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Disorders of White Blood Cells

The number of circulating WBC’s may be abnormally low as a result of failure of production, inhibition of release, increased margination in the circulation, pooling in an enlarged spleen or excessive consumption. 
• Neutropenia and Lymphopenia are common in the tropics. 
• The highest age-specific incidence of cancer in childhood in case of Burkett’s lymphoma has been reported from tropical Africa;
• There is a peak of incidence between the ages of 5 and 9 years;
There are three epidemiological patterns:
1. BL is endemic in tropical Africa;
2. Intermediate incidence in the North Africa, Western Asia and South America;
3. BL occurs sporadically in the Western world.

The infection by EBC (Epstein-Barr virus) in children immortalizes B-cells, resulting in their proliferation, where P. falciparum is endemic:
• recurrent infections;
• suppressed T-cell regulation;
• somatic mutations;
• BL also results as a complication of AIDS.

Hodgkin’s disease:
There are four histological types of Hodgkin’s disease (HD):
• nodular sclerosing (NS);
• mixed cellularity (MC);
• lymphocyte depleted (LD); 
• lymphocyte predominant (LP).
MC and LD carry poor prognosis.
EBV genomes are expressed by the malignant Reed-Steinberg cells from a high proportion of HD patients aged under 15 or over 50 years.
The remaining lymphomas, excluding BL and HD, are a heterogeneous group of B-cell and T-cell origin.
In the developed countries, follicle center cell lymphomas with follicular pattern are the most common NHL, with increasing incidence with age. A strong association has been reported in Africa between frequency of high grade NHLs and malarial endemicity.

Immunoproliferative small intestinal disease:

This condition responds to ampicillin, metronidazole and antihelminthic agents, followed by long-term tetracycline. Untreated, the condition may progress to a high-grade malignant lymphoma or large-cell immunoblastic plasmacytoid type. The anemia of chronic disorders is usual and complicated in about 40% of patients by malabsorbtion of iron, folate or vitamin B12.
The human T-cell lymphotropic virus type1 (HTV-1) is a type of retrovirus, which is causative of adult T-cell leukemia/lymphoma and tropical spastic paraparesis (HTLV-1) associated myelopathy (TSP/HAM) in a small number of infected individuals.
• HTLV-1 is transmitted by sexual intercourse, through breast feeding and by the exchange of blood.
• The largest pool of the virus is in sub-Saharan Africa, where there are probably about ten million infected subjects.
• Seroprevalence rises slowly with age, compatible with the slow rate of transmission in endemic areas. 
• The virus does not possess oncogenes, but the regulatory gene tax has oncogenic potentials through IL (Interleukin)-2 and IL-2 receptor.

Phases:
1. asymptomatic
2. acute 
3. chronic 
4. smouldering ATL 
5. Lymphoma type.

Predominant clinical findings are:
- lymphadenopathy
- hepatosplenomegaly 
- skin lesions 
- pulmonary infiltration
- osteolytic lesions 
- hypercalcaemia 
The WBC count is raised.
Smouldering ATL shows as skin rashes and a low count of ATL cells.
Prognosis is poor.

Myeloma in black Africans:
• High incidence is observed in black South Africans;
• Genetically determined;
• Patients 30-39 years of age;
• Plasmacytomas are not uncommon.

Leukemia:
1. Acute lymphoblastic leukemia (ALL).
2. Acute myeloblastic leukemia (AML).
3. Chronic myeloid leukemia (CML).
4. Chronic lymphocyte leukemia (CLL)
The peak of incidence of c ALL in early childhood in developed countries is explained by the following hypothesis: there is a putative childhood leukemia virus.
Transplacental infection by the virus is one step in the causation of c ALL. 

 Malignant infiltration (lymphadenoapthy, hepatosplenomegaly, bone pain).
 Anemia.
 Hemorrhage or thrombosis.
 Infections from immune depression.
 The total WBC count is raised in around two-third and may be normal or low in one-third of patients.
 The leukaemic blast cells can be mistaken for activated or transformed lymphocytes in response to malaria, viral or other infections.
 The bone marrow is infiltrated with blasts.
 The blasts are polymorphic with more abundant, agranular cytoplasm (L2).
 The blasts have dark-blue straining cytoplasm with vacuoles in both cytoplasm and nucleus.
Supportive treatment includes: 
- Red cell transfusion for anaemia;
- Platelet transfusion for hemorrhage from thrombocytopenia; 
- Antibiotics for infection;
- Allopurinol for hyperuricacidaemia;
- Antimalarial therapy and prophylaxis;
- Complex regimens of cytotoxic agents;
- Radiotherapy.

Poor prognosis (high leukocyte counts severe thrombocytopenia). Genetically determined poor prognosis in black African patients.

AML is classified by FAB criteria as: M0 and M1, with malignant blast cells that have few or no granules; M2 – with blasts that have granules; M3 – promyelocytic leukemia of hyper or hypo granular variants; M4 – myelomonocytic leukemia; M5 – monocytic leukaemia; M6 – erythroleukaemia; M7 – megakaryocytic leukaemia.
Risk factors: cigarette smoking, exposure to chemicals, radioactive waste, petrol-vendors, pesticides and irradiation.

Treatment:
- alkilating agents (cyclophoshamide);
- Monocytic and myelomonocytic leukaemoid reactions from tuberculosis may be mistaken sometimes for M4 and M5 AML.
- Survival without specific treatment is about 2 months.
- Marrow ablation followed by bone marrow transplant carries much better prognosis and possible cure.
In case of M3 – retinoic acid receptor α-gene on chromosome-17 to a locus.

Chronic myeloid leukaemia:
- incidence, with slightly higher rate in male Blacks;
- incidence rises with age from childhood;
- factor: excessive exposure to ionizing irradiation and benzene;

Signs: 
Abdominal discomfort from gross hepatosplenomegaly;
Lymphadenopathy;
Enlarged spleen and anaemia.
The WBC count is raised up to 500x109/l.
Mature granulocytes with neutrophils.

Tuberculosis, meningococcal meningitis, septicaemia, megaloblastosis in pregnancy, eclampsia, acute liver necrosis, amoebic liver abscess, burns, and severe haemorrhages may give leukemoid reaction resembling CML.

Treatment:
- initial antimalarial treatment and prophylaxis in endemic regions (Zambia);
- allopurinol;
- cytotoxic therapy (hydroxyurea);
- promote busulphan + mercaptopurine administration;
- bone marrow transplantant is currently the only treatment which can prolong life.

Chronic lymphocytic leukaemia:
- incidence rises rapidly with age;
- the male to female ratio is about 2:1;
- CLL occurs from the age of about 17 years;
- The probability of somatic mutation in B-cells is increased in an enlarged pool of proliferating B-cells resulting from recurrent malaria and other infections;
- A second genetic event could follow infection by a virus;
- Proliferation may be more rapid with depression of immunity by malaria and pregnancy.
- Onset is insidious;
- Hepatosplenomegaly and lymphadenopathy;
- Enlarged spleen (malaria);
- Following acute malaria, cells are marginated and the count in the peripheral blood falls temporarily;
- The bone marrow is infiltrated with the malignant clone only.

Treatment:
- initial antimalarial therapy, followed by long-term prophylaxis;
- reduction of peripheral lymphocyte count;
- chlorambucil or prednisolone, or both for tumor mass reduction.

Vocabulary:
Immortalize [ǐ`mo:təl a ǐz] Імморталізуватися
Genomes [dзǐ`nəυmz] Геноми
Putative [`pјu:tətǐv] Вдаваний
Radioactive waste [reǐdǐəυ`æktǐv`weǐst] Радіоактивні відходи
Irradiation [ǐrədǐ`eǐ∫n] Опромінення
Follicle [`folǐkl] Фолікул, пухирець
Antihelmintic [əntǐhǐl`mǐnθǐk] Засіб проти грибків
Infiltration [ǐnfǐl`treǐ∫n] Просочування
Ablation [əb`læ∫n] Видалення
Insidious [ǐn`sǐdǐəs] Підступна (про хворобу)


Questions:
1. What disorders of white cells do you know?
2. How many histological types of Hodgkin’s disease do you know?
3. What is the epidemiology of HTLV-1 in the tropics?
4. What phases of the virus do you know?
5. What is so important in case of leukaemias in the tropics?
6. How can we manage the chronic myeloid and lymphocytic anaemias?


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