Neoplastic disorders of white cells.pdf

DISORDERS OF WHITE CELLS Neoplastic disorders of white cells Ø Proliferations of white cells can be reactive or neoplastic. Ø Reactive proliferations in the setting of infections or inflammatory processes, when large numbers of leukocytes are needed for an effective host response, are fairly common....

DISORDERS OF WHITE CELLS Neoplastic disorders of white cells Ø Proliferations of white cells can be reactive or neoplastic. Ø Reactive proliferations in the setting of infections or inflammatory processes, when large numbers of leukocytes are needed for an effective host response, are fairly common. PASG 61310 Pathophysiology I L29 April 11th, Spring 2024 Ithaca College, Physician Assistant Program Ø Neoplastic disorders, though less frequent, are much more important clinically Elena Mueller, PhD q Myeloid Neoplasms q Lymphoid neoplasms include a diverse group of tumors of B-cell, T-cell, and NK-cell origin. § In many instances the phenotype of the neoplastic cell closely resembles that of a particular lymphocyte class or stage of maturation, a feature that is used in the diagnosis and classification of these disorders. q Myeloid neoplasms arise from early hematopoietic progenitors. Three categories of myeloid neoplasia are recognized: o acute myeloid leukemias (AMLs), in which immature progenitor cells accumulate in the bone marrow; o myelodysplastic syndromes (MDSs), which are associated with ineffective hematopoiesis and resultant peripheral blood cytopenias; and o myeloproliferative neoplasms, in which increased production of one or more terminally differentiated myeloid elements (e.g., granulocytes) usually leads to elevated peripheral blood counts. q The histiocytoses are uncommon proliferative lesions of macrophages and dendritic cells. § Although “histiocyte” (literally, “tissue cell”) is an archaic morphologic term, it is still often used. A special type of immature dendritic cell, the Langerhans cell, gives rise to a spectrum of neoplastic disorders referred to as the Langerhans cell histiocytoses. q Lymphoid Neoplasms Ø Ø Acute Myeloid Leukemia Ø Myelodysplastic Syndrome Ø Myeloproliferative Neoplasms o Chronic Myeloid Leukemia o Polycythemia Vera o Essential Thrombocytosis o Primary Myelofibrosis B- and T-Cell Neoplasms o Acute Lymphoblastic Leukemia/Lymphoma Ø Peripheral B-Cell Neoplasms o Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma o Follicular Lymphoma o Diffuse Large B-Cell Lymphoma o Burkitt Lymphoma o Mantle Cell Lymphoma o Marginal Zone Lymphomas o Hairy Cell Leukemia Ø Peripheral T- and NK-Cell Neoplasms o Peripheral T-Cell Lymphoma, Unspecified o Anaplastic Large-Cell Lymphoma (ALK Positive) o Adult T-Cell Leukemia/Lymphoma o Mycosis Fungoides/Sézary Syndrome o Large Granular Lymphocytic Leukemia o Extranodal NK/T-Cell Lymphoma Ø Plasma Cell Neoplasms and Related Disorders o Multiple Myeloma o Smoldering Myeloma o Solitary Osseous Plasmacytoma o Lymphoplasmacytic Lymphoma Ø Langerhans Cell Histiocytosis Ø Hodgkin Lymphoma q Myeloid Neoplasms q Lymphoid Neoplasms Ø Ø Acute Myeloid Leukemia Ø Myelodysplastic Syndrome Ø Myeloproliferative Neoplasms o Chronic Myeloid Leukemia o Polycythemia Vera o Essential Thrombocytosis o Primary Myelofibrosis B- and T-Cell Neoplasms o Acute Lymphoblastic Leukemia/Lymphoma Ø Peripheral B-Cell Neoplasms o Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma o Follicular Lymphoma o Diffuse Large B-Cell Lymphoma o Burkitt Lymphoma o Mantle Cell Lymphoma o Marginal Zone Lymphomas o Hairy Cell Leukemia Ø Peripheral T- and NK-Cell Neoplasms o Peripheral T-Cell Lymphoma, Unspecified o Anaplastic Large-Cell Lymphoma (ALK Positive) o Adult T-Cell Leukemia/Lymphoma o Mycosis Fungoides/Sézary Syndrome o Large Granular Lymphocytic Leukemia o Extranodal NK/T-Cell Lymphoma Ø Plasma Cell Neoplasms and Related Disorders o Multiple Myeloma o Smoldering Myeloma o Solitary Osseous Plasmacytoma o Lymphoplasmacytic Lymphoma Ø Langerhans Cell Histiocytosis Ø Hodgkin Lymphoma § Also called erythrocytosis § Polycythemia vera is a subtype of polycythemia and can be associated with the overproduction of more than just the erythrocytic lineage can be associated with the overproduction of all three cell lines but with a notable predilection towards red blood cells Polycythemia q Low serum EPO levels (Primary polycythemia) Polycythemia vera Primary familial and congenital polycythemia q High serum EPO levels (Secondary polycythemia) High altitude Respiratory disorders: Chronic obstructive pulmonary disease (COPD), Pickwickian syndrome, uncontrolled asthma Cyanotic heart diseases with right-to-left shunts Renal disorders: Renal cysts, kidney cancer, renal artery stenosis, Bartter syndrome, focal sclerosing glomerulonephritis Elevated carboxyhemoglobin: Usually seen in smokers, people working on cars in closed spaces, or people working in boiler rooms Hemoglobinopathies: High-affinity hemoglobins such as Hb Yakima, methemoglobinemia EPO-secreting tumors: sources include hepatomas, uterine leiomyomas, and cerebellar hemangiomas Iatrogenic causes: Including erythropoietin analog administration, anabolic steroids, and testosterone replacement therapy q Neonatal Polycythemia The increase in hematocrit is a normal compensatory mechanism in infants due to the relative tissue-level hypoxia in the intrauterine environment. It is exacerbated by the high affinity of fetal hemoglobin for oxygen. q Myeloid Neoplasms Ø In primary polycythemia, the Janus kinase 2 (JAK2) mutation is detected in approximately 90% to 95% of the cases. Ø JAK2 is found on the short arm of chromosome 9 with mutations of JAK2 rendering the patient susceptible to hypersensitivity of hematopoietic progenitor cells in myeloproliferative disorders to growth factors and different cytokines. Ø Ø Acute Myeloid Leukemia Ø Myelodysplastic Syndrome Ø Myeloproliferative Neoplasms Ø JAK2 mutations can also be seen in essential thrombocytosis (ET) and primary myelofibrosis (PMF) 60% of the time. o Chronic Myeloid Leukemia o Polycythemia Vera Ø This mutation can be detected in the serum and help support the diagnosis of polycythemia or other myeloproliferative neoplasms. o Essential Thrombocytosis o Primary Myelofibrosis Ø Calreticulin mutations have been observed in patients with ET and PMF, while MPL mutations have been seen in patients with familial ET. Ø Translocation of chromosomes 9 and 22 (t9/22) is seen in patients with chronic myeloid leukemia. q Lymphoid Neoplasms B- and T-Cell Neoplasms o Acute Lymphoblastic Leukemia/Lymphoma Ø Peripheral B-Cell Neoplasms o Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma o Follicular Lymphoma o Diffuse Large B-Cell Lymphoma o Burkitt Lymphoma o Mantle Cell Lymphoma o Marginal Zone Lymphomas o Hairy Cell Leukemia Ø Peripheral T- and NK-Cell Neoplasms o Peripheral T-Cell Lymphoma, Unspecified o Anaplastic Large-Cell Lymphoma (ALK Positive) o Adult T-Cell Leukemia/Lymphoma o Mycosis Fungoides/Sézary Syndrome o Large Granular Lymphocytic Leukemia o Extranodal NK/T-Cell Lymphoma Ø Plasma Cell Neoplasms and Related Disorders o Multiple Myeloma o Smoldering Myeloma o Solitary Osseous Plasmacytoma o Lymphoplasmacytic Lymphoma Ø Langerhans Cell Histiocytosis Ø FIP1L1-PDGFRA is a mutation seen in patients with hypereosinphilic syndromes. Ø Hodgkin Lymphoma q Myeloid Neoplasms q Lymphoid Neoplasms Ø Ø Acute Myeloid Leukemia Ø Myelodysplastic Syndrome Ø Myeloproliferative Neoplasms o Chronic Myeloid Leukemia o Polycythemia Vera o Essential Thrombocytosis o Primary Myelofibrosis B- and T-Cell Neoplasms o Acute Lymphoblastic Leukemia/Lymphoma Ø Peripheral B-Cell Neoplasms o Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma o Follicular Lymphoma o Diffuse Large B-Cell Lymphoma o Burkitt Lymphoma o Mantle Cell Lymphoma o Marginal Zone Lymphomas o Hairy Cell Leukemia Ø Peripheral T- and NK-Cell Neoplasms o Peripheral T-Cell Lymphoma, Unspecified o Anaplastic Large-Cell Lymphoma (ALK Positive) o Adult T-Cell Leukemia/Lymphoma o Mycosis Fungoides/Sézary Syndrome o Large Granular Lymphocytic Leukemia o Extranodal NK/T-Cell Lymphoma Ø Plasma Cell Neoplasms and Related Disorders o Multiple Myeloma o Smoldering Myeloma o Solitary Osseous Plasmacytoma o Lymphoplasmacytic Lymphoma Ø Langerhans Cell Histiocytosis Ø Hodgkin Lymphoma next q Myeloid Neoplasms q Lymphoid Neoplasms Ø Ø Acute Myeloid Leukemia Ø Myelodysplastic Syndrome Ø Myeloproliferative Neoplasms o Chronic Myeloid Leukemia o Polycythemia Vera o Essential Thrombocytosis o Primary Myelofibrosis B- and T-Cell Neoplasms o Acute Lymphoblastic Leukemia/Lymphoma Ø Peripheral B-Cell Neoplasms o Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma o Follicular Lymphoma o Diffuse Large B-Cell Lymphoma o Burkitt Lymphoma o Mantle Cell Lymphoma o Marginal Zone Lymphomas o Hairy Cell Leukemia Ø Peripheral T- and NK-Cell Neoplasms o Peripheral T-Cell Lymphoma, Unspecified o Anaplastic Large-Cell Lymphoma (ALK Positive) o Adult T-Cell Leukemia/Lymphoma o Mycosis Fungoides/Sézary Syndrome o Large Granular Lymphocytic Leukemia o Extranodal NK/T-Cell Lymphoma Ø Plasma Cell Neoplasms and Related Disorders o Multiple Myeloma o Smoldering Myeloma o Solitary Osseous Plasmacytoma o Lymphoplasmacytic Lymphoma Ø Langerhans Cell Histiocytosis Ø Hodgkin Lymphoma Leukemias § Chronic lymphocytic leukemia (CLL) is the most common leukemia overall; § Acute lymphocytic leukemia (ALL) is the most common leukemia in children. Pathogenesis of white cell malignancies Viruses as causative agents in lymphomas Three lymphotropic viruses have been implicated as causative agents in particular lymphomas: human T-cell leukemia virus-1 (HTLV-1) o HTLV-1 is associated with adult T-cell leukemia/lymphoma. EBV o EBV is found in a subset of Burkitt lymphoma, 30% to 40% of Hodgkin lymphoma (HL), many B-cell lymphomas arising in the setting of T-cell immunodeficiency, and rare NK-cell lymphomas. human herpesvirus-8 (HHV-8); also known as Kaposi sarcoma herpesvirus o HHV-8 is associated with an unusual B-cell lymphoma that presents as a malignant effusion, often in the pleural cavity Acute leukemias (ALL and AML) § General characteristics (1) There are two types of acute leukemias: ALL and AML. (2) The incidence increases with age. (3) In children 3 to 7 years old, ALL (80%) is more common than AML. (4) AML is primarily a disease of adulthood (median age at onset is 60 years) § Clinical features (1) Most clinical findings (pallor, dyspnea, tachycardia, infections, bleeding, bone pain) are related to the replacement of normal bone marrow with abnormal cells. (2) Gingival bleeding, epistaxis, and menorrhagia may be the presenting complaints in patients with thrombocytopenia. (3) Neutropenia predisposes to infections, most commonly those caused by Gram-negative bacteria or fungi. (4) Children and young adults present with fatigue, abrupt onset of fever, lethargy, headache, and bone and/or joint pain, especially in the sternum, tibia, and femur. (5) Older adults have a slow, progressive onset, with lethargy, anorexia, and dyspnea. (6) Symptoms of anemia, thrombocytopenia, gingival hyperplasia, rashes, or cranial nerve palsies may occur. (7) Lymphadenopathy and hepatosplenomegaly are more common in ALL than in AML. All-trans retinoic acid/arsenic trioxide (ATRA/ATO) synergistic treatment in Acute Promyelocytic Leukemia (APL) Ø Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML) accounting for 5–10% of all pediatric AML cases Ø APL is the result of the balanced translocation between promyelocytic leukemia (PML) gene on chromosome 15 and retinoic acid receptor alpha (RARA) on chromosome 17 leading to the fusion oncoprotein PML-RARA and myeloid differentiation block at promyelocyte stage Ø The combination of ATRA and ATO leads to ubiquitination and, ultimately, to proteasome degradation of the fusion protein, reactivation of the transcription of RARA target genes, and finally granulocytic differentiation https://www.mdpi.com/1422-0067/22/2/642 q Lymphoid Neoplasms Ø Ø Ø Ø Ø B- and T-Cell Neoplasms o Acute Lymphoblastic Leukemia/Lymphoma Peripheral B-Cell Neoplasms o Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma o Follicular Lymphoma o Diffuse Large B-Cell Lymphoma o Burkitt Lymphoma o Mantle Cell Lymphoma o Marginal Zone Lymphomas o Hairy Cell Leukemia Peripheral T- and NK-Cell Neoplasms o Peripheral T-Cell Lymphoma, Unspecified o Anaplastic Large-Cell Lymphoma (ALK Positive) o Adult T-Cell Leukemia/Lymphoma o Mycosis Fungoides/Sézary Syndrome o Large Granular Lymphocytic Leukemia o Extranodal NK/T-Cell Lymphoma Plasma Cell Neoplasms and Related Disorders o Multiple Myeloma o Smoldering Myeloma o Solitary Osseous Plasmacytoma o Lymphoplasmacytic Lymphoma Hodgkin Lymphoma q Myeloid Neoplasms Ø Acute Myeloid Leukemia Ø Myelodysplastic Syndrome Ø Myeloproliferative Neoplasms o Chronic Myeloid Leukemia o Polycythemia Vera o Essential Thrombocytosis o Primary Myelofibrosis Ø Langerhans Cell Histiocytosis ALL Origin of lymphoid neoplasms (A) Acute lymphoblastic leukemia/lymphoma (ALL). Lymphoblasts with condensed nuclear chromatin, small nucleoli, and scant agranular cytoplasm. Stages of B- and T-cell differentiation from which specific lymphoid tumors emerge are shown. (B and C) Phenotype of ALL shown in (A) analyzed by flow cytometry. BLB, Pre-B lymphoblast; CLP, common lymphoid precursor; DN, CD4/CD8 double-negative pro-T cell; DP, CD4/CD8 double-positive pre-T cell; GC, germinal center B cell; MC, mantle B cell; MZ, marginal zone B cell; NBC, naive B cell; PTC, peripheral T cell. Lymphoid Neoplasms (B) The lymphoblasts represented by the red dots express terminal deoxynucleotidyl transferase (TdT) and the B-cell marker CD22. (C) The same cells are positive for two other markers, CD10 and CD19, commonly expressed on pre-B lymphoblasts. Thus this is a B-ALL. q Lymphoid Neoplasms Ø Ø Ø Ø Ø B- and T-Cell Neoplasms o Acute Lymphoblastic Leukemia/Lymphoma Peripheral B-Cell Neoplasms o Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma o Follicular Lymphoma o Diffuse Large B-Cell Lymphoma o Burkitt Lymphoma o Mantle Cell Lymphoma o Marginal Zone Lymphomas o Hairy Cell Leukemia Peripheral T- and NK-Cell Neoplasms o Peripheral T-Cell Lymphoma, Unspecified o Anaplastic Large-Cell Lymphoma (ALK Positive) o Adult T-Cell Leukemia/Lymphoma o Mycosis Fungoides/Sézary Syndrome o Large Granular Lymphocytic Leukemia o Extranodal NK/T-Cell Lymphoma Plasma Cell Neoplasms and Related Disorders o Multiple Myeloma o Smoldering Myeloma o Solitary Osseous Plasmacytoma o Lymphoplasmacytic Lymphoma Hodgkin Lymphoma q Myeloid Neoplasms Ø Acute Myeloid Leukemia Ø Myelodysplastic Syndrome Ø Myeloproliferative Neoplasms o Chronic Myeloid Leukemia o Polycythemia Vera o Essential Thrombocytosis o Primary Myelofibrosis Ø Langerhans Cell Histiocytosis Chronic lymphocytic leukemia q Lymphoid Neoplasms Ø Ø Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder with an average age of diagnosis of 70 to 72. In the western part of the world, this disease stems from a b-cell clone, whereas in Asia, it stems from a t-cell clone. Lymphocyte count: XX,000 (normal: 1000–4300) The disease is characterized by progressive accumulation of lymphocytes that can populate in the blood, the nodes, the bone marrow, or other internal organs. Ø Often patients are asymptomatic and the diagnosis is only considered after routine labs confirm lymphocytosis. The presence of “smudge cells” on the peripheral blood smear is not diagnostic but can be suggestive of CLL. Ø The diagnosis can be made via peripheral flow cytometry, bone marrow aspiration and biopsy (which is often times not needed), or an excisional node biopsy. Ø B- and T-Cell Neoplasms o Acute Lymphoblastic Leukemia/Lymphoma Peripheral B-Cell Neoplasms o Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma o Follicular Lymphoma o Diffuse Large B-Cell Lymphoma o Burkitt Lymphoma o Mantle Cell Lymphoma o Marginal Zone Lymphomas o Hairy Cell Leukemia Peripheral T- and NK-Cell Neoplasms o Peripheral T-Cell Lymphoma, Unspecified o Anaplastic Large-Cell Lymphoma (ALK Positive) o Adult T-Cell Leukemia/Lymphoma o Mycosis Fungoides/Sézary Syndrome o Large Granular Lymphocytic Leukemia o Extranodal NK/T-Cell Lymphoma Plasma Cell Neoplasms and Related Disorders o Multiple Myeloma o Smoldering Myeloma o Solitary Osseous Plasmacytoma o Lymphoplasmacytic Lymphoma Hodgkin Lymphoma q Myeloid Neoplasms Ø Acute Myeloid Leukemia Ø Myelodysplastic Syndrome Ø Myeloproliferative Neoplasms o Chronic Myeloid Leukemia o Polycythemia Vera o Essential Thrombocytosis o Primary Myelofibrosis Ø Langerhans Cell Histiocytosis Hodgkin lymphoma (HL) Hodgkin lymphoma (HL) Ø Hodgkin lymphoma (HL) is a rare monoclonal lymphoid neoplasm characterized by the following four features: 1. HL usually presents in young adults, 2. commonly arises in cervical lymph nodes, 3. involves scattered large mononuclear Hodgkin and multinucleated Reed-Sternberg cells on a background of non-neoplastic inflammatory cells, and 4. characteristic neoplastic cells are often surrounded by T lymphocytes. Ø Hodgkin lymphoma generally has an excellent prognosis, though this depends on several factors Ø Hodgkin lymphoma is a rare malignancy with an estimated incidence rate of 2.6 cases per 100,000 people in the United States. Ø The disease represents 11% of all lymphomas seen in the United State Ø The exact etiology of Hodgkin lymphoma is unknown. Ø However, there is an increased risk of Hodgkin lymphoma in Epstein-Barr (EBV) and Human immunodeficiency virus (HIV) infections, autoimmune diseases, and immunosuppression. Ø There is also evidence of familial predisposition in Hodgkin lymphoma. Summary APL(t15,17) 1 A 71-year-old male presents to his primary care provider for an annual health maintenance examination. He offers no complaints and states that he feels well. He has a history of hypertension, atrial fibrillation, type 2 diabetes, and hyperlipidemia. Pertinent labs revealed the following: White blood count (WBC): 46,000 (normal: 4500–11,000) Hemoglobin (Hgb): 15.2 g/dL (normal: 13.5–17.5 g/dL) Hematocrit (HCT): 48% (normal: 41–50%) Platelet (PLT) count: 423,000 (normal 150,000–450,000) Neutrophil count: 6000 (normal: 1800–8800) Lymphocyte count: 38,000 (normal: 1000–4300) Basophil count: 200 (normal: 0.00–0.20) Eosinophil count: 800 (normal: 0.00–0.60) Monocyte count: 1000 (normal: 0.04–1.10) Peripheral smear: smudge cells noted Lactate dehydrogenase (LDH): 220 IU/L (normal: 100–190 IU/L) Blood urea nitrogen (BUN): 18 mg/dL (normal: 10–20 mg/dL) Creatine: 1.1 mg/dL (normal: 0.7–1.2 mg/dL) Total protein: 7.1 g/dL (normal: 6–8 g/dL) Albumin: 4.7 g/dL (normal: 3.5–5.0 g/dL) Globulin: 2.4 g/dL (normal: 2–3.5 g/dL) (A) Acute lymphoblastic leukemia (B) Acute myeloid leukemia (C) Chronic lymphocytic leukemia (D) Chronic myeloid leukemia (E) Waldenstrom’s macroglobinemia Full body computed tomography (CT) scans confirmed some clustered grouping of lymph nodes within the axillary region, cervical region, and retroperitoneal region. No organomegaly was noted. Which of the following is the most likely diagnosis? 33 A 45-year-old man presents to the office because of a dragging sensation in the abdomen for the past 2 months. He also reports easy fatigability in this same time period. Past medical history is significant for an upper respiratory tract infection treated with antibiotics 6 months ago. The patient has smoked a pack of cigarettes daily for the past 27 years. Temperature is 37.0°C (98.6°F), pulse is 95/min, respirations are 20/min, and blood pressure is 135/85 mmHg. Physical examination shows splenomegaly. Laboratory results are as follows: 38 References REQUIRED TEXTBOOK § Hammer GD, McPhee SJ. Pathophysiology pf Disease: An Introduction to Clinical Medicine. McGraw-Hill Education Companies; 2019. ISBN-13: 978-1260026504. https://accessmedicine.mhmedical.com/book.aspx?bookid=2468 SUPPLEMENTAL MATERIALS § McCance, Kathryn L., and Sue E. Huether. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 9th ed. Mosby Elsevier. 2024. ISBN-13: 978-0323789875 § Kumar, Vinay, et al. Robbins &Kumar Basic Pathology. 11th ed., Elsevier - Health Sciences Division. 2023. ISBN-13: 9780323790185 § Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. eds. Harrison's Principles of Internal Medicine, 21e. McGraw Hill; 2022. § White Blood Cell Disorders on Osmosis