fibers (10% of cases); mild organomegaly; extramedullary hematopoiesis is minimal
        
        late in the course: SPENT PHASE (extensive marrow fibrosis displacing hematopoietic cells with increased extramedullary hematopoiesis in spleen and liver)
        
        In 10% of cases, PCV tends to evolve to a “spent phase”, during which clinical and anatomic features of primary myelofibrosis develop
        
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        clinical features
        
        uncommon diagnosis
        
        insidious onset
        
        adults of late middle age
        
        symptoms
        
        related to the increased red cell mass and hematocrit, increased total blood volume, causing abnormal blood flow;
        patients are plethoric and cyanotic
        
        headache, dizziness, hypertension, GI symptoms, intense pruritus and peptic ulceration
        
        high cell turnover gives rise to hyperuricemia
        
        treatment
        
        without treatment, death from bleeding or thrombosis occurs within months of diagnosis
        
        simply maintaining the red cell mass at nearly normal levels extends the median survival to about 10 years
        
        current JAK2 inhibitors are not as effective as hoped
      - ESSENTIAL THROMBOCYTOSIS
        
        associated with diverse mutations that increase JAK-STAT signalling and mimic constitutive growth factor receptor signalling
        
        JAK2
        
        MPL
        
        CALR
        
        ET manifests clinically with elevated platelet counts
        
        pathogenesis
        
        progenitors become thrombopoietin-independent, leading to hyperproliferation
        
        morphology
        
        bone marrow cellularity is only mildly increased, but megakaryocytes are often markedly increased in number and include abnormally large forms
        
        modest degrees of extramedullary hematopoiesis may occur, producing mild organomegaly in about 50% of patients
        
        delicate reticulin fibrils can be seen, peripheral smears reveal large platelets and mild leukocytosis
        
        clinical features
        
        pts older than 60
        
        thrombosis and hemorrhage are the major clinical manifestations
        
        platelets demonstrate also qualitative abnormalities
        
        a characteristic symptom is erythromelalgia
        
        indolent disorder with long asymptomatic periods, punctuated by occasional thrombotic or hemorrhagic crises
        
        therapy
        
        “gentle” chemotherapeutic agents that suppress thrombopoiesis
      - PRIMARY MYELOFIBROSIS
        
        hallmark: development of complete obliterative marrow fibrosis, which reduces bone marrow hematopoiesis --> CYTOPENIAS and EXTRAMEDULLARY HEMATOPOIESIS in spleen, liver and lymph nodes
        
        same mutations as ET: JAK2, CALR and MPL
        
        histologically, it looks like the spent phase in late myeloproliferative neoplasms
        
        myelofibrosis could also be the evolution of the other myeloproliferative disorders
        
        pathogenesis
        
        extensive deposition of collagen and then fibrosis in BM by non-neoplastic fibroblasts
        
        displacement of hematopoietic elements, eventually leading to marrow failure
        
        probably caused by the inappropriate release of fibrogenic factors from neoplastic megakaryocytes
        
        factors involved: PDGF and TGF beta
        
        morphology
        
        early in the course, the BM is hypercellular due to an incrasde in maturing cells of all lineages
        
        erythroid and granulocytic precursors appear normal, but megakaryocytes are large, dysplastic, abnormally clustered and increased in number
        
        at this stage fibrosis is minimal, and the blood may show leukocytosis and thrombocytosis
        
        with progression, the marrow becomes more hypocellular and diffusely fibrotic
        
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        blood findings
        
        premature release of nucleated erythroid and early granulocyte progenitors (LEUKOERYTHROBLASTOSIS), TEARDROP-SHAPED RBCs (dacryocytes)
        
        clinical features
        
        pts older than 60
        
        progressive anemia and splenomegaly
        
        non-specific symptoms (fatigue, weight loss and night sweats)
        
        hyperuricemia and secondary gout
        
        normochromic normocytic anemia and leukoerythroblastosis
        
        treatment
        
        median survival is in the range of 3 to 5 years
        
        intercurrent infections, thrombotic episodes, bleeding related to platelet abnormalities, transformation to AML (5-20% of cases)
        
        JAK2 inhibitors
        
        HSCT in young and fit pts
- - - - driver mutations, e.g. BRAF V600E (the most common), but also TP53, RAS and MET
      - aberrant expression of chemokine receptors
    - - abundant, often vacuolated cytoplasm and vesicular nuclei containing linear grooves or folds
        
        Birbeck granules (pentalaminar tubules, often with a dilated terminal end, producing a tennis racket–like appearance, which contain the protein langerin)
        
        tumor cells express: CLA-DR, S100, CD1a
    - - multifocal multisystem LCH
        
        onset before 2 years of age, occasionally in adults
        
        development of cutaneous lesions, resembling a seborrheic eruption, which is caused by infiltrates of Langerhans cells over the front and back of the trunk and on the scalp
        
        concurrent hepatosplenomegaly, lymphadenopathy, pulmonary lesions and eventually destructive osteolytic bone lesions
        
        extensive infiltration of the marrow could be present and often leads to anemia, thrombocytopenia and a predisposition to recurrent infections such as otitis media and mastoiditis
        
        Langerhans cell sarcoma
        
        if untreated, rapidly fatal
        
        with intensive chemotherapy, 50% of patients survive 5 years
      - unifocal and multifocal unisystem LCH
        
        more frequent, also termed eosinophilic granuloma
        
        proliferation of Langerhans cells, mixed with variable numbers of eosinophils, lymphocytes, plasma cells and neutrophils
        
        eosinophils are usually, but not always a prominent component of the infiltrate
        
        typically within the medullary cavities of bones, most commonly the calvaria, ribs, femur
        
        bone lesions can be asymptomatic or cause pain, tenderness and in some instances pathologic fractures
        
        unifocal: indolent and may heal spontaneously or may be cured by local excision or irradiation
        
        multifocal unisystem: young children, who present with multiple erosive bony masses that sometimes expand into adjacent soft tissue
        
        spontaneous regression or successful treatment with chemotherapy
        
        BRAF inhibitors are active against BRAF-mutated disease but are not curative
      - pulmonary LCH
        
        the most frequent form
        
        most often seen in adult smokers
        
        may regress spontaneously upon cessation of smoking
        
        reactive proliferation of Langerhans cells or associated with BRAF mutations
        
        stellate interstitial collection, often near small airways, composed of eosinophils and Langerhans cells
        
        Langerhans cells feature a unique convoluted nucleus and a moderate amount of cytoplasm
        
        some binucleated forms may also be present
        
        admixture of pigmented alveolar macrophages, smoker’s macrophages, is also often present
        
        IHC for S-100 and CD1a