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«chronic leucemias» Methodic guidelines for the 6th year students Self-training on the practical study




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M. Gorky Donetsk National Medical University


«CHRONIC LEUCEMIAS»

Methodic guidelines for the 6th year students

Self-training on the practical study

at the Internal medicine # 1 department


Donetsk – 2010


Authors: N.T. Vatutin, N.V. Kalinkina, E.V. Keting


Reviewers:

R.V. Basiy, MD, PhD, anatomy department.


T.A. Parkhomenko, MD, PhD, internal medicine # 2 department.


I. Importance of the Subject.

Chronic leucoses are the most common hemoblastoses in the countries of Europe and North America. So, the incidence of the chronic lymphatic leukemia (CLL) is 30%, and that of the chronic myeloleukemia (CML) is 20% of the total leucosis incidence rate. The annual CLL morbidity rate in these countries ranges up to 3-3.5 in 100,000 population, representing 9% of all malignant tumors. As for CML thise figure range within 1-1.5 in 100,000 population.

In order to master the subject, knowledge of anatomy, histology, normal and pathological physiology of the hemopoiesis system, as well as propaedeutics of internal diseases, pharmacology and clinical pharmacology are required.

Changes in the blood analysis, lymphadenopathy and hepatosplenomegaly are syndromes typical of many hundreds of the diseases concerning various branches of medicine. According to the above, it is of a special importance for the doctor to have skills in making a correct differential diagnosis of the diseases, accompanied by these syndromes. Thus, taking into account difficulties of diagnosing chronic leucoses, the patients suffering from this pathology can be encountered in medical practice of any specialty.

If the importance of the subject has been understood, proceed to studying the learning objectives.


^ II. Learning Objectives


Key objective: to develop skills in making a differential diagnosis of chronic leucoses, and planning a patient management.


Specific Objectives – To gain knowledge of and develop skills in:

1. Identifying basic syndromes in chronic leucoses.


2. Making up an individual diagnostic chart and interpreting the obtained findings in chronic leucosis.


3. Making a provisional diagnosis of chronic leucoses. Making a differential diagnosis of chronic leucoses.


4. Explaining the principles of the chronic leucosis patient management.

Pre-practice knowledge and skills:


1. Selecting the data from the complaints and case history findings showing the presence of a chronic lympho- or myeloproliferative disease (Propaedeutics and Therapy Department).

2. To interpret indexes of physical and laboratory examination (complete blood count, biochemical blood examination, Immune marker analysis, Cytogenetic study) and instrumental (Sternal puncture, trepanobiopsy, ultrasound of abdomen) examination (Physiology and Pathophysiology department, Propaedeutics department).

3. To evaluate typical clinical picture of oncological, surgical, infectious diseases with lymphadenopathy, hepatosplenomegaly (Oncology, Surgery, Infectious Diseases departments). Make up conclusions, formulate a diagnosis due to classification.

4. Applying medications of pathogenetic and symptomatic therapy (Pharmacology department).


The information necessary for reviewing and revising the basic knowledge and skills can be found in the following references:


  1. Arthur C. Guyton, John E. Textbook of Medical Physiology (Textbook Binding). - Hall W.B. Saunders Company; 10th edition. – 2000.

  2. Aaron B. Caughey, Nancy Palmer, Christie Del Castillo, and Dana Tuttle. Pathophysiology: Hematology and Oncology. -Blueprints Notes & Cases Series. - 2003.

  3. Vinay Kumar, Nelso Fausto, Abul Abbas. Pathologic Basis of Disease. - Robbins & Cotran, Seventh Edition. – 2004.

  4. Carol Porth. Pathophysiology.- Lippincott Williams & Wilkins. – 2004.


Pre-Practice Knowledge and Skills Test Questions

Q1. A 63-year-old patient, has her cervical and axillary lymph nodes palpated that are as big as 2 cm in diameter, the liver sticks out as far as 3 cm, and the spleen does as far as 5 cm from under the edge of the costal margin. The blood count presents the following evidence: erythrocytes are 3.5×1012, Нb is 143 g/l, color index is 1.0, thrombocytes are 198 g/l, leucocytes are 38.6 g/l, 2 band neutrophils, 9 segmented neutrophils, 3 prolymphocytes, 85 lymphocytes, 1 monocyte, and ESR is 19 mm/h. Which of the following syndromes is the one described in this case?

  1. Anemic

  2. Toxic

  3. Plethoric

  4. Hyperplastic

  5. Hemorrhagic.


Q2. The general blood count of a 29-year-old patient showed the following data: erythrocytes were 3.7×1012, Нb was 122 g/l, color index was 1.0, thrombocytes were 109 g/l, leucocytes were 8.3 g/l, 1 eosinophil, 1 basophile, 4 band neutrophils, 58 segmented neutrophils, 32 lymphocytes, 4 monocytes, and ESR was 14 mm/h. Which of the following can be a correct diagnosis?

  1. NAD (no appreciable disease)

  2. Anemia

  3. Leukopenia

  4. Leukocytosis

  5. Thrombocytopenia.


Q3. The white blood cell count of a 49-year-old patient showed the following changes: 1% basophiles, 2% eosinophils, 2% band neutrophils, 42% segmented neutrophils, 50% lymphocytes, and 3% monocytes. Which of the following is an appropriate name for these changes?

  1. Basophilia

  2. Eosinophilia

  3. Neutrocytosis

  4. Lymphocytosis

  5. Monocytosis.


Q4. The doctor prescribed hemoexfusions with a subsequent compensation of the circulating blood volume to a 55-year-old patient affected by Osler's disease. Which of the following was supposed to be used with this object in view?

  1. Physiologic saline

  2. Rheopolyglukin

  3. Hemodez

  4. Neohemodez

  5. Ringer's solution.


Q5. A 32-year-old patient taking 80 mg dose of prednisolone per day as a constituent of one of her polychemotherapy regimen noticed an increased body weight, appearance of striae atrophicae on the skin of her thighs and abdomen, hair growing on her face, and along the white line of her abdomen. Which of the following syndromes occurred as a complication of glucocorticosteroidal therapies administered to this patient?

  1. Goodpasture's syndrome

  2. Felty’s syndrome

  3. Kimmelstil-Wilson's syndrome

  4. Itsenko-Cushing syndrome

  5. Zillinger-Ellison syndrome.


^ IV. Theory Topics on the Subject

To reach the learning objectives it is essential to master the following theory issues:

  1. Methods of clinical, laboratory and instrumental diagnostics of chronic leucoses.

  2. Differential diagnostics of chronic leucoses.

  3. Classification of chronic leucoses.

  4. Management of the patients affected by chronic leucoses.


Bibliography

The information necessary for mastering the theory issues may be found in the following references:

  1. Alan Rosenwald. Practical Diagnosis of Hematologic Disorders, Fourth Edition. – 2006. - P.168-197.

  2. Chris Cheson Clinical Laboratory Hematology.- Delphi Publishers. – 2007. –P. 54-109.

  3. Douglas Williams. Hematology, Seventh Edition. - Williams Hematology. – 2006. – P. 285-302.

  4. Clinical Hematology Atlas. - Robbins & Cotran. – 2007.

  5. Murray Longmore, Ian Wilkinson, Supraj Rajagopalan. Oxford handbook of clinical medicine, Sixth Edition. – 2006. - P.256-290.

  6. Lecture notes on therapy.

  7. A Flow Chart “Chronic Leucoses” (see Appendix 1).

  8. Diagnostic Algorithm of Hyperplastic Syndrome (see Appendix 2).

  9. Normal Indices of Blood (see Appendix 3).

  10. Classification of Chronic Leucoses (see Appendix 4).

  11. Classification of CLL (see Appendix 5).

  12. Classification of CML (see Appendix 6).


Then, proceed to solving some test questions.


Q1. The general blood count of a 33-year-old patient complaining of a low grade fever is the following: erythrocytes are 2.5×1012, Нb is 86 g/l, color index is 1.0, thrombocytes are 72 g/l, leucocytes are 1.9 g/l, 1 band neutrophil, 9 segmented neutrophils, 88 lymphocytes, 2 monocytes, and ESR is 20 mm/h. Which of the following changes have been registered?

  1. Anemia

  2. Thrombocytopenia

  3. Leukopenia

  4. Pan-cytopenia

  5. Absolute lymphocytosis


Q2. A 52-year-old patient presents a purple-cyanotic color of his skin, elevation of BP up to 180/100 mm Hg, enlargement of the spleen (+4 cm from under the edge of the costal margin). The blood test showed the following data: erythrocytes were 6.2×1012, Hb was 206 g/l, color index was 1.0, thrombocytes were 580 g/l, leucocytes were 11.3 g/l, 3 eosinophils, 8 band neutrophils, 74 segmented neutrophils, 15 lymphocytes, 4 monocytes, and ESR was 2 mm/h. Which of the following methods will be of crucial importance for refining the diagnosis?

  1. Sternal puncture

  2. Trepanobiopsy of the iliac bone

  3. Puncture biopsy of the spleen

  4. CT of the organs of the abdominal cavity

  5. US of the organs of the abdominal cavity.


Q3. The general blood count of a 46-year-old patient being under observation on account of essential hypertension showed the following findings: erythrocytes were 6,9×1012, Hb was 210 g/l, color index was 1.0, thrombocytes were 620 g/l, leucocytes were 18.7 g/l, 1 eosinophil, 5 band neutrophils, 65 segmented neutrophils, 25 lymphocytes, 4 monocytes, and ESR was 3 mm/h. The evidence presented gives grounds to assume the Osler's disease. Which of the following diseases must first be diagnosed on a differential basis?

  1. Acute myeloblastosis

  2. Acute lymphoblastosis

  3. Chronic lymphatic leukemia

  4. Chronic myeloleukemia

  5. Secondary polycythemia.


Q4. A 40-year-old patient complains of a general weakness, a low-grade fever for 2 months, a heavy sensation in the left hypochondrium, and enlargement of the spleen (sticking out as far as 8 cm from under the edge of the costal margin). The blood count shows the following: erythrocytes 3.0×1012, Hb is 95 g/l, color index is 1.0, thrombocytes are 170 g/l, leucocytes are 127,5 g/l, 2 eosinophils, 3 basophiles, 2 promonocytes, 7 myelocytes, 12 metamyelocytes, 8 band neutrophils, 62 segmented neutrophils, 3 lymphocytes, 1 monocyte, and ESR is 25 mm/h. Which of the following is the most probable diagnosis?

  1. Acute leucosis

  2. Chronic lymphoid leucosis

  3. Myeloleukemia

  4. Osler's disease

  5. Multiple myeloma.


Q5. A 60-year-old patient diagnosed to have a chronic lymphoid leucosis for the first time, manifests enlargement of the peripheral lymph nodes of all groups up to 1-1.5 cm in diameter, the blood count reveals the following: erythrocytes 4.0×1012, Hb is 140 g/l, color index is 1.0, thrombocytes are 220 g/l, leucocytes are 21,6 g/l, 1 eosinophil, 2 band neutrophils, 9 segmented neutrophils, 5 prolymphocytes, 81 lymphocytes, 2 monocytes, and ESR is 17 mm/h. Which of the following patient management techniques is preferable?

  1. Observation

  2. Monochemotherapy

  3. Polychemotherapy

  4. Radiation therapy

  5. Antibacterial therapy.


Teaching Guidelines for Practice Activities on Chronic Leucoses

At the beginning of the class, the instructor gives a test to check and correct the pre-practice level of knowledge. Then, the students start to see patients under the instructor’s supervision after which the students give an analysis of the practice patients and the instructor checks the mastering of the practice topics. A final test is provided to strengthen the knowledge gained. At the end of the class, the instructor reviews the students’ self-learning activity, considers and corrects the students’ typical mistakes with a subsequent improvement of knowledge and skills.

Appendix 1

Flow Chart of Chronic Leucoses

^

Chronic Leucoses




Significant symptoms and syndromes








Hyperplastic

Hemorrhagic

Anemic



Toxic

Infectious complications


Pleutoric







^

Additional investigation findings


Instrumental

Labratory







General blood count

Biochemical blood count

Myelogram

Trepanobiopsy

Immune marker analysis

Cytogenetic study


Radiological

Ultrasound investigation Computed tomography








Differential diagnosis by a diagnostic algorithm: acute leucoses, CML, CLL, Osler's disease, myelofibrosis, lymphogranulomatosis, and non-Hodgkin's lymphoma.









^

Chronic Leucoses Classification




Patient Management











^ Pathogenetic treatment

cytostatic agents, glucocorticosteroids, interferon α, bone marrow transplantation

Symptomatic treatment

Blood sample transfusion, antibacterial, antiviral, antifungal therapy,and hemoexfusions.

ix

Appendix 2

Diagnostic Algorithm For Hyperplastic Syndrome


List of Nosological Units


  1. Acute leucosis.

  2. Lymphogranulomatosis (LGM).

  3. Non-Hodgkin's lymphoma.

  4. Erythremia.

  5. Chronic lymphoid leucosis (CLL).

  6. Chronic myeloleukemia (CML).

  7. Myelofibrosis.



^

Hyperplastic Syndrome




Isolated hepatosplenomegaly

Hyperleukocytosis with neutrophilia, presence of immature myeloid cells in the blood

Osler's disease

(trepanobiopsy must be performed)

Polycythemia, elevation of haemoglobin, thrombocytosis, leukocytosis

CML

Hematologic pathology is dismissed, gastroenterologist’s and infection disease doctor’s advice is to be sought.

Cerebral fibrosis according to trepanobiopsy evidence

yes

no

yes

no

yes

no

Lymphoadenopathy with or without hepatosplenomegaly

Myelofibrosis

≥30% blast cells in myelogram

acute leukemia

yes

Hyperleukocytosis, intermediate lymphoid cells in the blood

no

CLL

yes

Reed-Sternberg cell by biopcy

no

LGM

yes

Immunophenotyping, CD-markers and lymphomas

no

Non-Hodgkin's lymphoma

yes

Hematologic pathology is dismissed, and infection disease doctor’s advice is to be sought.

no



Appendix 3

Normal Blood Indices

General Blood Count (WHO, 1999).

Erythrocytes

Women 3.7-4.7×1012

Men 4.0-5.1×1012

Hemoglobin

Women 115-145 g/l

Men 130-164 g/l

Color index

(Hb/erythrocytes х 30)

0.82-1.05

Leucocytes

4.0-9.0 g/l

Basophiles

0.5-1.0%

Eosinocytes

1-5%

Band neutrophils

1-6%

Segmented neutrophils

45-70%

Lymphocytes

18-40%

Monocytes

2-9%

Reticulocytes

0.2-1.2%

Thrombocytes

170-360 g/l

Hematocrit

Women 36-42%

Men 40-48%

ESR

Women 4-16 mm/h

Men 2-10 mm/h


Appendix 4

Classification of Chronic Leucoses

(WHO, 1996)

  1. Myeloid forms.

  1. Myeloleukemia.

  2. Erythremia.

  3. Idiopathic myelofibrosis.

II. Lymphoid forms.

  1. Chronic lymphoid leucosis.

  2. Paraproteinemic hemoblastoses (multiple myeloma, and Waldenstrom’s macroglobulinemia)

Appendix 5


Classification of Chronic Lymphoid Leucosis

(K. Rai, 1999)

Stage 0- isolated lymphocytosis (more than 15.0 g/l in the peripheral blood, more than 40% in the bone marrow).

Stage I - lymphocytosis and lymphadenopathy.

Stage II - lymphocytosis and splenomegaly and/or hepatomegalia irrespective of lymphadenopathy.

Stage III - lymphocytosis, hemoglobin less than 110 g/l irrespective of lymphadenopathy and organ enlargement.

Stage IV - lymphocytosis, the number of thrombocytes is less than 100.0 g/l irrespective of anemia, lymphadenopathy and organ enlargement.

Appendix 6

Classification of Myeloleukemia

  1. Clinical types:

  1. Typical (with Ph chromosome)

  2. Atypical (without Ph chromosome)

  1. Morphological types:

  1. Chronic eosinophilic leukemia

  2. Chronic basophilic leukemia

  3. Chronic monocytic leukemia

  4. Chronic neutrophilic leukemia

  1. Phases of clinical course (stage):

  1. Chronic (initial)

  2. Accelerations

  3. Acute (terminal, and blast phase of leukemia).

At the end of the practice class, you shall take a final test, and with this aim in mind, pay attention to the following example tests.


Final Test Questions

Q1. A physical examination of a 49-year-old patient, suffering from a chronic lymphoid leucosis, showed vesicular rash on his nasal wings, lips, and along the intercostal area. Turning and bending of the trunk were painful enough to restrict the movements. The blood count showed the following: erythrocytes 3.8×1012, Hb was 119 g/l, color index was 1.0, thrombocytes were 187 g/l, leucocytes were 128.2 g/l, 1 eosinophil, 1 band neutrophil, 9 segmented neutrophils, 1 lymphoblast, 6 prolymphocytes, 81 lymphocytes, 1 monocyte, and ESR was 20 mm/h. Which of the following syndromes is associated in this case?

  1. Anemic

  2. Contagious complication

  3. Hemorrhagic

  4. Hyperplastic

  5. Pleuthoric


Q2. Trepanobiopsy of the iliac bone crest revealed a growth of the collagenic fibers occupying 1/2 of the preparation and depletion of the cellular elements in the bone marrow in a 61-year-old patient referred to the hematology ward on account of splenomegaly of obscure etiology. Which of the following diseases is meant according to the findings of the investigation?

  1. Chronic lymphoid leucosis

  2. Myeloleukemia

  3. Lymphogranulomatosis

  4. Myelofibrosis

  5. Acute leucosis


Q3. A 52-year-old patient was admitted to the hematology ward complaining of enlargement of the cervical, axillary, and inguinal lymph nodes, herpetic rash on his lips and nasal wings. The lymph nodes are painless, soft and supple not united with the skin. The blood count is the following: erythrocytes are 2.9×1012, Hb is 90 g/l, color index is 1.0, thrombocytes are 120 g/l, leucocytes are 150,5 g/l, 1 eosinophil, 1 band neutrophil, 10 segmented neutrophils, 7 prolymphocytes, 80 lymphocytes, 1 monocyte, smudge cells 2-3, and ESR is 22 mm/h. Which of the following is a preliminary diagnosis?

  1. Acute leucosis

  2. Chronic lymphoid leucosis

  3. Myeloleukemia

  4. Osler's disease

  5. Subleukemic myeloleukemia


Q4. A 45-year-old patient suffering from myeloleukemia shows a general weakness, fever, pain in his bones, acute enlargement of the spleen, and presence of 35% blasts in the myelogram. Which of the following is an appropriate patient management?

  1. Preparations of hydroxyurea

  2. Interferon-α

  3. Polychemotherapy according to 7+3 regimen

  4. Splenectomy

  5. Radiation therapy

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