Pediatric leukemia

Introduction to childhood leukemia Leukemia is a malignant proliferative disease caused by abnormal proliferation and differentiation of hematopoietic stem cells. Childhood leukemia is the most common type of malignant tumor in children, and it is one of the main causes of death in children over 5 years old. The annual incidence of acute leukemia accounts for about 5/100,000 of the population, and the Beijing area accounts for about 2.8/100,000. Some domestic and foreign data show that the incidence of leukemia has increased year by year. basic knowledge The proportion of illness: 0.001% Susceptible people: children Mode of infection: non-infectious Complications: anemia, sepsis

Pediatric leukemia

Genetic factors (30%):

Some congenital diseases are prone to leukemia, such as congenital stupidity, Bloom syndrome, Fanconi anemia, Ataxia telangiectasis about 10% to 50% can be complicated by acute leukemia, one of the identical twins such as leukemia, the other leukemia The probability is 1/4.

Ionizing radiation factor (25%):

In 1945, the incidence of leukemia in survivors exposed to atomic bombs in Hiroshima and Nagasaki, Japan was five times higher than in other regions. Both systemic and local high-dose exposures increased the risk of developing leukemia. The incubation period was 2-16. Years, especially 5 to 10 years after irradiation, are the most dangerous period, which is related to the dose of radiation. Regardless of age, mothers receiving radiation therapy and X-ray diagnosis of children in the uterus may have certain effects on the fetus. The cause can be directly traced to the father's exposure to radiation. It is believed that the father's genitourinary organs and sperm are damaged by radiation, which may lead to the next generation of cancer.

Chemical factors (15%):

It is known that some chemical carcinogens can cause tumors, such as benzene and its derivatives. Drugs such as cyclophosphamide, chloramphenicol and phenylbutazone can increase the risk of complicated leukemia. Leukemia, in addition to some pesticides, nitrosamines, arsenic, lead paint, solder, etc. have an effect on the sperm of adult males, and can be passed on to the next generation, there are children who report that the father smokes than the parents do not smoke The risk of leukemia, lymphoma, etc. is 20% higher.

Virus factor (20%):

The carcinogenic effect and leukemia-induced effects of the virus on certain animals have been confirmed. It has been confirmed in humans that adult T-cell leukemia virus (HTLV) can cause adult T-lymphocytic leukemia, and no specific viral infection has been confirmed in pediatric leukemia. It is known that Burkitt's lymphoma is associated with EB virus infection. In short, the cause of hematopoietic stem cell disorder of leukemia is multifactorial, with external factors such as internal factors, internal and external factors, external factors, physicochemical, viruses, etc., internal factors have chromosomal changes, and DNA repair is abnormal. Immune dysfunction, etc., although the incidence of leukemia in congenital syndrome is increased, most leukemia may be acquired, and the exact cause of leukemia is still being explored.

Pathogenesis

Pathogenesis

The current study suggests that the pathogenesis of leukemia is related to the following mechanisms:

(1) Hematopoietic stem cell proliferation regulation abnormality: leukemia stem cell proliferation is not proportional to the proliferation of blood cells in various lines, no regulatory restriction, cell proliferation is unstable, and release is irregular. Acute leukemia cell colonies only produce small plexus, and abnormal response to CSF Chronic myeloid leukemia is known to be a pluripotent stem cell lesion.

(2) Pluripotent stem cell or progenitor cell differentiation and maturation disorder: The basic pathological changes of acute leukemia are massive accumulation of primitive and early-onset cells. They cannot differentiate into mature cells, and some inducers can promote the differentiation and differentiation of leukemia cells, such as The clinical application of low-dose cytarabine or retinoic acid promotes the relief of patients with promyelocytic leukemia.

(3) Oncogene activation: In recent years, molecular genetic studies have confirmed that human tumors are closely related to oncogenes. Almost all leukemia patients have c-myc or Ha-ras gene expression, acute leukemia and chronic catastrophe c- The expression of myc gene is increased, the activity of N-ras in acute myeloid leukemia is significantly increased, and the c-myc gene is amplified dozens of times when the promyelocytic and other acute myeloid leukemia recur. The activation of oncogene is usually through three pathways (point mutation). Proto-oncogenes mutate at a specific position in the coding sequence, causing a change in the corresponding amino acid), amplification (some oncogenes replicate multiple copies on the original chromosome, resulting in increased gene product, resulting in cell function Abnormalities and translocations (oncogenes are transferred to other chromosomes in their normal positions, making their resting proto-oncogenes become activated oncogenes).

2. Classification and classification

(1) According to the degree of leukemia cell differentiation and pathological classification: 1 acute leukemia: more common in children, natural course of about half a year, 2 chronic leukemia: rare in children, natural course > 1 year.

(2) According to the origin of cell clones: 1 acute lymphoblastic leukemia (rapid lymph node, ALL), 2 acute non-lymphocytic leukemia (an acute non-lymphocytic, ANLL) or acute myeloid leukemia (AML), 3 special types of leukemia: addiction Acidic granulocytic leukemia, basophilic leukemia, tissue basophils (mast cell leukemia), hairy cell leukemia, lymphoma leukemia, plasma cell leukemia, heterozygous leukemia, refractory (undifferentiated) leukemia, etc.

(3) According to FAB (French, American, British Collaboration) Classification: 1ALL: L1, L2, L3 type: A.L1 type: mainly small protolymphocytes (>75%) cell diameter <12m, nuclear round The nucleolus is not obvious, the nuclear chromatin is coarser, and the cytoplasm is less. B.L2 type: the large original lymphocytes are more than L1 (>25%), the cell diameter is >12m, the nucleus is irregular, and there may be folding, nucleolus Large and obvious, nuclear chromatin is loose, cytoplasm is rich, C.L3 type: mainly composed of vacuolized large original lymphocytes, the cell size is the same, the nuclear chromatin is fine, the karyotype is regular, the nucleolus is 1 or Multiple, obvious, cytoplasm often honeycomb, like Burkitt lymphoma cells, 2ANLL: ML ~ M7 type: A. Myeloblastic leukemia undifferentiated (ML): myeloblasts 90 in the bone marrow, promyelocytes are very Less, the myelocytes are not seen or rare in the following stages, B. Myeloblastic leukemia partial differentiation (M2): divided into M2a: 30% to 90% of myeloblasts, <20% of monocytes, promyelocytes The following stages >10%; M2b: abnormal primary and promyelocytes in the bone marrow increased significantly, with abnormal neutral mesenchymal cells (the nucleus often has nucleoli, there is obvious nucleoplasmic hair Unbalanced) >30%, C. Promyelocytic leukemia (M4) with increased particles: promyelocytes with increased particles in the bone marrow >30%, divided into coarse particles (M3a) according to particle size; fine particles Type (M3b), D. granulocyte-monocytic leukemia (M4): divided into four subtypes: M4a: primary granules and promyelocytic hyperplasia, primary, juvenile monocytes and monocytes >20%; M4b: primary, young mononuclear cell proliferation, primary and promyelocytes >20%, M4c blast cells have both granulocyte and mononuclear characteristics, such cells >30%, M4EO: In addition to the above characteristics, There are eosinophilic granules, which are darker and darker, accounting for 30% to 50%. E. Monocytic leukemia (M5): divided into undifferentiated (M54): primordial mononuclear cells in bone marrow 80% Partially differentiated (M5b): protomonocytic cells in the bone marrow <80%, primary and young monocytes >30%, F. erythroleukemia (M6): erythroid cells in the bone marrow 50%, often morphological abnormalities, non- Erythroid primordial cells >30%, G. megakaryocytic leukemia (M7): megakaryocytes in bone marrow 30%, proto-megakaryocytes confirmed by electron microscopy or monoclonal antibody, note: except ML ~ M5 bone marrow cell count Erythroid cells are counted as non-erythroid cells.

(4) According to the leukemia cell immunological classification: ALL is divided into two categories according to the origin of the cells, namely non-T cell type and T cell type, non-T cell ALL is actually B lymphocyte origin, also known as B line ALL, The two types of ALL are further divided into several subtypes based on the B line or T line differentiation antigen (CD) expressed by leukemia cells.

The immunophenotyping work of ANLL is started later than ALL, and more data need to be accumulated for research and exploration. For acute leukemia with morphologically difficult to determine type, the detection of immunophenotype can provide a basis for identification.

(5) Cytogenetic typing: The cytogenetic changes of ALL mainly include changes in the number and structure of chromosomes, and there are five types of changes in the number: 1 number is greater than 50, which is a high number of hyperdiploids, mostly occurs in The B-line ALL of CDL0( ) generally has a good prognosis. 2 The number of 47 to 49 is a low number of hyperdiploids, followed by a prognosis. 3 pseudo-diploid, although the number is 46, but there are structural abnormalities, such as translocation, more common in pre-B-ALL, the prognosis is not good. 4 diploid, the current inspection method did not find structural abnormalities, T-ALL more common this type. 5 subdiploid, some are near haploid, ALL this type is rare, the prognosis is very poor.

Chromosome structure changes with the most translocation, random and non-random translocation, specific translocation has a certain relationship with the cellular immune phenotype, T-ALL: t (10; 14), t (11; 14), t ( 8;14),t(1;14),inv(14),B-ALL:t(8;14),t(8;22),t(2;8),t(11;14),t (9;22)t(7;12),dic(9;12),Pre-B-ALL:t(1;19),t(9;22),C-ALL:t(9;22), 6q, t/del (12p).

Chromosomal translocation is a poor prognosis factor. If there are t(9;22), t(8;14), t(4;11), the prognosis is poor, and t(4;11) is more common in infant leukemia, including M4 or heterozygous leukemia of ALL and AML.

Chromosome changes in ANLL are associated with many clinical features, ML: t(9; 22), inv(3), M2: t(8; 21), t(9; 22), t(6; 9), t/del (12), M3: t(15; 17), M4: t(8; 21), 5q inv(3), t/del(11), M4E0: inv(16), del(16), M5a: t (11q), M5b: t(3; 16), M6: t(3; 5), M7: inv(3).

(6) According to clinical classification: ALL can be divided into standard critical rash (SR-ALL) and high-risk acute leaching (HR-ALL), the scoring standard is shown in Table 4, <3 is classified as standard risk, and >3 is divided into high risk.

(7) MIC classification: Internationally, the morphological classification of acute leukemia, immunological typing and cytogenetic typing are called MIC typing, which can more accurately reflect the biological characteristics of leukemia and guide clinical diagnosis and treatment.

Pediatric leukemia prevention

1. Avoid contact with harmful factors. Pregnant women and children should avoid exposure to harmful chemicals, ionizing radiation and other factors causing leukemia. When exposed to poisons or radioactive materials, various protective measures should be strengthened; avoid environmental pollution, especially indoor environmental pollution. Pay attention to the rational use of drugs, use cytotoxic drugs with caution.

2. Vigorously carry out prevention and treatment of various infectious diseases, especially viral infectious diseases, and do a good job of vaccination.

3. Do a good job in eugenics, prevent certain congenital diseases, such as 21-three-body, Fanconi anemia, etc., strengthen physical exercise, pay attention to food hygiene, maintain a comfortable mood, work and rest, and enhance the body's resistance.

Pediatric leukemia complications Complications anemia sepsis

Anemia and bleeding

Progressive anemia can occur, palpitations, tinnitus, different degrees of bleeding, subcutaneous hematoma, retinal hemorrhage, resulting in vision loss, digestive tract and urinary tract bleeding, increased intracranial pressure during intracranial hemorrhage, manifested as headache, vomiting, Convulsions and coma, etc., digestive tract and intracranial hemorrhage can cause death of children, hemolysis can occur, and DIC can be complicated.

2. Infection

Often complicated by infection, easy to spread to sepsis; common infection sites are respiratory system, skin bloated, intestinal inflammation, perianal inflammation, etc., can occur thrush, perianal fungal disease, fungal enteritis and deep fungal infections.

3. Leukemia cell infiltration

Can be complicated by bone marrow failure and systemic organ infiltration, liver and spleen, lymphadenopathy, superior vena cava syndrome, joint swelling and pain, the action is impaired, central nervous system infiltration can be complicated by central nervous system leukemia, can be expressed as intracranial Increased pressure, headache, vomiting, blurred vision caused by optic disc edema, can also cause cranial nerve damage such as facial paralysis, and even epileptic seizures, disturbance of consciousness, etc., both sides of the parotid gland are painless, testicular leukemia, kidney swelling Large, skin, gastrointestinal tract, lung, pleura and heart infiltration, causing symptoms of the corresponding organ dysfunction.

Pediatric leukemia symptoms Common symptoms Gingival hyperplasia Gingival bleeding Lymph node enlargement Gastrointestinal bleeding Bleeding Skin purpura Hepatitis Splenomegaly Skin mucous pale pale

Onset

More than half of children with acute leukemia have acute onset. The initial manifestations are anemia, hemorrhage, fever, infection and other symptoms. The symptoms and signs of organ infiltration after the prolonged course are more and more obvious. A small number of sick children slowly started to appear, manifested as fatigue, anorexia, lack of energy, pale complexion and obvious bleeding, and more can be diagnosed at this time.

Anemia

Anemia appears early and progressively aggravated, mostly positive cells are pigmented, showing progressive skin mucous membrane pale, easy to fatigue, weakness, post-exercise shortness of breath, etc., older children can complain of dizziness, headache, palpitations, tinnitus. Anemia is mainly caused by the inhibition of erythropoiesis. In addition, the ineffective formation of red blood cells in the bone marrow, hemolysis and varying degrees of bleeding are also contributing factors.

3. Bleeding

Most of the acutely ill children have different degrees of bleeding, and the symptoms are most common with nosebleeds, bleeding gums and purpura. Lighter only see a small number of sputum in the lower extremities, ecchymosis and a small amount of nosebleeds; severe cases can be seen extensive bleeding, large skin ecchymosis, nosebleeds, bleeding gums, hematuria, etc., respiratory, gastrointestinal bleeding and intracranial hemorrhage can often be fatal. Usually, AML is heavier than ALL bleeding, especially in the early stage of treatment of M3, which is complicated by diffuse intravascular coagulation and is fatal. The change in the quality and quantity of platelets is an important cause of bleeding. Insufficient production of factors I, II, and V after infiltration of the liver, and increased permeability after capillary damage can aggravate bleeding.

Pediatric leukemia examination

Blood picture

The blood picture of children with acute whiteness usually shows a decrease in platelet count (BPC) and a decrease in hemoglobin (Hb). The anemia is generally positive cell pigmentation, the total number of white blood cells is different, and the white blood cell count (WBC) is increased by more than half, and the rest can be normal or Decreased, leukemia cells are easy to see leukemia cells in the peripheral blood, is a strong evidence for the diagnosis of leukemia, leukopenia is not easy to see leukemia cells in the blood, also known as non-leukocytic leukemia (aleukemic leukemia), platelets are often reduced, there are The blood picture of 1024 children with ALL was reported as follows:

(1) White blood cells: 34% for <10×10 ⁹ /L, 25% for (1024)×10 ⁹ /L, 22% for (2549)×10 ⁹ /L, >50×10 ⁹ /L accounted for 19%.

(2) Hb level: <70g/L accounted for 44%, 70-110g/L accounted for 43%, and >110g/L accounted for 14%.

(3) BPC: 20×10 ⁹ /L accounted for 29%, (2049)×10 ⁹ /L accounted for 23%, (5099)×10 ⁹ /L accounted for 20%, 100×10 ⁹ / L accounted for 29%.

2. Bone marrow

Most of the bone marrow in the newly diagnosed acutely ill children are obviously active or extremely active. In a few cases, the proliferative hypoplasia is called hypoproliferative leukemia, and the latter has a better prognosis. So far, the bone marrow is still the most accurate basis for the diagnosis of acute whiteness. The ratio of the original plus naive cells is 30% to diagnose, and the ANLL also removes the erythroid and then calculates the ratio. Due to the differentiation and maturation of normal hematopoietic cells in the bone marrow, a large number of leukemias that are arrested at a certain stage are replaced. Cells, due to the absence of one or more stages in the process of maturation, are called "cracks". In AML, especially in promyelocytic cells, rod-shaped Auer bodies are often seen, which are certain in the identification of ALL. In recent years, it has been found that rod-shaped or spindle-shaped phi bodies can be found in AML cells stained with 3,3-diylbenzidine, and more than 50% of the acute particles can be detected, which is helpful for differential diagnosis.

3. Determination of glucocorticoid receptor (GCR)

Glucocorticoids are used in almost all ALL induction and remission treatments, but the treatment results are inconsistent. The study found that the number of GCR on leukemia cell membrane has a great relationship with its sensitivity to glucocorticoids, and it has a great relationship with prognosis. The methods include receptor radioligand binding assay and the like.

4. Other

The immunology, cytochemistry, and cytogenetic examination of leukemia have been described before, and the use of transmission electron microscopy can help diagnose M7 and acute undifferentiated leukemia. Terminal deoxynucleotidyl transferase (TdT) is in B- Significantly decreased in ALL and AML, significantly increased in T-ALL, C-ALL Pre-B-ALL, so there is a certain discriminative significance, X-ray findings: X-ray of acute white is mostly non-specific, chest X-ray often has lung The lymph nodes of the portal are swollen, and the leukemia infiltrates the lungs. The T-ALL often has a mediastinal mass. The bone X-ray often shows osteoporosis and decalcification. Sometimes there are focal osteolytic and lamellar periosteal reaction signs. A strip of reduced density at the end of the epiphysis is called a leukemia line.

Diagnosis and diagnosis of childhood leukemia

diagnosis

According to the clinical manifestations, the examination can be diagnosed.

Differential diagnosis

Must react with leukemia-like, aplastic anemia, infectious mononucleosis, myelodysplastic syndrome (MDS), other malignant tumors (such as neuroblastoma), extramedullary hematopoietic response (Jakish anemia, bone marrow Identification of fibrosis and marble bone disease, etc., typical symptoms and signs appear in the clinic. Leukemia cells are found in peripheral blood. The original naive cells in the bone marrow are 30%. It is not difficult to diagnose acute leukemia at this time. The signs are not typical. The peripheral blood does not see the original young cells. At this time, the diagnosis is difficult, and the following diseases should be diagnosed.

Leukemia-like reaction

Peripheral leukocytosis, a significant increase and / or emergence of immature white blood cells called leukemia-like reactions, usually infection, poisoning, tumors, blood loss, hemolysis, drugs, etc., granule, monocytic leukemia reaction often has a significant increase in white blood cells There are also immature white blood cells in the peripheral blood, but the former neutrophil alkaline phosphatase score is significantly increased, lymphocytic peripheral blood leukocytes can be slightly increased, but naive lymphocytes appear, in general, remove the cause of leukemia The reaction can return to normal, and usually the leukemia and platelets in the peripheral blood of the leukemia-like reaction are not affected, the leukemia has no leukemia-like changes, and the leukemia reaction in occasional cases is difficult to distinguish from leukemia. At this time, it should be closely observed and supplemented with immunity. , genetic and other methods carefully distinguish.

2. Aplastic anemia

The disease has anemia, hemorrhage, fever, and reduction of whole blood, which is easy to be confused with hypoproliferative leukemia. However, the liver, spleen and lymph nodes of the disease are not swollen, the bone marrow hyperplasia is low and there is no original, and the proportion of naive cells is increased.

3. Malignant histiocytosis

The disease is a malignant proliferative disease of the mononuclear-macrophage system. Clinically, fever, anemia, hemorrhage, enlargement of the liver, spleen and lymph nodes, as well as extensive invasive lesions of the whole body, are difficult to distinguish from leukemia, and peripheral blood is also associated with Similar to leukemia, Hb and BPC decrease, more than half of white blood cells are reduced, and immature red blood cells and immature granulocytes can be found. However, if malignant tissue cells are found, the disease is highly suggestive, bone marrow hyperplasia is active or decreased, and reticular cells are increased. How many different tissue cells can be divided into general abnormal tissue cells, mononuclear tissue cells, lymphoid tissue cells, multinucleated giant tissue cells and phagocytic tissue cells according to morphology. If a large number of phagocytic tissue cells are seen and general abnormalities occur Tissue cells, support for the diagnosis of this disease, malignant histiocytosis lack of specific diagnostic tools, bone marrow support and clinical non-conformity can not be diagnosed, and vice versa, clinical support and bone marrow inconsistency can not rule out the diagnosis, so the disease relies on comprehensive analysis Diagnosis, sometimes biopsy such as bone marrow and lymph nodes can provide some evidence.

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