Dysplastic and proliferative disorders Notes

NOTES NOTES DYSPLASTIC & PROLIFERATIVE DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Acquired disorders caused by defective hematopoiesis CAUSES ▪ Mostly idiopathic ▪ Gene mutations ▫ JAK2 gene in most myeloproliferative disorders COMPLICATIONS ▪ Can progress to serious conditions ▫ Acute myelogenous leukemia (AML) SIGNS & SYMPTOMS ▪ Can be asymptomatic ▪ When symptomatic, depends on cell line affected DIAGNOSIS LAB RESULTS ▪ Complete blood count (CBC) ▫ Cell line levels ▪ Peripheral blood smear ▫ Morphology ▪ Bone marrow aspiration/biopsy ▫ Morphology, cellularity (normal, hypo, hyper), % of blasts ▪ Cytogenetic studies ▫ Chromosomal abnormalities ▪ Molecular tests ▫ Gene mutations TREATMENT OTHER INTERVENTIONS ▪ Blood transfusion ▪ Hematopoietic stem cell transplant OSMOSIS.ORG 373

ESSENTIAL THROMBOCYTOSIS osms.it/essential-thrombocytosis PATHOLOGY & CAUSES ▪ Chronic myeloproliferative neoplasm due to overproduction of megakaryocytes in bone marrow ▪ AKA essential thrombocythemia ▪ ↑ platelets, abnormally shaped; ↓ platelet survival ▪ Thromboses; bleeding episodes may occur; other cell lines may be affected ▪ JAK2 mutation (50%), MPL (5–10%)/ calreticulin ▪ “Spent phase” of myelofibrosis/AML (rarely) SIGNS & SYMPTOMS ▪ Primary symptomatic manifestations due to thrombosis → potential ischemia in various organs, extremities (e.g. stroke, erythromelalgia) ▪ Headache, dizziness, fatigue, vision loss, abdominal pain, nausea ▪ Less frequently, paradoxical bleeding ▫ Epistaxis, bleeding gums, ecchymoses ▪ Splenomegaly DIAGNOSIS LAB RESULTS ▪ Platelets > 450 × 103/µL for ≥ two months; anisocytosis ▪ ↑ bleeding time Bone marrow aspiration/biopsy ▪ Normal cellularity Genetic testing ▪ JAK2 mutation OTHER DIAGNOSTCS ▪ History of thrombosis, bleeding, vasomotor symptoms, first trimester fetal loss TREATMENT MEDICATIONS ▪ Low risk for thrombosis ▫ Antiplatelet drugs (aspirin, anagrelide) ▪ High risk for thrombosis ▫ Hydroxyurea, interferon-alpha SURGERY ▪ In severe conditions ▫ Plateletpheresis (removal of platelets from blood) Figure 45.1 A peripheral blood smear from an individual with essential thrombocytosis. There are a higher than normal number of platelets visible. 374 OSMOSIS.ORG

Chapter 45 Dysplastic & Proliferative Disorders LANGERHANS CELL HISTIOCYTOSIS (LCH) osms.it/langerhans-cell-histiocytosis PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Rare, proliferative disorder affecting Langerhans cells (type of dendritic cells), myeloid progenitor cells in bone marrow ▪ AKA histiocytosis X ▪ Osteolytic bone lesions infiltrated with histiocytes; histiocytes, lymphocytes, macrophages, eosinophils infiltrate organs: skin, lymph nodes, bones, lungs, liver, spleen, central nervous system (CNS) ▪ Lytic bone lesions may be asymptomatic/ cause localized pain ▪ Skin lesions ▫ Brown to purplish papules pustular, purpuric, petechial, vesicular, papulonodular; eczema-like rash ▪ Mucous membranes ▫ Gingivitis, mucosal mass/ulcers, loose teeth ▪ Lymphadenopathy ▪ Liver, spleen ▫ Hepatic lesions, hepatosplenomegaly ▪ Lungs ▫ Recurrent spontaneous pneumothorax, dyspnoea, chest pain ▪ CNS ▫ Diabetes insipidus, neurological deficits ▪ Systematic symptoms ▫ Fever, lethargy, weight loss Proliferating cells ▪ Functionally immature ▪ Immunohistochemistry ▫ CD1a, S100 positive ▪ Abundant, foamy cytoplasm ▪ Folded, grooved nuclei ▪ Birbeck granules, “tennis racket”/rodshaped cytoplasmic organelles RISK FACTORS ▪ Usually affects children; also present in adults ▪ Mutations detected; most common (55– 60%) activates BRAF gene COMPLICATIONS ▪ CNS ▫ Pituitary gland → diabetes insipidus, pons, basal ganglia; cerebellum → cognitive deficits, neuromotor dysfunction ▪ Liver, spleen ▫ Worse prognosis; sclerosing cholangitis may require liver transplant DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ CNS involvement LAB RESULTS ▪ Accumulation of inflammatory cells, Langerhans cells (large, mononuclear cells with prominent nuclear groove), few cytoplasmic vacuoles, pale eosinophilic cytoplasm OSMOSIS.ORG 375

TREATMENT ▪ Spontaneous regression can occur MEDICATIONS ▪ Systemic corticosteroids ▪ Chemotherapeutic agents ▫ Alkylating agents, antimetabolites, vinca alkaloids SURGERY ▪ Surgial excision OTHER INTERVENTIONS ▪ Radiation therapy Figure 45.3 An MRI scan of the head in the sagittal plane demonstrating a subcutaneous soft-tissue mass, destroying the frontal bone. The diagnosis was confirmed as Langerhans histiocytosis on biopsy. 376 OSMOSIS.ORG Figure 45.2 The histological appearance of Langerhans cell histiocytosis. There are numerous clonal dendritic cells (light pink) with associated eosinophils (red).

Chapter 45 Dysplastic & Proliferative Disorders LEUKEMOID REACTION osms.it/leukemoid-reaction PATHOLOGY & CAUSES ▪ Excessive, reactive leukocytosis (WBCs: 40,000–100,000/mL), resembling leukemia, with increase in neutrophil precursors, “left shift” (e.g. myeloblasts, promyelocytes, myelocytes) in peripheral blood ▪ Cytoplasmic toxic granulation, Dohle bodies, blue-gray inclusions in peripheral cytoplasm of neutrophils ▪ Lymphocytic reaction can occur COMPLICATIONS ▪ Severe/chronic infections ▫ Clostridium difficile infection (CDI), Mycobacterium tuberculosis, Bordetella pertussis, Epstein–Barr virus (EBV) ▪ Sepsis ▪ Non-infectious inflammation ▫ Burns, postoperative state, acute asthma attack, acute episodes of gout ▪ Severe hemolysis ▪ Acute hemorrhage ▫ Peritoneal cavity ▪ Tissue necrosis ▫ Hepatic necrosis, ischemic colitis ▪ Metastatic cancer ▪ Paraneoplastic syndrome ▫ Lung carcinoma, renal cell carcinoma ▪ Drugs ▫ Sulfonamides, dapsone, glucocorticosteroids, granulocyte-colony stimulating factor (G-CSF) ▪ Asplenia ▪ Metabolic ▫ Diabetic ketoacidosis, preeclampsia, uremia SIGNS & SYMPTOMS ▪ Fatigue, weakness, high fever DIAGNOSIS LAB RESULTS ▪ ↑↑↑ WBCs ▪ Rule out blood malignancies ▫ Mature neutrophil precursors, unlike immature cells in acute leukemia (blasts < 20%); toxic granulation, Döhle bodies unlike chronic myelogenous leukemia (CML) ▫ Serum leukocyte alkaline phosphatase (LAP) score normal/elevated, unlike CML ▫ Confirm CML by Philadelphia chromosome with BCR/ABL fusion gene + FISH/PCR ▫ Bone marrow aspiration/biopsy TREATMENT ▪ Treatment of underlying condition OSMOSIS.ORG 377

MYELODYSPLASTIC SYNDROMES (MDS) osms.it/myelodysplastic-syndrome PATHOLOGY & CAUSES ▪ Group of malignant hematopoietic stem cell disorders ▪ Abnormal, ineffective hematopoiesis → peripheral cytopenia Dysplastic cells ▪ Pseudo Pelger–Huët cells ▫ Bilobed neutrophils ▪ Ring sideroblasts ▫ Erythroblasts with granules of iron accumulated in mitochondria ▪ Megaloblastoid maturation ▪ Nuclear budding abnormalities ▪ Pawn ball megakaryocytes ▫ Discrete nuclear lobes/multinucleation CAUSES ▪ Can be idiopathic/secondary to exposure ▫ Toxins, genotoxic drugs, immunosuppressive agents, chemotherapy, radiation therapy (tMDS, therapy related MDS) ▪ Genetic defects due to ▫ Epigenetic factors, RNA splicing factors, transcription factors ▫ 5q (5q-) deletion most common ▪ Affects elderly individuals; mean age of onset is 70 years COMPLICATIONS ▪ MDS = pre-leukemias, high risk of conversion to AML ▪ % of blasts (1–20%) ▫ How close individual is to AML (> 20%) ▪ Progresses slowly → most succumb to bleeding, infections before AML 378 OSMOSIS.ORG ▪ Functional defects in red (RBCs), white blood cells (WBCs), platelets → anemia, infections, bleeding SIGNS & SYMPTOMS ▪ Asymptomatic in early stages ▪ Fatigue (anemia), infections (neutropenia), bleeding (thrombocytopenia) DIAGNOSIS LAB RESULTS ▪ Low RBCs, WBCs, platelets, normal/mildly elevated mean corpuscular volume (MCV), increased red cell distribution width (RDW) ▪ Low reticulocyte count, dysplastic RBCs, WBCs, normal platelets, 1–20% blasts ▪ Dysplastic cells, increased blasts ▪ Chromosomal abnormalities, gene mutations TREATMENT MEDICATIONS ▪ Tumor necrosis factor (TNF) inhibitors (e.g.lenalidomide, thalidomide), DNA methylation inhibitors OTHER INTERVENTIONS Allogeneic hematopoietic stem cell transplant ▪ Only curative option, for young individuals ▪ If transplant not an option → blood product transfusions, infection control (supportive)

Chapter 45 Dysplastic & Proliferative Disorders Figure 45.4 A neutrophil from a in the peripheral blood smear of an individual with myelodysplastic syndrome. The neutrophil is hypogranulated and has a hypolobated nucleus, known as a pseudo Pelger–Huët nucleus. POLYCYTHEMIA VERA (PCV) osms.it/polycythemia-vera PATHOLOGY & CAUSES ▪ Chronic myeloproliferative neoplastic disease ▪ Hematopoietic stem cell disorder → erythroid, granulocytic, megakaryocytic lineages proliferate ▪ Increased ▫ RBCs, independent of erythropoietin (EPO); platelets; basophils; eosinophils; cell turnover → hyperuricemia ▪ Polycythemia → increased blood viscosity; increased total blood volume → abnormal blood flow ▪ Abnormal blood flow, defective platelet function → vein thrombosis, infarcts, bleeding ▪ PCV may evolve to “spent phase” ▫ Myelofibrosis, extramedullary hematopoiesis in liver, spleen RISK FACTORS ▪ Occurs in all ages; median age at diagnosis 60 years ▪ Genetic ▫ JAK2V617F mutation (95% of cases) COMPLICATIONS ▪ Hypertension, Budd–Chiari syndrome, deep vein thrombosis, arterial thrombosis, myocardial infarction (MI), gout (high cell turnover, hyperuricemia), PCV → AML (rare) ▪ If untreated ▫ Thrombotic, hemorrhagic complications → death within months OSMOSIS.ORG 379

SIGNS & SYMPTOMS ▪ Symptoms due to ↑ in RBCs → blood viscosity ▫ Headache, fatigue, dizziness, dyspnea, plethora, cyanosis ▪ Symptoms due to ↑ in basophils → histamine release ▫ Pruritus (intense itching, especially after hot shower), gastric ulcers ▪ Thrombosis ▫ Deep vein thrombosis, MI, Budd–Chiari syndrome (portal vein thrombosis), erythromelalgia (hyperemic and inflamed extremities due to microvascular occlusion of vessels) ▪ Bleeding ▫ Bleeding gums, epistaxis, ecchymoses, GI bleed ▪ Hepatosplenomegaly, splenomegaly ▪ Hypertension DIAGNOSIS LAB RESULTS ▪ Exclude secondary polycythemia (hypoxia, renal cell, hepatocellular carcinoma); ↑ EPO serum ▪ CBC ▫ ↑ RBCs, hematocrit, hemoglobin; ↑ platelets/WBCs ▪ ↑ Lactate dehydrogenase ▪ ↓ serum EPO ▪ Bone marrow aspiration/biopsy confirms diagnosis ▪ Genetic testing ▫ JAK2 mutation Figure 45.5 The clinical appearance of erythromelalgia; a sign of numerous diseases, including polycythemia vera. TREATMENT MEDICATIONS ▪ Hydroxyurea ▫ ↓ RBC production ▪ Interferon-alpha ▫ ↑ RBC destruction ▪ Aspirin ▫ ↓ risk of thrombosis OTHER INTERVENTIONS ▪ Phlebotomy ▫ ↓ hematocrit, hemoglobin Figure 45.6 The clinical appearance of erythromelalgia; a sign of numerous diseases, including polycythemia vera. 380 OSMOSIS.ORG

Chapter 45 Dysplastic & Proliferative Disorders PRIMARY MYELOFIBROSIS (PM) osms.it/myelofibrosis PATHOLOGY & CAUSES ▪ Chronic myeloproliferative disease of hematopoietic stem cells resulting in bone marrow fibrosis ▪ AKA essential thrombocythemia ▪ Overproduction of megakaryocytes in bone marrow ▪ Increased platelets, abnormally shaped; decreased platelet survival ▪ Thromboses; bleeding episodes may occur; other cell lines may be affected ▪ JAK2 mutation (50%), MPL (5–10%)/ calreticulin ▪ “Spent phase” of myelofibrosis/AML (rarely) SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ When symptomatic, thrombosis, potential ischemia in various organs ▫ Headache, dizziness, fatigue, numbness in extremities, erythromelalgia, vision loss, abdominal pain, nausea ▪ Less frequently, bleeding ▫ Epistaxis, bleeding gums, bruises ▪ Splenomegaly DIAGNOSIS LAB RESULTS ▪ ↓ RBCs, platelets ▪ Leukoerythroblastosis, dacryocytes OTHER INTERVENTIONS Bone marrow aspiration ▪ Dry tap, no sample (accumulation of collagen fibers) Figure 45.7 The histological appearance of the bone marrow in an individual with myelofibrosis. The fibrosis is seen as fine silver strands upon staining with reticulin. TREATMENT MEDICATIONS ▪ Low risk for thrombosis ▫ Antiplatelet drugs (aspirin, anagrelide) ▪ High risk for thrombosis ▫ Hydroxyurea, interferon-alpha SURGERY ▪ In severe conditions ▫ Plateletpheresis (removal of platelets from blood) Bone marrow biopsy ▪ Hypocellularity, fibrosis OSMOSIS.ORG 381

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