Pregnancy with leukemia
Introduction
Introduction to pregnancy with leukemia Leucemia is a common malignant disease of unexplained hematopoietic tissue. It is characterized by a type of white blood cells that have tumoric hyperplasia in bone marrow or other hematopoietic tissues. Infiltration of various organs and tissues in the body can produce corresponding symptoms and signs. Immature cells can appear in peripheral blood, and red blood cells and platelets are often significantly reduced. basic knowledge The proportion of the disease: the incidence of this disease is low, about 0.01% in a specific population Susceptible population: pregnant women Mode of infection: non-infectious Complications: anemia, disseminated intravascular coagulation, central nervous system leukemia, adult respiratory distress syndrome, sarcoidosis, pleural effusion, pulmonary fibrosis, pericardial effusion, arrhythmia, hypertension, acute abdomen, diabetes, hemolytic anemia
Cause
Pregnancy with leukemia
Radiation factor (25%):
Ionizing radiation has a leukemia-like effect and is positively correlated with dose. There are three types of ways in which leukemia can be caused by ionizing radiation:
1 iatrogenic exposure (such as radionuclide examination or treatment and radiation examination or treatment).
2 occupational exposure (such as radiology medical staff, cardiac catheterization staff, etc.).
3 accidental radiation damage, etc.
Virus factor (20%):
The discovery of HTLV-I is one of the important contributions to the virology of leukemia. In areas where ATL is found, there is a local epidemic of the virus, but only 1% to 2% of HTLV-I infections occur in ATL, and the incubation period is quite long. 10 to 30 years, the route of transmission of HTLV-I has not been fully elucidated. The lateral transmission route includes semen transmission, lymphocyte infusion, blood transfusion, mosquito bites, syringe needles after HTLV-I contamination, etc. Generation, Zeng Yi of China investigated 10012 serums and 8 HTLV-I positives in 28 provinces, municipalities and autonomous regions, 3 of which were Japanese, 2 were Chinese Taiwanese, and 2 were Japanese and Chinese Taiwanese wives. One case is a seafarer who frequently goes to a foreign port. Most of the HTLV-I seropositive patients in the United States are those who receive blood products and intravenous drugs for a long time.
Genetic factors (15%):
Epidemiological studies have found that the incidence of leukemia in different races is different, and there are also familial leukemia aggregation, which suggests that leukemia may be related to heredity. For example, if a single egg has a leukemia before the age of 10, Another person has a 20% chance of developing leukemia, but some people think that the role of some of the same leukemia-causing factors cannot be ruled out. Occasionally, two or more leukemias of the same type appear in one family, some autosomal recessive hereditary Diseases such as congenital vasodilatation erythema (Bloom syndrome), Fanconi anemia and telangiectasia ataxia are often accompanied by chromosomal instability and prone to leukemia, the incidence of which can reach 0.5% to 1%, other easy Congenital diseases in which leukemia occurs are congenital stupid (Down syndrome) and X-linked agammaglobulinemia (XLA).
Chemical factors (30%):
Certain chemicals can also cause leukemia, and some of the therapeutic drugs, especially chemotherapy-induced leukemia, are also called secondary leukemia, medical treatment related leukemia (MTRL).
(1) Chemotherapeutic drugs: alkylating agents are relatively recognized drugs with leukemia. Patients usually develop 4 to 6 years after receiving these drugs, the incidence rate is 6% to 12%, and the AML caused by leukemia See, procarbazine, nitrosourea is also a relatively common leukemia chemotherapy drug, and daunorubicin, doxorubicin, pingyangmycin, methotrexate and other drugs cause leukemia is relatively rare.
(2) Ethyleneimine and Ethyleneimine Derivatives: Ethyleneimine and Ethyleneimide Derivatives Bicazoline, ICRF-154, ICRF-159 is a class of drugs for the treatment of tumors and psoriasis, which cause leukemia. The first is the use of ICRF-159 in the UK to treat colon cancer and psoriasis. Currently, leukemia secondary to this drug has attracted widespread attention. Ye Hui and other retrospectively collected 22 cases of psoriasis, 11 cases of taking B double? The morpholine was 3 to 84 months, and the average dose was 170.82 g, of which 3 cases developed acute leukemia (2 cases of M3 type, 1 case of M2 type), and 2 cases of myelodysplastic syndrome (MDS), but so far, The mechanism of action of leukemia caused by acetimimine and ethyleneimine derivatives has not been elucidated. Wang Yongzheng and other studies have found that bis-morpholine can cause chromosome aberration and spindle breakage. Yang Yanping found that imipenem has micronuclear effects on animals. Its effect is enhanced with increasing dose.
(3) Chemicals such as benzene: Occupational long-term, a large amount of exposure to benzene often leads to a decrease in myeloproliferation, and sometimes it can progress to leukemia. Infante et al found that the risk of various types of leukemia in American workers exposed to benzene from 1940 to 1949 was normal. 5 times, while the risk of granulocyte and mononuclear leukemia is 10 times that of normal people. Benzene and toluene are important solvents. With the development of society, the contact in daily life is increasing. In the national census, the petrochemical industry area The incidence of leukemia is relatively high and deserves attention.
(4) Others: chloramphenicol, bupropion (potasone), sulfonamides and other drugs that inhibit bone marrow can induce secondary leukemia, 309 cases of childhood leukemia in Shanghai, 34% have a history of chloramphenicol, followed by Patients with early stage leukemia often have manifestations of myelodysplastic syndromes. Cytogenetic tests often show abnormalities of chromosomes 5, 7, and 8. Chloramphenicol has been banned abroad, and the use of chloramphenicol has been restricted in China. Related reports of leukemia have been rare. In addition, there are reports of leukemia caused by cimetidine (cimetidine).
Pathogenesis
Studying the pathogenesis of leukemia can provide a basis for early detection of leukemia and early blockade of its occurrence and development process, as well as to seek new therapeutic strategies from its pathogenesis. It is currently believed that the occurrence of leukemia is multi-stage, different causes The pathogenesis of leukemia is not the same. Usually, physical and chemical factors cause single cell mutation, and then the body's genetic susceptibility and immunity are low. Virus infection, chromosomal aberrations, etc. activate oncogenes and inactivate some cancer genes. The overexpression of apoptotic genes eventually leads to the inhibition of apoptosis in the mutant cells, which in turn leads to malignant proliferation. Some of the mechanisms that are more in-depth are described below.
1. Pre-leukemia cells and leukemia stem cells
The growth of acute leukemia cells is characterized by clonal proliferation of hematopoietic cells in the immature stage. The malignant clones replicate and proliferate without restriction, but the stages of transformation are not identical. Some malignant cells of AML are derived from undifferentiated stem cells. Departments, mononuclear, erythroid and megakaryocyte lines have glucose-6-phosphate dehydrogenase (G6PD) isoenzymes consistent with leukemia cells, while in other AML only granules and/or mononuclear lines are present. Clonal hyperplasia suggests that malignant transformation begins from the granulocyte-monocyte stage. In ALL, myeloid cells have no malignant markers, suggesting that ALL cells are not derived from at least the earliest hematopoietic stem cells, but from partially differentiated hematopoietic progenitor cells.
In the immunophenotypic analysis of AML cells, some AML cells were expressed to express more than one cell antigen, indicating that AML originated from stem cells with multi-directional differentiation potential. Leukemia stem cells are different in genes involved in transformation or progression. It is characterized by different subtypes of AML with different differentiation characteristics. However, some scholars have found that PML-RAR fusion gene formed by characteristic genetic alteration of acute promyelocytic leukemia (APL) t(15;17)(q22;q21) It is not present in CD34 CD38-, but in CD34 CD38 cells in the mature stage of hematopoietic targeting, which indicates that the earliest hematopoietic stem cells are not involved in APL, which is a malignant transformation mechanism of AML. In particular, PML/RAR is the key molecular basis for the pathogenesis of APL. Severe combined immunodeficiency mice (SCID) leukemia initiation cells (SL-IC) are the most primitive leukemia stem cells, and SL-IC is inoculated into NOD/SCID mice. AML can occur in mice, about 2% of cells still retain CD34 CD38- characteristics, SL-IC is amplified at least 30-fold, and most AML cells are CD34 CD38 CD33 cells, indicating that SL-IC has differentiation potential, S L-IC can produce AML-CFU-forming cells, CD34+CD38+ and relatively differentiated leukemia cells. Although SL-IC has limited differentiation ability, it denies the view that AML cells are completely blocked.
In most cases, leukemia patients with normal erythroid, myeloid and megakaryocyte hematopoiesis are inhibited due to excessive proliferation of leukemia cells, but for a small number of acute leukemia patients with low myeloproliferative, the above reasons are not enough to explain normal Hematopoietic inhibition is a phenomenon; abnormal cellular or humoral immunity in this part of the patient is likely to be the mechanism of normal hematopoietic suppression. In short, there are still normal hematopoietic stem cells in the bone marrow of leukemia patients, and effective chemotherapy can minimize tumor burden. Thus, the inhibition of proliferation and differentiation of normal hematopoietic stem cells is relieved, and normal hematopoiesis is gradually restored.
2. The role of chromosomal abnormalities in the pathogenesis of leukemia
Since the 1970s, many chromosomal abnormalities have been found to be associated with a subtype of leukemia by cytogenetics. With the wide application of molecular biology techniques in hematology, it is possible to further explore the pathogenesis of leukemia at the molecular level. So far, although the exact cause and mechanism of malignant transformation of normal hematopoietic cells have not been fully elucidated, a large number of studies have confirmed that some tumors repeatedly have highly consistent chromosomal abnormalities, and their chromosomal breakpoints involve previously known or new proto-oncogenes. Therefore, it is confirmed that chromosomal abnormalities play an important role in the mechanism of tumorigenesis. The abnormalities of chromosomes are karyotype abnormalities, chromosome number or structural abnormalities, structural abnormalities including translocation, inversion and deletion, such as AML subtype acute granulocyte-single cell leukemia The characteristic abnormal karyotype with eosinophilia (M4Eo) is chromosome 16 inversion (16). The characteristic cytogenetic change of CML is the translocation between chromosome 9 and chromosome 22, ie t ( 9;22)(q341;q11), almost all B-lineage lymphocytic leukemia is associated with chromosomal translocation, for example, c-myc Translocation of genes to immunoglobulin heavy and light chain genes, such as t(7;14), t(8;2), t(8;22) translocation, due to high levels or abnormalities of c-myc transcriptional regulatory proteins Increased, B cell growth is out of control, in addition, the gene MLL located at chromosome 11q23 is a region that is easily involved in chromosomal translocations and deletions, and more than 30 chromosomal regions with translocation of MLL, more commonly including AFXl (xq13 ), AF1p (1p32), AF1q (1q21), AF6 (6q27), AF10 (10p12) and AF17 (17q21), these genes are either involved in a novel transcription factor, or a common sequence with different cytokines, or The domain-associated amino fragment of transcriptional repression or activation, after translocation with the 11q23 MLL gene, is altered by its normal function and is one of the major causes of leukemia.
The change in chromosome number is another important genetic abnormality of leukemia. For example, this abnormality accounts for 40% to 70% of ALL. The mechanism of abnormal chromosome number to leukemia is still unclear. The possible mechanisms are:
1 Some recessive gene expression leads to uncontrolled cell growth and differentiation regulation.
2 Abnormal expression of genes with proto-oncogene potential.
3 Overexpression of a certain gene causes abnormal proliferation and differentiation of cells.
3. The role of cell oncogenes and tumor suppressor genes in the development of leukemia
The protooncogene is involved in the regulation of the growth and development of human cells under physiological conditions. Under pathological conditions, protooncogenes can be activated into oncogenes by gene amplification, chromosomal translocation, insertion and point mutation. The ability of cells to gain undead and malignant proliferation, which plays an important role in the development of leukemia and other tumors.
In the occurrence of leukemia, gene translocation is the most common, and the effect of translocation on proto-oncogenes is mainly reflected in the following two aspects:
1 The proto-oncogene is linked to the T cell receptor or immunoglobulin gene to activate the latter, such as the c-myc gene of chromosome 8 and the Ig heavy chain gene translocation of 14q32 (8; 14), making c-myc The transcription of the gene is transformed, and the misexpression of the c-myc gene causes excessive formation of the c-myc-MAX dimer, leading to transcription of the downstream target gene and causing leukemia.
2 The proto-oncogene is placed under the control of another vigorously expressed gene, causing it to be expressed or ectopically expressed. The most representative is the Ph chromosome of CML, ie t(9;22)(q34;q11) From the Abelson proto-oncogene abl translocation of chromosome 9 to the chromosome 22 breakpoint concentration region (bcr), the bcr-abl fusion gene produces an abnormal 8.5 kb RNA encoding the 210 kD fusion protein p210, and the normal ABL gene product. Compared with p145, p210 has abnormally high tyrosine kinase activity, which can phosphorylate various enzyme substrates such as GAP, GRB-2, SHC, FES and CRKL, and stimulate abnormal proliferation of hematopoietic precursor cells. Studies have shown that bcr- The abl fusion gene can cause tumor cell transformation in vitro, and transfection of the bcr-abl fusion gene into mouse bone marrow cells can lead to hematological changes similar to CML, such as acute promyelocytic leukemia (APL) labeling. The chromosome is t(15;17)(q22;q21), the retinoic acid receptor alpha (RAR) gene on chromosome 17 and the promyelocytic leukemia (PML) gene fusion on chromosome 15, and the excess of PML-RARot fusion protein Expression can significantly inactivate RAR and some other nuclear receptor functions, and these nuclei Receptors may be involved in the differentiation of promyelocytic cells, thereby blocking cell differentiation and maturation. The t(8;21) translocation in AML is one of the most common karyotypic abnormalities, forming an AML1-ETO fusion protein, which is currently considered The fusion protein mainly blocks the transcriptional activation of AML1 by a dominant negative pattern by multiple domains of the ETO gene and a nuclear receptor transcriptional co-repressor (N-COR)/histone deacetylase (HDAC) complex. In order to block the differentiation of hematopoietic cells, it plays an important role in leukemia with t(8;21). In addition, AML1-ETO can also inhibit the function of the transcription factor PIZF, so that genes normally inhibited by PLZF are unsuppressed. Expression can also activate the transcription of the oncogene bcl-2, possibly participating in the development of M2b leukemia through the anti-apoptotic pathway.
Point mutation is another way of activation of protooncogenes. For example, ras gene point mutations in human leukemia occur at codons 12, 13 and 61. Mutations cause amino acids in the p21 protein peptide chain to be replaced, affecting the body of p21 protein. The conformation, therefore, cannot be inactivated by the hydrolysis of GTP into GDP, and is continuously activated, resulting in massive proliferation of cells, causing malignant transformation. In the occurrence of leukemia, 20% or more of AML contains ras gene activation, and each subtype can occur. .
Suppressor gene is a normal human genome member. Its function is to induce terminal differentiation of cells, maintain gene stability and negatively regulate cell growth and differentiation, and inactivate tumor suppressor genes. It is also an important link in the development of leukemia. Under physiological conditions, cells die in a special time and specific location, called programmed cell death.
Although oncogenes are involved in human leukemia, there is still insufficient evidence to demonstrate its role in the development of leukemia. From animal retroviruses and similar oncogenes activated under experimental conditions, blood cells cultured in vitro are transformed and susceptible. The fact that leukemia is induced in animals strongly suggests that oncogenes may play an important role in the development of human leukemia.
4. Other
The role of mitochondrial DNA (mt-DNA) in the development of leukemia has also received increasing attention. The morphology, structure and function of mitochondria in leukemia cells are abnormal. Almost half of the lines are one of the pathogenesis of leukemia. In addition, cell culture in vitro is not To determine the relationship between the degree of dysfunction and the degree of hematopoietic disorders characterized by myeloid leukemia and disease progression in the body.
Prevention
Pregnancy with leukemia prevention
1. Reduce or avoid the contact of harmful substances such as ionizing radiation, chemicals, and chemicals.
2. Active treatment should be given early for certain acquired diseases that may be converted to leukemia.
Complication
Pregnancy with leukemia complications Complications anemia diffuse intravascular coagulation central nervous system leukemia adult respiratory distress syndrome sarcoidosis pleural effusion pulmonary fibrosis pericardial effusion arrhythmia hypertension acute abdomen diabetes hemolytic anemia
The complications of leukemia are mainly found in infection, hemorrhage, anemia, disseminated intravascular coagulation, central nervous system leukemia, tumor lysis syndrome and leukemia, extramedullary complications, adult respiratory distress syndrome, sarcoidosis, pleural effusion, lung Fibrosis, pericardial effusion, arrhythmia, heart failure, hypertension, acute abdomen, portal hypertension, gastrointestinal bleeding, renal insufficiency, thrombosis or autoimmune hemolytic anemia, bone marrow necrosis, diabetes, urine Injury, electrolyte imbalance and leukemia-associated paraneoplastic syndrome, Sweets syndrome, gangrenous pyoderma, arthritis, vasculitis syndrome.
Symptom
Pregnancy with leukemia symptoms Common symptoms Melanosis lymph node enlargement Skin bleeding point Skin mucous membrane pale tibia tenderness Repeated hyperthermia
The initial diagnosis of leukemia during pregnancy is often difficult because pregnant women often have a variety of symptoms similar to the atypical symptoms of leukemia, the most common initial manifestations of fatigue, bleeding, anemia and repeated high fever, pale skin mucous membranes , skin bleeding spots or ecchymoses, large liver, swollen lymph nodes, and various symptoms of infection, sternum, tibia tenderness in acute leukemia.
Examine
Examination of pregnancy with leukemia
Peripheral blood
Anemia is often normal cell normal pigmented anemia, with mild thrombocytopenia, occasional white blood cells are slightly lower than normal, various blood cells (primary) hyperplasia in the peripheral blood of acute leukemia.
2. Bone marrow
The original cell proliferation >30% can diagnose acute leukemia. Chronic leukemia can be divided into chronic phase, accelerated phase and blast phase. The chronic white blood cells can be hyperplasia >50×109/L, even up to 700×109/L, and the red blood cell morphology is normal. Hemoglobin is normal, blood cells are easy to see nucleated red blood cells, platelets are normal or elevated, hemoglobin and platelets can be significantly decreased during accelerated and blast phase, bone marrow shows extremely active bone marrow, grain: red can be as high as 50:1, original + early In the young and chronic phase <10%, the blast phase can be as high as 30% to 50%, or higher, acidophilus, basophils often increase, megakaryocytes increase early, and the blast phase is significantly reduced.
According to the condition, choose ECG, B-ultrasound, X-ray, MRI, biochemical liver and kidney function tests.
Diagnosis
Diagnosis and differentiation of pregnancy complicated with leukemia
diagnosis
According to the patient's typical symptoms, signs and blood, bone marrow changes, most leukemia diagnosis is not difficult, but because some patients have atypical clinical symptoms or some clinicians have incorrect diagnosis, some cases may be misdiagnosed, such as fever. Leukemia, which is the main manifestation of onset, is often misdiagnosed as an infection. It is only necessary to confirm the diagnosis of leukemia after the anti-infection is ineffective or the disease develops. Therefore, it is extremely important to ask about the medical history in detail, comprehensive physical examination and the ability to have correct thinking analysis and differential diagnosis.
Differential diagnosis
A small number of cases with low white blood cells must be differentiated from AA, ITP, agranulocytosis, MDS, paroxysmal nocturnal hemoglobinuria, such as low proliferative leukemia due to decreased peripheral blood 3, low myeloproliferative, easy to phase with AA Confusion, but the primordial cells in the bone marrow account for more than 30% of the nucleated cells to confirm the diagnosis of leukemia. What is really confused with leukemia is the leukemia-like reaction, infectious mononucleosis and hemophagocytic syndrome (HPS). ), the main points of identification are as follows:
Leukemia-like reaction
It is the rise of peripheral blood leukocytes in the human body under the stimulation of certain causes, accompanied by the increase of primitive blood and bone marrow in the peripheral blood or bone marrow. It is clinically similar to leukemia. Its common causes are infection, tumor, poisoning, hemorrhage, acute hemolysis. Shock and trauma, especially in severe infections and malignant tumors, because the treatment and prognosis of white and leukemia are completely different, the diagnosis should be very careful.
First, leukemia-like causes are induced. After the cause is removed, the leukemia-like reaction can disappear, and the blood and bone marrow images quickly return to normal. Most leukemia patients are different from leukemia, without thrombocytopenia and anemia; Cases may have decreased red blood cells and platelets. The number of leukocytes in leukemia-like patients is above the normal range, but it is rarely more than 50×109/L. The ratio of immature granulocytes in blood is not high, and the granulocytes are rare. Significant toxic granules and vacuoles can be seen in the cytoplasm of cells, lack of cell malformations seen in leukemia, imbalance of nucleoplasm development and Auer corpuscles. NAP and PAS staining is significantly elevated during white-like, whereas in granulocytic leukemia Most of the time is normal or lower.
2. Infectious mononucleosis
Hyperplasia is a lymphocytic reactive hyperplastic disease caused by Epstein-Barr (EB) virus infection, which is common in children and adolescents, fever, cervical lymphadenopathy and sore throat are the unique triad of the disease, and may also be associated with the liver. Splenomegaly, rash, etc., due to the increased proportion of lymphocytes and monocytes in peripheral blood leukocytes, and a large number of abnormal lymphocytes, easily misdiagnosed as ALL, but no progressive anemia, no thrombocytopenia and hemorrhage, peripheral blood Although abnormal lymphocytes can reach more than 10% of the total number of white blood cells, there is only a small amount of heterologous lymphocytes in the bone marrow, and there is no increase in primordial and immature granulocytes. The serum heterophilic agglutination test is positive in patients with infectious mononucleosis. Up to 1:2000, the bovine erythropoietin test titer can reach 1:400 or more. In addition, the leaflet is a self-limiting disease, and its abnormal blood picture disappears within 1 to 2 months.
3. Hemophagocytic syndrome (HPS)
The hemophagocytic systemic proliferative disease of mononuclear macrophage cell line is a histopathological disease, which is divided into hereditary primary HPS and reactive/secondary HPS. The former is mainly found in infants and young children and is an autosomal inheritance. Sexually transmitted diseases, the latter being seen at any age, can be induced by infection or certain blood or non-hematological malignancies and certain drugs.
HPS is often characterized by high fever, with hepatic and spleen lymphadenopathy, rapid onset, severe condition, and symptoms similar to AL, but HPS peripheral blood mostly shows complete blood cell reduction, while AL usually manifests as elevated white blood cells, accompanied by anemia and platelets. The reduction, of course, is that many leukemia patients show a decrease in peripheral blood 3 system. At this time, the differential diagnosis must be confirmed by bone marrow cytology or lymph node pathology. HPS bone marrow examination may have different degrees of bone marrow macrophage increase. Macrophages are sometimes vacuolated by phagocytic cell debris, while AL bone marrow examination shows a marked increase in primordial cells, no increase in macrophages, HPS lymph node biopsy can be found in hemophagocytic cells, no lymph nodes Destruction, leukemia lymph node biopsy has no hemophagocytic cells. In addition, HPS without underlying disease has a good prognosis and is easy to recover, while AL has a poor prognosis.
