Developmental abnormalities of the bone marrow
Introduction
Introduction The most common disease of bone marrow dysplasia is myelodysplastic syndrome (MDS), a group of heterogeneous clonal disorders that originate from hematopoietic myeloid stem cells or pluripotent stem cells. Hematopoietic stem and dysplasia, leading to inefficient hematopoiesis and increased risk of malignant transformation. The main features are ineffective hematopoiesis and high-risk evolution to acute myeloid leukemia. The clinical manifestations are abnormal changes in the quality and quantity of hematopoietic cells. The incidence of MDS is about 10/10 million to 12/100,000 people, mostly involving middle-aged and elderly people, 50% to 70% of cases over 50 years old, and the ratio of male to female is 2:1. MDS 30% to 60% is converted to leukemia. In addition to leukemia, most of the causes of death are due to infection, bleeding, and especially intracranial hemorrhage.
Cause
Cause
(1) Causes of the disease
The cause of MDS is still unclear. It is speculated that due to biological, chemical, or physical factors, genetic mutations cause chromosomal abnormalities to cause clonal proliferation of a malignant cell. It has been recognized that mutagens such as viruses, certain drugs (such as chemotherapeutics), radiation (radiotherapy), industrial reactants (such as benzene, polyethylene) and environmental pollution can cause carcinogenic effects. Mutagens can cause chromosome weight. Rows or gene rearrangements may also cause only changes in gene expression leading to MDS. However, it has been confirmed from cell culture, cytogenetics, molecular biology and clinical studies that MDS is a clonal disease derived from the level of hematopoietic stem/progenitor cells. The cause of the disease is similar to that of leukemia. At least two lymphoblastic proliferative diseases, adult T-cell leukemia and cutaneous T-cell lymphoma, have been shown to be caused by retroviral infection. Experiments have also shown that the pathogenesis of MDS may be related to retrovirus action or (and) cell proto-oncogene mutation, tumor suppressor gene deletion or abnormal expression. A common proto-oncogene involved in the pathogenesis of MDS patients is the N-ras gene. The Ras gene family is divided into three types: H, N, and K. The most common mutation in NDS is N-ras gene mutation, which occurs in exons 12, 13, and 61. The expression of N-ras gene encoded protein is abnormal after interference. The normal cell proliferation and differentiation signals lead to abnormal cell proliferation and differentiation. There are also reports of abnormal expression of p53 and Rb tumor suppressor genes in patients with MDS, but these genetic changes are more common in MDS than in advanced RAEB and RAEB-T patients, and less in early RA and RAS in MDS, suggesting that genetic mutations are difficult to explain. The cause of all MDS patients.
Patients with secondary MDS often have obvious pathogenesis. Benzene aromatic compounds, chemotherapeutic drugs, especially alkylating agents, and radiation can induce cell gene mutations leading to MDS or other tumors. In addition, MDS occurs mostly in middle-aged and elderly people. Whether age can reduce the function of intracellular repair gene mutation may also be one of the pathogenic factors.
(two) pathogenesis
MDS patients cause hematopoietic stem cell damage under the influence of pathogenic factors. The G6PD isoenzyme type, X chromosome with restriction length fragment polymorphism methylation, X chromosome inactivation analysis and other methods have determined that most MDS are lesions. Crohn's disease occurs at the level of hematopoietic stem cells, so not only the myeloid, erythroid, and megakaryocytic cells are involved, but also the lymphocyte lineage is affected, resulting in abnormal numbers and functions of T and B cells, and clinical manifestations of immunodeficiency or autoimmunity. disease. However, in some patients, the incidence can only be limited to the levels of granulocytes, red, megakaryocytes, and macrophage progenitor cells. Only granules, red, megakaryocytes, macrophages, etc. are involved and no lymphocytes are involved.
The onset of MDS has stage characteristics and may be related to changes in different proto-oncogenes and tumor suppressor genes. Proto-oncogene activation includes gene overexpression, expansion, rearrangement, translocation, point mutation, etc. The tumor suppressor gene changes include allelic loss, deletion, rearrangement, mutation, and decreased expression. Hematopoietic stem cells are regulated by different protooncogenes and tumor suppressor genes in different stages of proliferation and differentiation. This regulation is through their expression products such as growth factors, cell surface receptors, tyrosine kinases, ATP, cytosine threonine. / Serines, nuclear proteins, etc. are completed. These expression products are directly involved in various physiological steps of cell proliferation and differentiation according to strict procedures. For example, a physiological link may cause disorder of cell proliferation and differentiation due to abnormal regulation of protooncogene or tumor suppressor gene, leading to MDS or other diseases.
In the early stage of MDS, some hematopoietic stem cells with proto-oncogene or tumor suppressor gene changes have some abnormalities in their own proliferative differentiation function, but they can still be in a relatively stable stage for a long time. At this time, the patient's clinical condition is stable, only mild. Anemia, white blood cells, thrombocytopenia, but when this abnormal clone progresses further, another cloned stem cell with chromosomal aberrations derived from this clone is used as the main hematopoietic stem cell instead of hematopoiesis. Chromosomal aberrations make this stem cell have More obvious hyperplasia and differentiation, the blood cells in different stages of the various lines are often unable to differentiate and mature, the proportion of apoptosis in the middle is increased, and the blood cells of the peripheral blood 3 are further reduced. The feedback stimulates the bone marrow abnormal hematopoietic stem cells to strengthen the hyperplasia, and the bone marrow hyperplasia is accompanied by pathological conditions. Hematopoietic performance. Hyperproliferative abnormal clones Hematopoietic stem cells often have two evolutionary pathways: one is due to excessive proliferation and gradually evolves into hematopoietic decline, the bone marrow can be converted to hyperplasia, and the clinical manifestation is hematopoietic failure, which is the cause of death in more than half of patients with MDS. The other evolved into acute leukemia. Most of the acute leukemias converted from MDS to acute myeloid leukemia, only a small number of acute lymphoblastic leukemia, chemotherapy is poor, often difficult to relieve, even if the relief, the remission period is short.
Examine
an examination
Related inspection
Bone marrow imaging
Symptom
There is no specific clinical manifestation of MDS. MDS usually has a slow onset and a few onset are acute. It usually turns from leukemia to leukemia, which is about 50% or more within one year. Anemia patients account for 90%. Including pale, fatigue, palpitations after the event, shortness of breath, anemia in the elderly often makes the original chronic heart and lung disease worse. Fever accounts for 50%, of which unexplained fever accounts for 10% to 15%, manifested as recurrent infections and fever, with respiratory tracts, around the anus and urinary tract. Severe granulocytopenia can reduce the patient's resistance. Bleeding accounts for 20%, common in the respiratory tract, digestive tract, and also from intracranial hemorrhage. The early bleeding symptoms are mild, mostly skin and mucous membrane bleeding, gum bleeding or nasal discharge, and female patients may have menorrhagia. The trend of late bleeding is worse, and cerebral hemorrhage is one of the main causes of death. Severe thrombocytopenia can cause skin bruising, nosebleeds, bleeding gums, and visceral bleeding. A small number of patients may have joint swelling and pain, fever, skin vasculitis and other symptoms, mostly accompanied by autoantibodies, similar to rheumatism.
2. Signs
The signs of MDS patients are not typical. Often caused by anemia, pale, thrombocytopenia caused by skin spots, spots. Hepatosplenomegaly accounts for about 10%. Very few patients may have lymphadenopathy and skin infiltration, mostly in patients with chronic myelomonocytic leukemia (CMMoL).
3. Special types of clinical manifestations
(1) 5q-syndrome: The patient's chromosome 5 long arm is missing without other chromosomal aberrations. Occurred in older women, the clinical manifestations of refractory giant cell anemia, in addition to occasional blood transfusion, the clinical condition is long-term stable, rarely converted to acute leukemia. 50% of patients may have splenomegaly, normal or occasional increase in platelets. The most prominent manifestations in the bone marrow are low-lobed or non-lobulated megakaryocytes, often with moderately morbid hematopoiesis, but normal granulocyte hematopoiesis.
There are five important hematopoietic growth factor genes in the long arm of chromosome 5, namely IL-3, IL-4, IL-5, GM-CSF, G-CSF, and GM-CSF receptor gene. How 5q-syndrome affects the regulation of hematopoietic growth factors on hematopoiesis is not well understood.
(2) Monomer 7 syndrome: The cytoplasmic change of chromosome 7 occurs mostly in patients who have received chemotherapy before. Monomer 7 rarely appears alone, often with other chromosomal aberrations. Isolated monomeric 7 chromosome aberrations are common in children and can occur in FAB typing subtypes, most have hepatosplenomegaly, anemia and varying degrees of leukopenia and thrombocytopenia, 25% of patients with mononucleosis, neutral The main glycoprotein on the surface of granulocytes is reduced, and the chemotactic function of granules and monocytes is weakened, which is often prone to infection. Monomer 7 is a poor prognostic indicator and some patients can develop acute leukemia.
(3) 11q-syndrome: The long arm of chromosome 11 is lost, mostly accompanied by other chromosome aberrations. Most of them are ring-shaped iron granulocytic refractory anemia (RAS) type, with ring-shaped iron granules increased and iron storage increased. Part of it is refractory anemia with blast-producing (RAEB) type. Clinically, 20% of patients with RAS have 11q-. The location of the long arm break point of chromosome 11 is different, between q14 and q23. The significance of the q14 breakpoint is unknown, but the ferritin H chain gene is known to be adjacent to q14 at q13. The connection between the two remains to be studied.
(4) 5q-syndrome: The long arm deletion of chromosome 5 (5q-) is one of the common cytogenetic abnormalities of MDS, which can be found in various subtypes of MDS. 5q- has two cases: one is a single 5q-, that is, 5q- is the only karyotype abnormality; the other is complex 5q-, that is, in addition to 5q-, there are other chromosomal abnormalities. Because of the unique clinical manifestations and prognosis of a single 5q-RA and RARS, the 5q-syndrome of MDS is specifically referred to.
5q-syndrome mainly occurs in elderly women. The peripheral blood shows large cell anemia, the number of white blood cells is slightly reduced or normal, and the number of platelets is normal or increased. The most prominent change in the bone marrow is abnormal development of megakaryocytes, and the number of small megakaryocytes with reduced lobes is significantly increased. The manifestations of erythroid cell dysplasia may not be obvious at present, and there may be circular iron granule cells. The patient has a chronic clinical course, mainly refractory anemia, and bleeding and infection are rare. Generally, anti-anemia treatment is ineffective, but it can survive for a long time only by regular blood transfusion. The median survival time can reach 81 months, and the whitening rate is extremely low.
(5) iron granulocyte anemia (SA): SA is a group of heterogeneous diseases, the common feature is the heterogeneous heme biosynthesis disorder in young red blood cells due to different reasons, resulting in mitochondria The iron is overloaded to form iron particles arranged around the nucleus, ie, circular iron granule cells. SA can be divided into three categories: 1 hereditary and congenital SA; 2 acquired SA; 3 reversible SA caused by alcoholism and certain drugs. The RARS of the MDS belongs to the acquired SA. One of the major subtypes of acquired SA is idiopathic acquired sideroblastic anemia (IASA). Kushner et al. analyzed the literature and his own IASA cases and found that: 1 the young red blood cells were negative for PAS staining; 2 the long course of disease, the median survival time was up to 10 years; 3 the survival curve of the patients was the same as the normal population, and not A mode of malignant disease; 4 whitening rate is very low (7.4%). Whether the RARS of MDS is equivalent to IASA, no specific description is given in FAB typing and WHO typing. However, the authors have suggested that there are two types of cases in RARS, one should be diagnosed as MDS, and the other should still be diagnosed as SA.
Diagnosis
Differential diagnosis
Differential diagnosis of dysplasia of the bone marrow:
Bone marrow dysplasia should be differentiated from acute myeloid leukemia, myelofibrosis, aplastic anemia, hemolytic anemia, megaloblastic anemia, and non-hematopoietic tumors.
1. Acute myeloid leukemia: Acute leukemia is a malignant transformation of one or more hematopoietic stem cells and progenitor cells, losing normal proliferation, differentiation and maturation, uncontrolled continuous proliferation, gradually replacing bone marrow and invading the whole body through blood. organ.
2, myelofibrosis: myelofibrosis (MF) referred to as myelin. It is a kind of myeloproliferative disease caused by collagen hyperplasia in bone marrow hematopoietic tissue, and its fibrous tissue seriously affects hematopoietic function. Primary medullary fiber is also called "osteomyostacle" and "unexplained myeloid metaplasia" ". The disease has different degrees of myelofibrosis, as well as extramedullary hematopoiesis mainly in the spleen, followed by liver and lymph nodes. The typical clinical manifestations are juvenile, immature erythrocyte anemia, and more teardrop-shaped red blood cells. The bone marrow puncture often shows dry pumping, the spleen is often swollen, and has different degrees of bone sclerosis.
3, aplastic anemia: aplastic anemia (aplastic anemia) referred to as aplastic anemia. It is a group of syndromes in which hematopoietic disorders caused by various causes lead to a decrease in the total volume of red bone marrow, which is replaced by fat marrow, hematopoietic failure, and complete blood cell reduction. According to the survey of 21 provinces (municipalities) in China, the annual incidence rate is 0.74/100,000 people, which is significantly lower than the incidence of leukemia; the incidence of chronic aplastic anemia is 0.60/100,000, and the rate of acute aplastic anemia is 0.14/100,000. All age groups can develop disease, but it is more common in young adults; the incidence rate of males is slightly higher than that of females. Generally manifested as anemia, bleeding, infection, fever (high fever or low fever), accompanied by walking weakness, dizziness and other symptoms.
4, hemolytic anemia: hemolytic anemia (hemolytic anemia) refers to the acceleration of red blood cell destruction, and the type of anemia occurs when the bone marrow hematopoietic function is insufficient. If the bone marrow can increase erythropoiesis and is sufficient to compensate for the shortened survival of red blood cells, no anemia will occur. This state is called compensatory hemolytic disease. "Hemolytic anemia", anemia caused by excessive destruction of red blood cells, but less common; often accompanied by jaundice, known as "hemolytic jaundice."
