Pathology Lecture 10 PDF

10 Mahde sabbagh, Yahia Jarosha Mahde sabbagh  Acute leukemia and histiocytosis Topics that will be discussed today: *These are modified slides that contain a lot of extra information for understanding purposes, original slide...

10 Mahde sabbagh, Yahia Jarosha Mahde sabbagh  Acute leukemia and histiocytosis Topics that will be discussed today: *These are modified slides that contain a lot of extra information for understanding purposes, original slide notes are bold, other than that, everything is extra. 1. An overview (extra) 2. Acute Leukemia: AML, ALL 3. Langerhans cell histiocytosis 1. NEOPLASTIC PROLIFERATIONS OF WHITE CELLS (overview, nothing is required): The most important disorders of white cells are neoplasms. Virtually all of these tumors are considered to be malignant, but they demonstrate a wide range of behaviors, ranging from some of the most aggressive cancers of man to tumors that are so indolent that they were only recognized recently as true neoplasms. classifying white cell neoplasms rely on a mixture of morphologic and molecular criteria, WHO classified WBCs neoplasms into 3 groups: Lymphoid neoplasms: include certain leukemias and the non-Hodgkin and Hodgkin lymphomas. In many instances these tumors are composed of cells resembling some normal stage of lymphocyte differentiation, a feature that serves as one of the bases for their classification. Leukemia: involve the bone marrow and peripheral blood/ lymphoma: masses in lymph nodes. Myeloid neoplasms: which include certain leukemias, myelodysplastic syndromes (MDSs), and myeloproliferative neoplasms. These tumors have in common an origin from a hematopoietic stem cell or some other very early hematopoietic progenitor, and they typically involve the bone marrow. Histiocytic neoplasms: which include proliferative lesions of macrophages and dendritic cells. Of special interest is a spectrum of proliferations of Langerhans cells (Langerhans cell histiocytosis). Next page is an overview done by me for the most important neoplastic disorders.  Neoplasms of WBCs Lymphoid Myeloid Histiocytosis Precursor B and T Multisystem cell lymphoblastic Langerhans cell myelodysplastic myeloproliferative Acute myeloid lymphoma/ histiocytosis leukemia syndromes (MDS) neoplasms Leukemia Mantle cell Unisystem lymphoma Langerhans cell Extranodal Essential primary polycythemia Chronic myeloid histiocytosis marginal zone lymphoma thrombocythemia myelofibrosis vera leukemia (CML) Chronic lymphocytic leukemia/small lymphocytic lymphoma Burkitt lymphoma Diffuse large B cell lymphomas Hodgkin lymphoma Follicular lymphoma Multiple myeloma and related neoplasms that are going to be discussed today are marked by entities 1. Acute Leukemia: A. Acute myeloid leukemia: Acute myeloid leukemia (AML) is an aggressive hematologic disease and is considered one of the most serious conditions in the field of hematology, it occur at all age groups, but more common in elderly. Heterogeneous, meaning that two patients with acute myeloid leukemia (AML) may have different prognoses and responses to treatment. Diagnosis is made by morphologic (Examination of appearance and count) immunophenotypic (Determining protein expression on cells to differentiate AML from lymphoblastic leukemia.) and karyotype studies (identify specific genetic mutations). Karyotype: the appearance of patient's chromosomes, which helps identify any genetic abnormalities. Prognosis is bad in general, but it depends most importantly on type of mutations (molecular and cytogenetic studies). Symptoms are accelerated, become significant within few weeks (If left untreated, the disease can be fatal), and are related to: Anemia: Fatigue and weakness, Thrombocytopenia: Increased bleeding and bruising, Neutropenia: Increased susceptibility to infections due to low white blood cell counts. The leukemic blast cells (myeloid cells) infiltrate the bone marrow, disrupting the production of normal blood cells, leading to these symptoms. Unlike lymphoblastic leukemia, AML tends to remain in the bloodstream and bone marrow rather than infiltrating tissues. However, involvement of lymph nodes, the spleen, and solid organs can happen, but it is rare. When it does occur, it is called myeloid sarcoma (acute monoblastic leukemia). Pathogenesis: 1.Mutations in genes of transcription factors required for maturation and differentiation of myeloblasts​ which can lead to maturation arrest. These mutations interfere with the differentiation of early myeloid cells, leading to the accumulation of myeloid precursors (blasts) in the marrow. 2.Additional mutations in tyrosine kinase pathways (RAS)​. 3.Epigenetic mutation (refer to changes in gene expression or cellular phenotype that do not involve alterations to the underlying DNA sequence. These changes can affect how genes are turned on or off, like changes in methylation status) is common (20%); mutation in isocitrate dehydrogenase (IDH) produces an oncometabolite that blocks the function of enzymes that regulate the epigenome and interferes with myeloblast differentiation. WHO-classification: As stated earlier, AML is heterogeneous. In making a diagnosis, we evaluate four types, usually starting from the most common, If the first type is negative, we proceed to the next: 1-Therapy related AML (very poor prognosis): occurs after treatment with chemo or radiotherapy. It’s crucial to ask the patient if they have received such treatments, as chemotherapy can induce mutations in bone marrow cells. If a patient has a history of another cancer and subsequently develops AML, we classify it as therapy-related AML. 2-If the patient has not received previous treatments, we will check the karyotype to search for genetic aberrations, As there are some translocation are common among patients, if these are present, we classify it as AML with recurrent cytogenetic mutation. 3-If no translocations are present, we will examine the cellular morphology for dysplasia. Dysplasia refers to abnormal development or growth of tissues or organs, which may include changes in the size, shape, and organization of cells. Dysplasia can be a precursor to cancer, depending on the context and tissue type. If dysplasia is identified, we classify it as AML with myelodysplasia, occurs de novo (new, without any prior cause or condition) or develop from complicated MDS ​(Myelodysplastic Syndromes). myelodysplastic syndrome (MDS) refers to a group of clonal stem cell disorders maturation defects that are associated with ineffective hematopoiesis and a high risk of transformation to AML. 4-If none of the above classifications apply, we designate it as AML-Not otherwise specified. Diagnosis of AML: 20% or more of myeloblasts in peripheral blood or bone marrow (of nucleated cells). Morphology: large, high N/C ration (high nucleus to cytoplasm ration), Upon close examination of the cytoplasm, fine granules can be observed in cytoplasm which contain myeloperoxidase, fine and pale chromatin, prominent nucleoli. All these features indicate that the cells are immature and have not yet differentiated. Auer rods: small pink, needle-shaped rods present in cytoplasm, represent peroxidase enzyme. these structures do not appear in lymphoblasts. Myeloblasts express several surface markers, including: CD34 (Present only on blast cells, either myeloblasts or lymphoblasts, its presence indicates an immature cell), Myeloperoxidase (MPO): Found in the form of granules or Auer rods; lymphoblasts do not express MPO. CD13 and CD33: Commonly expressed in myeloblasts. Sometimes AML can arise from other lineages: monoblast, erythroblast, megakaryoblast, but it's rare and not in our interest. Outcome: Generally poor, Worse than ALL (acute lymphoblastic leukemia), B, more common in T lymphocytes), and Acute lymphoblastic leukemia when it circulates peripheral blood and involve bone marrow (B>T, more common in B lymphocytes). ALL: refers to both acute lymphoblastic leukemia and lymphoma. Aggressive neoplasms, express CD34 (marker of immature cells, hematopoietic stem and progenitor cell marker) and TDT (an enzyme specifically expressed in pre–B and pre–T cells, helps to distinguish ALL from AML) B-ALL is the most common childhood malignancy, while T-ALL is less common, presents in adolescents, involving Thymus and to a lesser extent bone marrow and blood, more common in boys. B-ALL tends to disseminate to solid organs (brain, testis, spleen). Pathogenesis: Mutations in transcription factors for genes responsible for maturation of blasts. These mutations promote maturation arrest and increased self-renewal, a feature of immortalized cells, which is one of the hallmarks of cancers. 1. B-ALL: mutation in PAX5 gene, Mutations in RAS signaling and tyrosine kinase proteins promoting cell survival. Most childhood B-ALL have hyperdiploidy (>50 chromosomes in the cell) and a translocation (chromosome 12 and 21) involving ETV6 and TUNX1 genes, creating new transcription factor. Hyperdiploidy: Having a chromosome number greater than the diploid number (46). Adult B-ALL exhibits a translocation (chromosome 9 and 22) between ABL and BCR genes, similar to chronic myeloid leukemia, creating a new tyrosine kinase protein (imatinib). Known as Philadelphia chromosome, one of the most common and important translocations. 2. T-ALL shows mutation in NOTCH1 gene (70% of cases), PTEN gene (tumor suppressor) and CDKN2A (promotes cell cycle). Memorize those genes since they are occasionally encountered in clinical practice. Morphology of ALL: Similar to AML: Blasts are large, high N/C ration, Chromatin is open (pale), Nucleolus sometimes present. Different from AML: Cytoplasm is very minimal and not granular, Auer rods not present.  Flow cytometry here shows the presence of some markers on the surface of ALL cells, sometimes used for diagnosis, lets break them down: TdT (immature cell marker) and CD22 (B cell marker) are seen on the left. CD19 (B cell marker) and CD10 (used as a marker of malignant B cells, found on immature B-cells but high amounts indicate malignancy). If we suspect a T-cell malignancy, we must look for CD3. Clinical features: 1.Anemia, thrombocytopenia (due to bone marrow destruction). 2.Bone pain, Lymphadenopathy and hepatosplenomegaly, Testicular enlargement, damage to solid organs all secondary to leukemic infiltration (caused by neoplastic infiltration), and in T-ALL, complications related to compression of large vessels and airways in the mediastinum (Mediastinal mass). 3.CNS involvement (resulting from meningeal spread, requires intrathecal chemotherapy). Favorable prognostic factors in B-ALL (respond well to chemotherapy): hyperdiploidy, low WBC count, age between 2-10 years. Poor prognostic factors in B-ALL: age < 2 years, age in adolescents or adults, WBC count >100k. 2. Langerhans cell histiocytosis: Neoplasm of dendritic cells, Langerhans cells are immature dendritic cells found in the epidermis; they function to capture antigens and display them to T cells. The proliferating Langerhans cells express CD1a and Langerin, langerin is a transmembrane protein, attached to Birbeck granules (tennis ricket shape under electron microscope. So, if these granules are seen in large numbers under the microscope, this might indicate malignancy) The proliferating Langerhans cells do not resemble their normal dendritic counterparts. Instead, they appear larger, and show vacuolated cytoplasm, an appearance similar to that of tissue macrophages (called histiocytes by morphologists)—hence the term Langerhans cell histiocytosis. Pathogenesis: acquired mutation in serin/threonine kinase BRAF, leads to hyperactivity of this kinase. Langerhans cell histiocytosis can be grouped into two major entities: A. Multisystemic LCH: Occurs mostly in children less than 2 years. Multiple cutaneous lesions, composed of Langerhans cells, as a result of these lesions, patients have Hepatosplenomegaly, lymphadenopathy, Pulmonary lesions, Osteolytic lesions (Extensive bone marrow infiltration leads to pancytopenia). Treated with chemotherapy. B. Unisystem LCH: AKA eosinophilic granuloma, affects a single organ, most commonly bone, then skin, lung, stomach. Can be unifocal or multifocal. Proliferating Langerhans cells are admixed with numerous eosinophils, lymphocytes, plasma cells and neutrophils. Unifocal is commonly asymptomatic but can cause pain. Treatment: surgical excision. Multifocal unisystem disease presents in children, with multiple erosive bony masses, commonly affects calvaria bone (the top part of the skull). Can sometimes extend into soft tissues, with involvement of pituitary gland, the tumor disrupts ADH production causing diabetes insipidus and exerts physical pressure on the optic structures leading to exophthalmos. The combination of calvarial bone defects, diabetes insipidus, and exophthalmos is referred to as the (Hand- Schuller-Christian triad). Treatment: chemotherapy, sometimes spontaneous regression.