Acute lymphoblastic leukemia

Introduction to acute lymphoblastic leukemia Acute lymphoblastic leukemia (ALL) is a neoplastic disease originating from B-lineage or T-lineage lymphoid progenitor cells. The primordial cells proliferate and aggregate in the bone marrow and inhibit normal hematopoiesis, leading to anemia, thrombocytopenia and neutrophils. Reduced; primitive cells can also invade extramedullary tissues, such as meninges, gonads, thymus, liver, spleen, or lymph nodes, causing corresponding lesions. basic knowledge The proportion of illness: 0.001% Susceptible people: no special people Mode of infection: non-infectious Complications: gastrointestinal bleeding thrombocytopenia anemia central nervous system leukemia

Cause of acute lymphoblastic leukemia

(1) Causes of the disease

The occurrence and development of leukemia cells originate from the malignant transformation of different hematopoietic progenitor cells or stem cells. Specific ALL subtypes may have specific stages of markers. The etiology and pathogenesis are not fully understood, but are related to the following risk factors:

1. Genetic and family factors: Many facts prove that genetic factors are one of the risk factors for leukemia, 5% of ALL cases are related to genetic factors, some patients with genetic predisposition syndrome have an increased incidence of leukemia, and children with Down syndrome have leukemia. The risk is 10 to 30 times higher than that of the normal population, and it is more likely to have B cell precursor ALL, and the incidence of leukemia in patients with Fanconi anemia is also increased.

Cases of 2 or 3 leukemias in the same family are rare, suggesting that genetic factors may only play a minor role in the pathogenesis of ALL, but when a twin brother develops leukemia, another 20% chance of developing leukemia within 1 year. If leukemia occurs within 1 year of age, another is almost inevitable, and leukemia will occur. Typically, it occurs within a few months. One of the non-identical twins, such as leukemia, has a normal incidence of leukemia. 2 to 4 times, the mechanism of chromosomal abnormalities with leukemia is still unclear. The reason may be that the protein encoded by the affected gene affects the stability of the gene and DNA repair, or the sensitivity of the defective chromosome to carcinogens increases, thus causing The gene that controls cell proliferation and differentiation is caused by mutation.

2. Environmental factors: Ionizing radiation can induce experimental leukemia in animals. It is exposed to diagnostic X-ray during pregnancy. The risk of ALL is slightly increased, and it is related to the number of exposures. After exposure to nuclear radiation, the incidence of ALL is significantly increased. Ionizing radiation is used as One of the causes of human leukemia has been affirmed, but the mechanism is unclear. Pre-pregnancy and pregnancy exposure to pesticides, active and passive smoking may be related to the incidence of childhood ALL. The incidence of childhood ALL is higher in industrialized countries, and women are contaminated with trichloroethylene. The water quality and the incidence of ALL in smokers older than 60 years old increased, suggesting that environmental factors play a role in the pathogenesis of leukemia.

Chemical-induced experimental leukemia in animals has been confirmed, among which benzene and benzene congeners, alkylating agents are considered to be closely related to human leukemia. Among the biological factors related to leukemia, viruses account for the most important status, and viruses are the cause of animal leukemia. One has confirmed that in the 1980s, a type C retrovirus, the human T cell leukemia virus type I (HTLV-I), was found from the cell line of adult T cell leukemia, which was the first to be found with human leukemia and Lymphoma-associated retroviruses, but the relationship between leukemia virus and lymphocytic leukemia has not yet yielded reliable experimental results.

These factors do not fully explain the cause of the disease in all cases. Although there are many clues, the pathogenesis of most cases remains unclear. It is generally believed that the occurrence of leukemia reflects the interaction between multiple genetic and environmental factors.

3. Acquired genetic alterations: Leukemia cells in all ALL cases have acquired genetic alterations, at least 2/3 are non-random, including changes in chromosome number and structure, the latter including translocation (which is the most common abnormality), Position, deletion, point mutation and duplication, these rearrangements affect the expression of genes, interfere with the differentiation, proliferation and survival of normal cells.

(two) pathogenesis

There are usually two mechanisms for the development of leukemia, one that depends on the protooncogene or the activation of a mixed gene with proto-oncogene properties. The resulting protein product affects cell function, and the other mechanism is one or more tumor suppressor genes. Inactivation, such as p53 and INK4a, encoding p16 and p19ARF, p53 as a tumor suppressor gene, the cells unable to repair after DNA damage to apoptosis, MDM-2 proto-oncogene is an antagonist of p63 gene, its overexpression It can prevent the function of wild-type p53. The abnormalities of these two genes have been found in leukemia. p16 and p19ARF negatively regulate the cell cycle and reduce the proportion of cells entering S phase. Therefore, it can not prevent leukemia cell proliferation or prevent it. Programmed death, loss of tumor suppressor function, p15 and p16 homology deletion can be detected in 20% to 30% of B cell precursor ALL and 60% to 80% of T-ALL, the study confirmed that p15/ The p16 deletion is often seen in the recurrence of ALL, suggesting that the protein encoded by this deletion gene plays a role in disease progression.

The basic pathological changes of ALL are mainly the proliferation and infiltration of leukemia cells. This is a specific pathological change of leukemia. In addition to the hematopoietic system, other tissues such as liver, brain, testis, kidney and other tissues also have obvious infiltration and destruction.

1. Bone marrow, lymph nodes, liver, and spleen are the most important organs involved.

Most of the bone marrow showed obvious hyperplasia. The leukemia cells showed diffuse flaky hyperplasia and infiltration, with different degrees of differentiation and maturation. The whole body bone marrow had leukemia cell hyperplasia, and the infiltration of vertebrae, sternum, pelvis and ribs was the most obvious. Low proliferation, can be accompanied by varying degrees of fibrosis.

Lymph node enlargement is more common (about 70%), generally systemic or multiple lymphadenopathy, early lymph node involvement, lymph node structure is still identifiable, leukemia cells often only involve a certain area of the lymph nodes, appearing flaky Uniform naive cells proliferate and infiltrate, lymph cords widen, sinus narrows, primary follicles or secondary follicles are atrophied by compression, and advanced lymph node structures are completely destroyed.

The spleen has different degrees of swelling. The white pulp in the white pulp has diffuse infiltration of leukemia cells, which can affect the red pulp and sinusoids. The leukemia cells in the liver mainly infiltrate the portal vein area and the portal vein area, causing liver enlargement.

The tonsils and thymus are often invaded. The ALL thymus is affected by 78.5%. Among them, T-ALL is the most common, and the infiltrated thymus is enlarged. The clinical manifestation is mediastinal mass, especially in children with T-ALL.

2. Nervous system: The nervous system is a common site of leukemia infiltration. The damage of ALL combined with central nervous system is more common than other types of leukemia. The pathological changes are mainly localized or extensive infiltration of meningeal and brain parenchymal leukemia cells, which may be accompanied by hemorrhage. Hematomas, meningitis, and epidural masses of transverse myelitis are common in the subarachnoid space. The brain parenchyma is followed by the cerebral hemisphere, basal ganglia, brainstem and cerebellum. Diffuse or nodular infiltration, infiltration of surrounding white matter tissue edema and necrosis, about 20% of patients with central nervous system leukemia (CNS-L) have cranial nerve palsy, facial nerve (VII) paralysis is most common, followed by abduction ( VI), eye movement (III), trochlear (IV) nerve, and spinal cord and peripheral nerve involvement are rare.

3. Urogenital system: ALL is more common in the testis, especially in children with ALL. There is a large amount of leukemia cells infiltrating in the testicular stroma, which causes atrophy caused by compression of the fine tubules. The clinical manifestations are unilateral or bilateral painless swelling of the testicles. Inflammatory sensation, leukemia cells infiltrating the corpus cavernosum or due to accumulation of leukemia cells in the sinus, embolism, blocked blood flow or thrombosis can cause abnormal erection of the penis, ALL involving the kidney, grayish white spots or nodules visible under the renal capsule And bleeding point, renal pelvis bleeding point is also more common, skin, medulla scattered in grayish white nodules, microscopically seen under the microscope, medulla scattered or focal leukemia cells infiltration, glomerular and tubular epithelial compression atrophy or degeneration and necrosis.

4. Others: The lung is one of the organs often involved in leukemia. Most of the infiltrating lesions are diffuse. A few miliary, even nodular lesions can invade the alveoli, small pulmonary vessels and interstitial. Leukemia infiltrates most often involve the bronchi Lymph nodes can cause oppression, but also involve the pleura, diffuse infiltration of varying degrees, and pleural effusion; the oropharynx is also one of the sites that are easily invaded by ALL, and often combined with infection; leukemia involves the heart with myocardial infiltration, Diffuse and focal infiltration between the myocardium and the muscle bundle, leading to conduction disorders, heart failure, epicardial and intima can be involved, pericardial effusion, infiltration of the gastrointestinal tract can form nodules, ulcers, necrosis and hemorrhage, Mucosa and submucosa are the main, sometimes mucosal exfoliation and pseudomembrane formation, lesions of the intestine can be perforated due to necrosis, from the cardia to the rectum can be involved, less invasion of the esophagus, skin invasion typical change to the blood vessels The leukemia cells around the hair follicles and sebaceous glands infiltrate to form single or multiple nodules, which are focally distributed.

The reason why leukemia is malignant from a hematopoietic progenitor or stem cell is:

1 Almost all ALL leukemia cells have cloned expression of immunoglobulin (Ig) or T cell receptor (TCR) gene rearrangements.

2 All leukemia cells of the same patient have the same cytogenetic abnormalities, 6-phosphate glucose dehydrogenase (G-6PD) isoenzyme type and immunophenotype.

3 Most patients with complete remission (CR) relapse, their leukemia cell genotype and phenotype reproduce the clone at the time of diagnosis.

The exact mechanism of leukemia cell proliferation and normal hematopoietic cell suppression has not been determined, but growth factor, normal and growth factor receptors of leukemia cells, and growth factor receptor reactivity play an important role in the proliferation and inhibition of the two types of cells, growth Factor receptors or growth factor transcription signals from the cell membrane to the nucleus are encoded by oncogenes expressed by leukemia cells. It has been observed that leukemia cells can produce colony-stimulating factor (CSF), which may be related to the infinite proliferation of leukemia cells. Normal CSF has a stimulating effect on leukemia clonal cells in vitro, peripheral red blood cells, thrombocytopenia, and leukemia cells in the bone marrow are dominant. It is a common hematological feature of acute leukemia. It is speculated that due to the exclusion of normal hematopoietic stem cells by leukemia cells, However, some patients have low bone marrow hyperplasia, which is difficult to explain by leukemia cell exclusion. It is believed that leukemia cells inhibit normal hematopoietic cells through cell-mediated or humoral mechanisms, and then it is confirmed that there is an inhibitory active substance in leukemia cell extract or medium, specifically inhibition Normal progenitor colony forming unit (CFU-C) during DNA synthesis, a large number of interleukin-2 receptor (IL-2R) on the surface of leukemia cells with multiple lymphocytic leukemia, which may block IL- as a blocking factor 2 Binding to normal activated lymphocytes affects the activity of normal lymphocytes and the release of lymphokines, thereby facilitating the proliferation of leukemia cells.

Acute lymphocytic leukemia prevention

1. Reduce or avoid the contact of harmful substances such as ionizing radiation and chemicals.

2. For some acquired diseases that may be converted to ALL, active treatment should be given early.

Acute lymphoblastic leukemia Complications, gastrointestinal bleeding, thrombocytopenia, anemia, central nervous system leukemia

1. Fever and fever is the most common complication of acute leukemia. About half of the patients have fever. When the body temperature is >38.5 °C, it is often caused by infection. The main types of fever are different and the heat is different. The main cause of fever It is a bacterial or viral infection, and in a very small number of patients, focal or multi-site necrosis can occur, causing high fever or bone pain.

2. In the whole course of bleeding acute leukemia, almost all patients will have different degrees of bleeding, 40% to 70% of patients have bleeding at the onset, there are reports that adult ALL patients with platelets at 10 × 109 / L and 20 The mortality rate of ×109/L was not significantly different. Only when the platelets were <5×109/L, fatal bleeding may occur. Severe infections, especially Gram-negative bacilli infection, may induce DIC.

3. Leukemia extramedullary complications Because leukemia cells can invade various tissues and organs, or affect the function of various systems, it can cause a variety of complications, and sometimes the complications of these systems even become the main clinical manifestations of patients, most of the systems reported. Complications are directly related to leukemia cells, and some are not clear about their pathogenesis.

(1) Respiratory complications: adult respiratory distress syndrome; sarcoidosis; pleural effusion, pulmonary fibrosis.

(2) Circulatory system complications: pericardial effusion, the first manifestation of some ALL is pericardial effusion, for refractory ALL or recurrent ALL, pericardial effusion is not uncommon, arrhythmia, heart failure, hypertension Wait.

(3) Digestive system complications: acute abdomen, portal hypertension, gastrointestinal bleeding.

(4) urinary tract complications: renal infiltration, children with ALL may be more prone to renal infiltration; renal insufficiency, testicular leukemia; can occur ALL of any age, with children ALL most common, ALL under 8 years old accounted for 86.6% of all TL CLL and CML occasionally occur TL, high-risk ALL is more likely to occur, white blood cells >30 × 109 / L at the initial diagnosis of TL is a risk factor for TL.

(5) Hematologic complications: thrombocytopenia and DIC; thrombosis formation; hemolytic anemia; bone marrow necrosis; high white blood cell status and leukocyte stasis syndrome: in general, peripheral blood leukocyte count of AL patients is greater than 100 × 109 / L Or chronic peripheral blood leukocyte count greater than 500 × 109 / L is called high white blood cell state, and the resulting white blood cell stasis is called high white blood cell stasis syndrome, accounting for 15% to 20%, more likely to occur in high white blood cell state. The AL types are ALL, AML-M5, AML-M1 and the like.

(6) endocrine and metabolic complications: diabetes, diabetes insipidus, pathological thyroid syndrome, electrolyte imbalance, TLS in leukemia, often manifested as hyperkalemia, hyperphosphatemia and hypocalcemia, leukemia complicated by electrolytes Disorders can also be manifested as hypokalemia, hypercalcemia, hypokalemia is not as common as hyperkalemia, abnormal growth and development, long-term chemotherapy in children with leukemia can cause abnormal growth and development, ovarian leukemia, leukemia cells infiltrating the ovary More common, mainly seen in ALL.

(7) Nervous system complications: intracranial hemorrhage, which is a serious complication of leukemia patients, is one of the main causes of death in patients. The causes of intracranial hemorrhage are: markedly reduced platelets, leukemia cells infiltrating cerebral blood vessels, DIC, anticoagulation in vivo Increased substances, etc., central nervous system leukemia is the most common complication of ALL, epilepsy: leukemia patients with seizures may be caused by CNSL, intracranial hemorrhage, intracranial infection or systemic infection, side effects of drugs, some patients failed to identify the cause In addition, leukemia patients can also be complicated by facial nerve palsy, oculomotor nerve palsy, common peroneal nerve palsy, meningitis, acute brain-myelitis, cerebellar syndrome, infectious toxic encephalopathy, encephalitis, etc., mostly with leukemia cell infiltration, Compression, infection, drug toxicity and other factors are related.

4. Other complications such as skin damage, bone and joint disease, retinal hemorrhage, edema, deafness, acute mumps.

Symptoms of acute lymphoblastic leukemia Common symptoms Splenomegaly, hemorrhagic leukemia, infiltration of gingival bleeding, vaginal bleeding, hepatomegaly, intracranial hemorrhage

The clinical manifestations of various types of acute leukemia mainly include the manifestations of hematopoietic dysfunction caused by leukemia cell infiltration of bone marrow tissue (such as anemia, infection, hemorrhage, etc.) and systemic infiltration of leukemia cells causing abnormalities of organs (such as lymph nodes, liver and spleen). Swollen, etc.) two major aspects.

First, the onset: Most patients have an acute onset, rapid progress, often with fever, anemia or bleeding as the first symptom. Some cases have a slow onset, with progressive anemia as the main performance.

Second, the symptoms:

(1) Anemia: There are anemias in the onset, but the severity varies.

(B) bleeding: Most patients have different degrees of bleeding in the course of the disease, with skin defects, ecchymosis, bleeding gums, nasal discharge is common. Severe cases may have visceral bleeding, such as blood in the stool, blood in the urine, hemoptysis and intracranial hemorrhage.

(3) Fever: It is one of the common symptoms of acute leukemia.

Third, physical signs:

(1) The liver, spleen and lymph nodes are swollen.

(B) bone and joint performance: bone and joint pain is a common manifestation, sternal tenderness has a certain value in the diagnosis of leukemia.

(C) other signs of infiltration: male testicular involvement can be diffuse enlargement, which is one of the causes of leukemia recurrence.

Fourth, central nervous system leukemia:

Table 1 has a meningeal infiltration, which can affect the circulation of cerebrospinal fluid, resulting in increased intracranial pressure, headache, nausea, vomiting, blurred vision, papilledema, abductor nerve paralysis and other phenomena. 2 Cranial nerve palsy is mainly the infiltration of nerve roots, especially through the third and seventh pairs of cranial nerve involvement at the cranial nerve hole. 3 The spinal cord is infiltrated by leukemia cells and is characterized by progressive paraplegia. 4 Infiltration of vascular endothelium and stasis of leukemia cells, secondary hemorrhage, clinical manifestations of cerebrovascular accidents.

Examination of acute lymphoblastic leukemia

1, blood leukocyte changes are the characteristics of this disease. The total number of white blood cells can be higher than 100 × 10 ⁹ /L, and can also be lower than 1 × 10 ⁹ /L. About 30% is below 5×10 ⁹ /L. The proportion of immature lymphocytes in the classification may vary depending on the diagnosis of morning and evening and typing. Most of them are over 20%, and there are also more than 90%. A small number of patients do not have immature lymphocytes in the early stage, and lymphocytes are mainly classified in this type of leukemia.

Anemia is generally positive pigmentation of positive cells. However, in severe cases, the MCV may increase, possibly due to bone marrow erythropoiesis. Reticulocytes are normal or low. The degree of anemia is different, the incidence is acute, and the degree of anemia is mild. Platelets are mostly reduced, about 25% in the normal range.

2, bone marrow bone marrow examination is an important basis for establishing diagnosis and evaluation of efficacy. Myeloid hyperplasia is active or extremely active, and a few can show low proliferation. The classification is dominated by primitive and naive lymphocytes, more than 50%, and even more than 90%. Some bone marrow is almost entirely occupied by leukemia cells, and erythroid and megakaryocytes are not easily seen.

3. Histochemical staining is mainly used to study the biochemical properties of bone marrow cells and help to identify different types of leukemia. The histochemical characteristics of ALL are

1 Peroxidase staining and negative staining with Sudan black.

2 glycogen staining.

3 Acid phosphatase (-) ~ (±), T cell cytoplasm is massive or granular, other subtypes are negative.

4 Non-specific lipase is negative, and sodium fluoride is not inhibited.

4, other examinations for prolonged bleeding time may be due to abnormal platelet quality and quantity. Leukemia cell infiltration can cause a decrease in prothrombin and fibrinogen, leading to prolonged prothrombin time and bleeding. Liver function tests SGOT mild or moderate elevation. Due to the massive destruction of myeloid leukemia cells, LDH is increased.

Chest X-ray examination of 5% to 15% of children with mediastinal mass, thymus infiltration or mediastinal lymphadenopathy. About 50% of the long bone fragments can be seen in a wide range of bone sparse, and the horizontal or transverse band with reduced density can be seen on the proximal side of the iliac crest, which is the leukemia line. Changes in bone defects and periosteal hyperplasia are sometimes seen.

4, molecular biology examination: acute lymphoblastic leukemia may have some molecular biological markers, and there is a certain correlation with prognosis and treatment options. Among them, BCR-ABL is the most common, can be seen in 10-15% of ALL patients, such patients can try targeted drug therapy. In addition, children with ALL can also see E2A-PBX, BCR-ABL [1-2] and other fusion genes, which are signs of poor prognosis.

Diagnosis and differentiation of acute lymphoblastic leukemia

Diagnostic criteria

According to clinical manifestations, peripheral blood, bone marrow morphology and cytochemistry, cytogenetics and molecular biology, acute lymphoblastic leukemia can be diagnosed. The diagnostic criteria for ALL morphological classification are as follows:

1. Domestic Diagnostic Standards In September 1980, the National Leukemia Classification and Classification Experience Exchange Seminar was held in Suzhou, Jiangsu Province. The following recommendations were made on the classification criteria for acute lymphoblastic leukemia (ALL):

Type 1 (L1): primitive and naive lymphocytes are mainly small cells (<12m in diameter), with rounded nucleus, occasional depressions and folds, coarse chromatin, uniform structure, few nucleoli and small, unclear The cytoplasm is less, mild or moderately basophilic, and the original cells positive for peroxidase or Sudan black staining generally do not exceed 3%.

Type 2 (L2): The original and immature cells are mainly large cells (more than 2 times larger than normal small lymphocytes, >12 m), irregular nucleus, visible and folded, and the chromatin is loose and the structure is inconsistent. The nucleolus is clearer, one or more; the cell mass is often more, mild or moderate basophilic, and some cells are deeply stained.

Type III (L3): Like Burkitt type, the original and naive lymphocytes are relatively uniform in size, with large cells as the main type, the karyotype is more regular, the chromatin is evenly fine, the nucleolus is obvious, one or more, is a vesicle Shape; the cell mass is more, dark blue, the vacuole is often obvious, and it is honeycomb.

2. Foreign diagnostic criteria France, the United States, the United Kingdom (FAB) collaborative group in 1976 using Romanowsky staining to observe blood and bone marrow smear, according to cell size, nucleoplasmic ratio, nucleolar size and number, cytoplasmic basophilic degree, etc. .

According to the latest WHO classification, 20% can be diagnosed. Immunological typing can classify ALL into different subtypes according to the different expression of leukemia cell differentiation antigen, providing more accurate diagnosis for 99% of ALL patients, cytogenetic classification and Compared with other methods, it provides biological characteristics more relevant to the disease, and the diagnostic criteria for typing into the CNS-L are as follows:

1 have CNS-L symptoms and signs, especially the symptoms and signs of increased intracranial pressure.

2 Cerebrospinal fluid (CSF) changes: increased pressure > 200mmH2O; white blood cells > 0.01 × 109 / L; protein > 450mg / L; or Pan's test positive; smear see leukemia cells.

Differential diagnosis

1. The most common is the identification of ALL and AML. In addition to cell morphology and cytochemical staining, immunophenotyping can also be used for cases with difficult diagnosis. T cell surface antigens and gene molecular biological examinations can be used for identification, some non-random Cytogenetic abnormalities are also characteristic of ALL, whereas for chronic lymphocytic leukemias of different origins, juvenile lymphocytic leukemia and hairy cell leukemia, the identification depends mainly on different clinical features and cell morphology, while in patients with lymphoma leukemia Diagnosis is often difficult to distinguish from ALL, but because it is similar in treatment to ALL, there is generally no need for precise identification in clinical practice.

2. ALL and aplastic anemia through the bone penetration and bone marrow biopsy are most easily identified but for rare low-proliferative ALL, especially whole blood cell reduction, myeloproliferative, and the proportion of primitive cells is low, the identification The diagnosis is difficult. Some scholars suggested in the early years that glucocorticoid therapy should be considered for such patients. If the patient has rapid cell recovery within a few months, the possibility of ALL is greater, and the diagnostic technique is perfect. Today, this method of identification seems to be unnecessary.

3. Some small round cell malignancies of non-hematopoietic system may show clinical manifestations and laboratory characteristics similar to ALL when bone marrow invasion occurs, such as neuroblastoma or rhabdomyosarcoma, which is common in children, and Ewing's sarcoma or small in adults. In cell lung cancer, if the primary disease can be found in these cases, the diagnosis is not difficult, and for those patients without the primary disease, the immunophenotype and gene rearrangement of the tumor cells should be tested to provide a basis for diagnosis.

4. There are some benign episodes of infectious diseases. Patients may also have fever, swollen lymph nodes, splenomegaly, cytopenia and peripheral blood lymphocytes, so they need to be differentiated from ALL, such as infectious mononucleosis. Patients with fever, superficial lymph node enlargement, abnormal lymphocytes in peripheral blood as the main feature, bone marrow is an important examination for identification, ALL patients contain a large number of leukemia cells, serum heterophilic agglutination test is negative, the course of disease is progressive deterioration After that, sometimes infectious mononucleosis and ALL can coexist, ALL has joint symptoms, fever and anemia should also be differentiated from rheumatoid arthritis or systemic lupus erythematosus.

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