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DANYLO HALYTSKY LVIV NATIONAL MEDICAL UNIVERSITY DEPARTMENT OF PATHOPHISIOLOGY Methodical recommendations for independent work of English medium students of Pharmaceutical faculty for preparing to practical classes by the theme “LEUKOSES” on the discipline “Pathological Physiology” Lviv 2011 1 DANYLO HALYTSKY LVIV NATIONAL MEDICAL UNIVERSITY DEPARTMENT OF PATHOPHISIOLOGY METHODICAL RECOMMENDATIONS for independent work of English medium students of Pharmaceutical faculty for preparing to practical classes by the theme “LEUKOSES” Subject Module # 2 Thematic module # 1 Year of study Faculty Pathological Physiology Pathology organs and sistems Pathology of blood 2-3 Pharmaceutical Lviv 2011 2 Methodical recommendations made by: prof. Regeda M. S., as. Sementsiv N.G., Baida M.L., PhD; ass. prof. Lubinets L.A., Kathmarska M.O. In the methodical recommendations for independent work of English medium students of Pharmaceutical faculty for preparing to practical classes by the theme “Leukoses” main theoretical information necessary for understanding of the material are given in full volume and according to the study program “Pathological Physiology”. Responsible for edition: First prorector on scientific-pedagogical work of Danylo Halytsky Lviv National Medical University acad. Gzhegotsky M.R. Reviewers: Associate professor of the department of pathological anatomy with the course of forensic medicine of Danylo Halytsky Lviv National Medical University Vovk V.I. Associate professor of the department of pharmacology of Danylo Halytsky Lviv National Medical University Gavryluk I.M. Confirmed by medical commission on medico-biological disciplines of Danylo Halytsky Lviv National Medical University Protocol №3 from September 1, 2011 3 LEUKOSES I. SIGNIFICANCE OF THE THEME Leukoses are the most common diseases of the hematopoietic system – they make 40% of the total pathologies of blood. Increasing morbidity and mortality rate of leukoses is due to progressively rising incidence of acute leukoses which make up almost 60% of all hematologic cases. According to the data of the WHO, there has not been established any prevalence of leukoses in either the part of the world or the groups of population , that is, leukoses occur in all countries of the world and at any age, whereas contemporary methods of treatment for leukoses have not proved sufficiently efficacious. In addition, certain aspects of etiology and pathogenesis of leukoses seek for further clarification. Ensuing from the aforementioned, the problems concerning leukocytoses can be claimed of a great significance and their study is viewed as an important integral part of medical education. Epidemiology The incidence of leukaemia of all types in the population is approximately 10/100 000 per annum, of which just under half are acute leukaemia. Males are affected more frequently than females, the ratio being about 3:2 in acute leukaemia, 2:1 in chronic lymphocytic leukaemia and 1.3:1 in chronic myeloid leukaemia. Geographical variation in incidence does occur, the most striking being the rarity of chronic lymphocytic leukaemia in the Chinese and related races. Acute leukaemia occurs at all ages. Acute lymphoblastic leukaemia shows a peak of incidence in the 1-5 age group. All forms of acute myeloid leukaemia have their lowest incidence in young adult life 4 and there is a striking rise over the age of 50. Chronic leukaemias occur mainly in middle and old age. Aetiology The cause of the leukaemia is unknown in the majority of patients. Several factors, however, are associated with the development of leukaemia and these are listed in scheme Terminology and classification In acute leukaemia there is proliferation of primitive stem cells leading to an accumulation of blasts, predominantly in the bone marrow, which causes bone marrow failure. In chronic leukaemia the malignant clone is able to differentiate, resulting in an accumulation of more mature cells. Leukaemias are traditionally classified into four main groups: acute lymphoblastic leukaemia (ALL) acute myeloid leukaemia (AML) chronic lymphocytic leukaemia (CLL) chronic myeloid leukaemia (CML). FACTORS ASSOCIATED WITH THE DEVELOPMENT OF LEUKAEMIA Ionising radiation A significant increase in myeloid leukaemia followed the atomic bombing of Japanese cities An increase in leukaemia was observed after the use of radiotherapy for ankylosing spondylitis and diagnostic X-rays of the fetus in pregnancy Cytotoxic drugs These, particularly alkylating agents, may induce myeloid leukaemia, usually after a latent period of several years Exposure to benzene in industry Retroviruses One rare form of T-cell leukaemia/lymphoma appears to be associated with a retrovirus similar to the viruses causing leukaemia in cats and cattle There is a greatly increased incidence of leukaemia in the identical twin of patients with leukaemia Increased incidence occurs in Down's syndrome and certain other genetic disorders Genetic Immunological Immune deficiency states (e.g. hypogammaglobulinaemia) are associated with an increase in haematological malignancy 5 The diagnosis of leukaemia is usually suspected from an abnormal blood count, often a raised white count. The diagnosis is made from examination of the bone marrow. This includes the morphology of the abnormal cells, analysis of cell surface markers (immunophenotyping), clonespecific chromosome abnormalities and molecular changes. Not only does this allow an accurate diagnosis but also gives valuable prognostic information, allowing therapy to be tailored to the patient's disease. The World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues divides these diseases into lineages and incorporates results from immunophenotyping, genetic and molecular analysis. ACUTE LEUKAEMIA There is a failure of cell maturation in acute leukaemia. Proliferation of cells which do not mature leads to an accumulation of useless cells which take up more and more marrow space at the expense of the normal haematopoietic elements. Eventually, this proliferation spills into the blood. Acute myeloid leukaemia is about four times more common than acute lymphoblastic leukaemia in adults. In children the proportions are reversed, the lymphoblastic variety being more common. Investigations WHO CLASSIFICATION OF ACUTE LEUKAEMIA Acute myeloid leukaemia with recurrent genetic abnormalities AML with t(8;21) gene product AML/ETO AML with eosinophilia inv(16) or t(16;16), gene product CBFβ/MYH11 Acute promyelocytic leukaemia t(15;17), gene product PML/RARA AML with 11q23 abnormalities (MLL) Acute myeloid leukaemia with multilineage dysplasia e.g. Following a myelodysplastic syndrome Acute myeloid leukaemia and myelodysplastic syndromes, therapy-related e.g. Alkylating agent or topoisomerase ll inhibitor Acute myeloid leukaemia not otherwise specified e.g. AML with or without differentiation, acute myelomonocytic leukaemia, erythroleukaemia, megakaryoblastic leukaemia, myeloid sarcoma Acute lymphoblastic leukaemia Precursor B ALL Precursor T ALL CHRONIC MYELOID LEUKAEMIA (CML) Chronic myeloid leukaemia is a myeloproliferative stem cell disorder resulting in proliferation of all haematopoietic lineages but manifesting predominantly in the granulocytic series. Maturation proceeds fairly normally. The disease occurs chiefly between the ages of 30 and 80 years, with a peak incidence at 55 years. It is rare, with an annual incidence in the UK of 1.8/100 000, and accounts for 20% of all leukaemias. The disease is found in all races. The aetiology is unknown. Cytogenetic and molecular aspects Approximately 95% of patients with CML have a chromosome abnormality known as the Philadelphia (Ph) chromosome. This is a shortened chromosome 22 and is the result of a reciprocal translocation of material with chromosome 9. The break on chromosome 22 occurs in 6 the breakpoint cluster region (BCR). The fragment from chromosome 9 that joins the BCR carries the abl oncogene, which forms a chimeric gene with the remains of the BCR. This BCR ABL chimeric gene codes for a 210 kDa protein with tyrosine kinase activity, which plays a causative role in the disease, influencing cellular proliferation, differentiation and survival. In some apparently Ph chromosome-negative patients, the BCR ABL gene product is detectable by molecular techniques. Natural history The disease has three phases: a chronic phase, in which the disease is responsive to treatment and is easily controlled, typically lasting 3-5 years an accelerated phase (not always seen), in which disease control becomes more difficult blast crisis, in which the disease transforms into an acute leukaemia, either myeloid (70%) or lymphoblastic (30%), which is relatively refractory to treatment. Blast crisis occurs at a rate of 10% per year and is the cause of death in the majority of patients. Patient survival is therefore dictated by the timing of blast crisis, which cannot be predicted. CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) This is the most common variety of leukaemia, accounting for 30% of cases. The male to female ratio is 2:1 and the median age at presentation is between 65 and 70 years. In this disease B lymphocytes, which would normally respond to antigens by transformation and antibody formation, fail to do so. An ever-increasing mass of immuno-incompetent cells accumulate, to the detriment of immune function and normal bone marrow haematopoiesis. Clinical features The onset is very insidious. Indeed, in around 70% of patients the diagnosis is made incidentally on a routine full blood count. Presenting problems may be anaemia, infections, painless lymphadenopathy and systemic symptoms such as night sweats or weight loss. However, these more often occur later in the progress of the disease. Investigations The diagnosis is based on the peripheral blood findings of a mature lymphocytosis (> 5 × 109/l) with characteristic morphology and cell surface markers. Immunophenotyping reveals the lymphocytes to be monoclonal B cells expressing the B-cell antigens CD19 and CD23 with either kappa or lambda immunoglobulin light chains and, characteristically, a T-cell antigen, CD5. Other useful investigations in CLL include a reticulocyte count and a direct Coombs test as autoimmune haemolytic anaemia may occur Serum immunoglobulin levels should be estimated to establish the degree of immunosuppression, which is common and progressive. Bone marrow examination by aspirate and trephine is not essential for the diagnosis of CLL, but may be helpful in difficult cases, for prognosis (patients with diffuse marrow involvement tend to do worse) and to monitor response to therapy. The main prognostic factor is stage of disease ; however, newer markers such as CD38 expression, mutations of IgVH genes, and cytogenetic abnormalities of chromosome 11 or 17 may also suggest a poorer prognosis. Management STAGING OF CHRONIC LYMPHOCYTIC LEUKAEMIA Clinical stage A (60% patients) No anaemia or thrombocytopenia and less than three areas of lymphoid enlargement 7 Clinical stage B (30% patients) No anaemia or thrombocytopenia, with three or more involved areas of lymphoid enlargement Clinical stage C (10% patients) Anaemia and/or thrombocytopenia, regardless of the number of areas of lymphoid enlargement II. CONCRETE TEACHING GOALS Students have to gain knowledge of: 1. Definitions of leukoses, their etiology and pathogenesis. 2. Principles of classification of leukoses; kinds of acute and chronic leukoses. 3. Hematological characteristics of acute and chronic leukoses. 4. Criteria for differentiation between acute myeloblastic leukosis and chronic lympho- and myeloleukosis. Students have and to be able to differentiate them by the data of hemogram of patients with leukoses. 5. General disorders in the organism in leukoses. 6. Basic principles of the therapy of leukoses. III. BASIC KNOWLEDGE, CAPABILITIES AND SKILLS ESSENTIAL TO THE STUDY OF THIS THEME (interdisciplinary integration). Names of subjects Histology previously Normal physiology studied Obtained knowledge and skills Kinds of leukocytes and specific features of their structure. Kinds of leukocytes, their functional characteristics. Differentiation of the individual kinds of leukocytes. Calculation of the number of leukocytes and components of leukoformula in the norm. 8 IV. ASSIGNMENTS FOR INDEPENDENT WORK TO BE DONE WHILE PREPARING FOR THE PRACTICAL CLASS 1. Basic terms, parameters and characteristics necessary to learn while preparing for the practical class Term Hemoblastosis Definition The disease characterized by clonal neoplasms which originate in the hematopoietic cells. Leukosis The systemic hematologic disease of tumoral origin with inevitable affections of the hematopoietic tissue, development of extramedullar foci of hematopoiesis, and appearance of blast cells in the peripheral blood. Lymphomas The generalized term used to define tumours which develop from lymphoid cells located mostly outside the bone marrow (in the lymph nodes, spleen, aggregations of lymphoid tissue in various organs – intestines, nasal sinuses and others). Lymphogranulomatosis The malignant tumoral disease of the lymphatic system with the formation of polymorphic cellular granulomas which contain atypical polynuclear cells (Berezovsky-Ridd- Shternberg cells) of unclear genesis 2. Theoretical questions for the practical class 1. Concepts of hemoblastoses and characteristics of their major groups. 2. Definitions of leukoses and principles of their classification. 3. The main etiologic agents of the genesis of leukoses, their characteristics. 4. Typical processions and peculiarities of the development of leukoses. 5. Morphological, cytogenetic, cytochemical and immune phenotype characteristics of leukoses. 6. Peculiarities of the peripheral blood picture in acute and chronic forms of leukoses. 7. Hematological characteristics of acute myeloblastic leukosis. 8. Hematological characteristics of chronic myeloblastic leukosis. 9. Hematological characteristics of lympholeukosis. 10. General disorders in the organism in leukoses. 11. Principles of diagnosis and treatment of leukoses. 9 V. CONTENT OF THE THEME: Structure-logical scheme 1 (after O.V.Byts, 2001) LEUKOSIS CHRONIC ACUTE Megakaryo -cytic Monocytic Erythromyelosis Lympholeukosis Myeloleukosis Monoblastic Erythromyelosis Lymphoblastic Myeloblastic Nondifferrentiated Classification Etiology Oncogenic viruses Chemical cancerogens Genetic anomalies Ionizing irradiation Pathogenesis: Gene mutation or epigenomic impairment of the regulation of division and differentiation of cells of class I-IV hematopoiesis main links Metastasis of leukemic cells in the system of blood Nuclear shift to the left Cellular content depending on the kind and stage of leukosis Auto-allergic reactions Concomitance of secondary infection Reduction of antibody production Disorders of functioning of the immune and associated systems Reduction of phagocytic activity of leukocytes Nonadherence to cytostatic therapy Leukemic infiltration of the non-hematopoietic organs Tumoral progression (transformation of monoclonal stage into polyclonal) Blastic crisis Thrombocytopenia, hemorrhagic syndrome Anemia Disorders of normal progenitors of hemocytopoiesis Inhibition of normal leukocytopoiesis Enhargement of lymph nodes, spleen and liver Change of hemogram Formation of the clone of leukemic cells in the bone marrow Change of myelogram Clinical manifestations Blastic crisis Mechanism of appearance mechanism of developmen Atypical cells; degenerative changes 10 3. Assignments for practical work to be done in class. Assignments Instructions for the assignments Calculate and write down leukogram. Depict Divide blood smear into the 4 imaginary fields blood picture. and, moving the smear in the broken line, count 25 leukocytes in each of them, Calculate the individual kinds of leukocytes with the use of calculator. Make a diagnostic conclusion on the kind of . leukosis on the basis of the data of leukogram. VI. MATERIAL FOR SELF-CONTROL A. Assignment for self-control Assignments Instructions for the assignments Give an account of causes and mechanisms of Focus on the theoretical concepts of the the development of leukoses. genesis of leukoses and give the facts which confirm these concepts. Give classifications of leukoses. Give the principles on which classification of leukoses is based. Give an account of the main manifestations of Give at least three of them. tumour progression in leukoses. Give characteristics of acute and chronic Indicate peculiarities of the peripheral blood leukoses. picture in acute and chronic leukoses. B. Tasks for self-control Task 1. Patient B., aged 38, for the last year noticed growing fatigue and general malaise. After the blood analysis, he was directed to the inpatient clinic. Blood count: E – 4.1 x 1012/l, Hb – 119 g/l, RCI – 0.87. reticulocytes 0.7%. Leukocytes – 57 x 109/l. Leukoformula: B – 0%, E – 0%, J.n. – 0%, R.n. – 0%, S.n. – 9%, lymphoblasts – 7%, lymphocytes – 81%, M – 3%. Thrombocytes – 160 x 109/l. In the blood smear: normochromia, large amounts of shadow cells (Botkin-Humprecht cells). Which pathology of the hematopoietic system is this hemogram indicative of? 11 Task 2. Patient B., aged 26, was hospitalized for excudative pleurisy. In the anamnesis: relapsing quinsy, bronchopneumonia, furunculosis. Objectively: pallor, enlarged but painless and not coalescent lymph nodes (cervical, mandibular, axillary, inguinal), enlarged spleen and liver, rightside excudative pleurisy. Blood count: E – 2.8 x 1012/l. Hb – 90g/l. Leukocytes – 100 x 109/l. Leukogram: B – 0%, E – 1%, C – 9%, lymphoblasts – 1%, prolymphi\ocytes – 5%, lymphocytes 80%, monocytes – 4%. Thrombocytes – 160 x 109/l. ESR – 25 mm/hr. In the blood smear: prevailing micro-generations of lymphocytes, large amounts of shadow cells (Botkin-Humprecht cells). Explain the mechanism of changes of the amount of leukocytes in this patient. Task 3. Patient T., aged 54, sought medical advice for pains in the left hypochondrium. About 3 months before he had noticed increasing fatigue and general malaise. He assumed that they were due to his overexertion at work. Blood count: E – 3.5 x 1012/l, Hb – 110g/l, RCI – 0.94. Leukocytes – 23 x 109/l. Leukoformula: B – 4%, E – 6%, myeloblasts – 2%, promyelocytes – 8%, myelocytes – 16%, J.n. – 20%, R.n. – 16%, S.n. – 12%. L – 12%, M – 4%. Thrombocytes – 160 x 109/l. In the blood smear: normochromia, anisocytosis, poikilocytosis. Reticulocytes – 0.4%. Give characteristics of the detected pathology: by the imparted hematopoietic progenitor; by the degree of cellular maturity of the impaired progenitor; by the number of leukocytes in the peripheral blood. Task 4. Patient A., aged 42, was hospitalized for general malaise, fever, pains in the bones and joints. Blood count on admission: E – 2.8 x 1012/l, Hb – 84 g/l, RCI – 0.9. Reticulocytes – 0.4%. Leukocytes – 82 x 109/l. Leukoformula : B – 0%, E. – 0%, myeloblasts – 68%, S.n. – 20%, L – 10%, M – 2%. Thrombocytes – 142 x 109/l. In the blood smear: normochromia, anisocytosis, poikilocytosis. Which classes of hematopoietic cells are probable sources of the tumoral clone in this case? Task 5. Patient’s blood count: E – 3.6 x 109/l, Hb – 140 g/l, RCI – 1.0. Leukocytes – 30 x 109/l. Leukoformula : B – 9%, E. – 8%, myeloblasts – 2%, promyelocytes -3%, myelocytes – 4%, J.n. – 1%, R.n. – 11%, S,n. – 43%, L – 15%, M – 4%. Thrombocytes – 210 x 109/l. What is the mechanism of the pathogenesis of these changes? Task 6. Female patient M., aged 17, sought medical advice for multiple hemorrhagic spots on the skin. She had noticed separate spots before but hadn’t paid special attention to them as she viewed them as signs of minor injuries. Blood count: E – 3.6 x 1012/l, Hb – 100g/l, RCI – 0.83. Leukocytes 12 – 6.5 x 109/l. Leukoformula: B – 0%, E – 0%, J.n. – 0%, R.n. – 1%, S.n. – 18, lymphoblasts – 67%, lymphocytes – 12%, M – 2%. Thrombocytes – 60 x 109/l. In the blood smear: normochromia, moderate anisocytosis, poikilocytosis. Reticulocytes – 1.2%. What is the pathogenesis of hemorrhages in this patient? Task 7. Female patient K, aged 24, was hospitalized in a grave condition: increasing weakness, retardation, high temperature (up to 39°C). bilateral pneumonia, petechial eruption on the skin. Moderate enlargement of liver and spleen. Blood count: E – 1.2x 1012/l, Hb – 40 d/l, RCI – 1.0. Leukocytes – 2.4 x109/l. Leukoformula: B – 0%, E – 0%, J.n. – 0%, R.n.. – 0%, S.n. – 2l, M – 6%, blast cells – 57%. Thrombocytes – 89 x 109/l. In the blood smear: large, irregular blast cells with large nuclei. By the main cytochemical characteristics, blast cells belong to the cells of monocytic line. 1. What is the diagnosis of the pathology of the hematopoietic system in this patient? 2. What leukopoietic changes is the appearance of blast cells in the peripheral blood indicative of? 3. Which cytochemical signs prove that blast cells belong to the cells of monocytic line? Task 8. Patient B., aged 15, complains of recurrent seizures of pain in the shanks and soft tissues of the forearms. Objective changes of the skin and configuration of extremities are absent. Blood count: E – 2.3 x 1012/l, Hb – 60g/l, RCI – 0,8. Leukocytes 137 x x109/l. Leukoformula: B – 0%, E – 0.5%, R.n.. – 0.5%, S.n. – 12%, L – 18%, M – 6%, blast cells – 63%. Thrombocytes – 140 x 109/l. In the blood smear: large, irregular blast cells with distinctly vacuolized cytoplasm which contains rough granulation. By the main cytochemical characteristics, blast cells belong to the cells of myeloid line. 1. Which hematopoietic pathology does this blood count indicate? 2. What is the mechanism of detected changes of the red blood cells? Task 9. Patient’s blood count: E – 3.6 x 109/l, Hb – 140 g/l, RCI – 1.0. Leukocytes – 30 x 109/l. Leukoformula: B – 1%, E – 3%, J.n. – 0%, R.n.. – 4%, S.n. – 43%, L – 15%, monoblasts – 2%, promonocytes -3%, M – 14%.Thrombocytes – 210 x 109/l. In the blood smear: atypical monocytes with nuclear fragmentation. Which blood pathology are these hematopoietic changes characteristic of? Task 10. Patient A., aged 22, was hospitalized for the complains of weakness, fever, hyperhydrosis, pains in the throat on swallowing. Blood count: E – 30 x 109/l, Hb – 70g/l. Reticulocytes – 0.2%. Leukocytes – 45 x 109/l. Leukoformula: B – 1%, E – 2%, blast cells – 79%, myelocytes – 0%, 13 metamyelocytes – 0%, R.n.. – 0%, S.n. – 13%, L – 4%, M – 1%. Thrombocytes – 100 x109/l. ESR – 34 mm/hr. In the blood smear: anisocytosis, poikilosis, anisochromia. What is the change of organism’s reactivity caused by? Task 11. Patient presents with the poorly healing cavity after tooth extraction and sanies discharge from the cavity. Blood count: E – 3.6 x 1012/l, Hb – 140g/l, RCI – 1.0. Leukocytes – 25 x 109/l. Leukoformula: B – 8%, E – 8%, myeloblasts – 3%, promyelocytes – 2%, myelocytes – 3%, J.n. – 1%, R.n. – 12%, S.n. – 44%, L – 16%, M – 3%. Thrombocytes – 220 x 109/l. Explain pathogenesis of this disease. REFERENCES 1. Robbins Pathologic basic of disease. - 6th ed.-/ Ramzi S. Cotnar, Vinay Kumar, Tucker Collins. – Philadelphia, London, Toronto, Montreal, Sydney, Tokyo. – 1999. 2. Gozhenko A.I., Gurcalova I.P., General and clinical pathophisiolodgy/ Study guide for medical students and practitioners. – Odessa, 2003. 3. Hematology. Basic Principles and Practice. -/ Ronald Hoffman, Edward J. Benz Jr., Sanford J. Shattil, and others . - Elsevier, Churchill, Livingstone. - 2005. 4. Harrison’s Manual of medicine .- 17th ed.- /Anthony S. Fauci, Eugene Braunwald, Dennis L. Kasper, and others.- New York, Chicago, San Francisco, London, Madrid, Mexico City, New Delhi, Sydney, Toronto.- 2008. 14