OVERVIEW
Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders characterized by hematopoiesis, with routine blood counts showing either a decrease in whole blood cells or a decrease in any one or two lineages. It is characterized by hyperplasia of the bone marrow, abnormal development of one or more lineages of myeloid cells, ineffective hematopoiesis and an increased risk of evolving into acute myeloid leukemia (AML).MDS is very rare in children, and its occurrence is closely related to congenital disorders and lacks the typical clinical manifestations, which are often anemic, sometimes with infections or hemorrhages, and in some cases with hepatosplenomegaly. According to the 2008 WHO classification, refractory cytopenia in children (RCC) is a common type of MDS in children, accounting for about 50% of all pediatric MDS.
Etiology
The pathogenesis of MDS is unclear, and it can be clinically categorized as primary or secondary. The etiology of primary cases may be related to chemical, viral or radiological damage; secondary cases may be caused by the use of chemotherapeutic drugs in the primary disease, and the important related drugs are alkylating agents, and the presence of proto-oncogene mutations, abnormal bone marrow in vitro cultures, and cytogenetic mutations in MDS suggest that the disease is a clonal disorder.
1. Primary
Compared with adult MDS, there is little difference between the clinical manifestations of children’s MDS. However, 30% to 50% of children’s MDS have chromosomal abnormalities, most of which are abnormalities in the number of chromosomes, and less than 10% are abnormalities in the structure of chromosomes, of which monosomy of chromosome 7 is the most common, accounting for about 30%, followed by trisomy of chromosome 8 and trisomy of chromosome 2l, and 5q-is very rare.
2. Secondary
MDS can be induced by malignant hematologic diseases, immunosuppressive therapy, occupational or other exposure to environments containing carcinogens. Secondary MDS and secondary leukemia are different stages of a single disease. Diseases that cause MDS/AL as a result of chemotherapy or (and) radiotherapy include Hodgkin’s disease, non-Hodgkin’s lymphoma, multiple myeloma, ovarian, lung, breast, testicular, gastrointestinal tract, brain, and true erythrocytosis. About 1/3 of children with MDS are secondary to genetically abnormal disorders with a predisposition to develop MDS/AML, and the onset of MDS in such children is early, most often younger than 2 years of age.
Symptoms
Can be seen at any age from infancy to adolescence. The minimum age is 2 months and the maximum age is 14 years. It is slightly more common in boys than in girls. Symptoms include anemia, hemorrhage, fever, infection, and hepatosplenomegaly.The clinical manifestations of MDS vary widely and increase in severity as the disease progresses.
1. Anemia
Most of the children have different degrees of anemia, and a small number of children only have bleeding and fever without anemia.
2. Bleeding
The incidence is 23%～95%, mostly mild skin and mucous membrane bleeding. When the disease progresses to the late stage, there may be serious bleeding, and even cerebral hemorrhage and death.
3. Fever and infection
Patients are prone to infections due to decreased granulocytes or abnormal function, and fungal infections are often found in the late stage of the disease, and sepsis is often a complication of the end stage of the disease and the main cause of death.
4. Enlargement of liver, spleen and lymph nodes
10%～76% can be seen, mild-moderate hepatomegaly, splenomegaly, hepatomegaly is more common than splenomegaly, lymph node enlargement is less common, accounting for 0%～27%, the degree of enlargement is not significant.
Examination
1. Blood tests
(1) Blood routine More than 90% of patients have anemia, and 50% of patients have decreased total blood count. Hemoglobin F may be increased. Platelets are mildly decreased and occasionally increased. Most children have a white blood cell count <5×109/L, and half of the patients have an absolute neutrophil count <2×109/L. Those with leukopenia tend to have an increased proportion of lymphocytes.
(2) Blood smear Erythrocytes are macrocytic or normocytic, erythrocyte volume is large, MCV is often >95/fl. Cell size varies, and giant erythrocytes are occasionally seen. The cells are of variable size, occasionally huge erythrocytes are seen, and anomalous erythrocytes, punctate colored cells, HJ bodies and nucleated erythrocytes are seen, often with Pelger-Hut leukocyte abnormality and annular nuclei, and the cytoplasmic specific granulocytes are reduced or absent. Naïve granulocytes and degranulation are seen. Platelets on blood smears were of uneven size, occasionally giant platelets were seen, and in some patients platelets were loosely present and could not be aggregated into clusters. Some patients have loose platelets that do not aggregate into clusters. Individual patients have lymphoid megakaryocytes or mononuclear megakaryocytes in the blood smear.
2. Bone marrow examination
(1) Bone marrow image: Bone marrow proliferation is active, and the erythrocyte lineage has obvious megaloblastic changes, showing “old plasma and young nuclei”, multinucleation, nuclear fragmentation, and strange nuclear morphology, and binucleation is characterized by odd-nucleated erythrocytes and giant erythrocytes. The granulopoietic system is stagnant, with unbalanced nucleoplasmic development and binucleated granulocytes, and the RA and RAS red systems are hyperproliferative, while the granulopoietic system is relatively diminished, with reduced or inverted granulopoiesis and increased numbers of young and medium-sized granulocytes. In RAEB-T there may be an increase in the granulocyte system and a decrease in the red system. Granulocytes at all stages are seen to be binucleated, with binucleated cell cytosol approximately double the normal, which is characteristic for the diagnosis of MDS. Monocytes are increased, megakaryocytes are mostly increased or normal in number, and megakaryocytes are decreased in about 1/4 of patients. There are lymphoid megakaryocytes, mononuclear megakaryocytes, multinuclear megakaryocytes, large mononuclear megakaryocytes, binucleated megakaryocytes, or multifollicular megakaryocytes in a variety of different morphologies. Among them, lymphoid cells are the most characteristic.
(2) Bone marrow biopsy may show abnormal localization of granulomatous immature preinvasive cells (AL-IP). ALIP positive patients have a short survival period. ALIP can also be seen in bone marrow smears.
(3) Bone marrow histochemical staining Neutrophils have decreased peroxidase and alkaline phosphatase, monocytes have decreased nonspecific lipase and acid phosphatase, and iron granulocytes have increased.
(4) Immunophenotyping Flow cytometry (FC) for immunophenotyping can quantitatively and qualitatively evaluate hematopoietic cells and may be the most promising method for diagnosing MDS. FC is especially useful when the characteristics of primitive cells and pathological hematopoiesis are not significant and there is a lack of cytogenetic evidence. For example, decreased mean fluorescence intensity of CD38 expression on CD34+ cells can be used as a surrogate indicator for the diagnosis of abnormal cells in MDS. The use of FC scoring system and FC assessment of telomere dynamic changes (length of telomeres, telomere fluorescence intensity of granulocytes and CD34+ cells) are helpful in the prognosis of MDS.
3. Chromosome examination
Chromosomal abnormalities are found in 30% to 50% of children with MDS, mostly in the number of chromosomes and less than 10% in the structure of chromosomes, with monosomy of chromosome 7 being the most common, accounting for about 30% of cases, followed by trisomy of chromosome 8 and trisomy of chromosome 2l, and 5q- being very rare. Those with abnormal karyotypes have a high likelihood of transforming into leukemia.
4. Progenitor cell culture
Bone marrow progenitor cells are cultured in vitro, and some of them resemble leukemia cell growth, with low or absent colony formation of CFU-GM, CFU-MK, and CFU-E. Small clumping type, no growth type and significantly elevated clumping ratio are all pre-leukemic growth types, suggesting a poor prognosis.
(1) Multidirectional progenitor cells (CFU-MIX) Most of them show poor growth, suggesting that MDS lesions begin with pluripotent stem cells.
(2) Granulosa-monocytic progenitor cells (CFU-GM) mostly show decreased colonization, increased clustering, and increased cluster-to-colony ratio.
(3) Erythroid progenitor cells (CFU-E and BFU-E) Mostly thought to have decreased production of both CFU-E and BFU-E, with no increase in BFU-E after removal of T-cells from the culture: suggesting that the decrease in MDS erythroid progenitor cells is not due to suppressive effects of T-cells.
(4) Megakaryotic progenitor cells (CFU-MK) The growth is related to FAB typing. RA and RAS have better CFU-MK growth, about half of the colonies are normal, and most colonies of RAEB, RAEBT and CMML have reduced or no growth.
5.Molecular biology
Methylation studies of RAEB or RAEB-T in children have shown that more than 50% of children have hypermethylation of the CDKN2B(p15) gene or the CALCA gene, with a frequency similar to that of MDS in adults.Although the relationship between methylation and MDS is not known, it has become an important area of exploration for the early diagnosis of MDS.
6. Other
Application of CD41 monoclonal antibody to bone marrow smear or bone marrow section for immunoenzymatic examination can improve the detection rate of pathological megakaryocytes. X-ray and ultrasound are routinely done, and CT examination is done when necessary.
Diagnosis
According to the clinical manifestations and in addition to other diseases with pathological hematopoiesis, the diagnosis can be made on the basis of laboratory examination of peripheral blood with cytopenia of any one or two lineages or whole blood cells, occasional leukocytosis, nucleated red blood cells or giant red blood cells, or other pathological hematopoiesis phenomena, and the diagnosis can be made by the bone marrow with pathological hematopoiesis of blood cells from three or two lineages or any one of the lineages.
In 2003, Hasle et al. proposed a WHO typing standard for MDS in children by referring to the WHO diagnostic typing standard for adult MDS, which can enable more than 95% of children with MDS to obtain a clear diagnosis and typing, and therefore it was continued to be adopted in the latest WHO typing standard in 2008 (Table 1), which is now commonly referred to for diagnosis of MDS in both adults and children.
Differential diagnosis
MDS should be differentiated from the following diseases
1. Aplastic anemia
It is a kind of bone marrow hematopoietic insufficiency due to various causes, and is more common in pediatrics, with the main symptoms being anemia, bleeding and recurrent infections. Clinically, there is a group of syndromes in which there is a decrease in the number of whole blood cells without enlargement of the liver, spleen, or lymph nodes. Karyotype examination can help to distinguish the two.
2. Megaloblastic anemia
Megaloblastic anemia is a disease caused by a biochemical disorder of deoxyribonucleic acid (DNA) synthesis and a slowing of DNA replication. It affects the hematopoietic cells of the bone marrow – erythrocyte, granulocyte and megakaryocyte lineages, resulting in anemia and even thrombocytopenia. Bone marrow hematopoietic cells are characterized by asynchronous development and maturation of the nucleus and cytoplasm, with the former being more delayed than the latter, which results in the formation of cells with abnormal morphology, quality, quantity, and function, i.e., megaloblastic degeneration.The bone marrow erythropoietic system of MDS sometimes has megaloblastic degeneration, which makes it easy to confuse it with megaloblastic anemia, but the folate and vitamin B12 are increased in the blood in the case of MDS and are decreased in the blood in megaloblastic anemia. The treatment of MDS with folic acid or vitamin B12 is ineffective, while megaloblastic anemia is effective.
3. Hemolytic anemia
Hemolytic anemia is a kind of anemia that occurs when the destruction of red blood cells is accelerated by various causes and the compensation of bone marrow hematopoietic function is insufficient. The life span of normal red blood cells is 110-120 days. Under normal circumstances, about 1% of senescent red blood cells are phagocytosed and destroyed in the spleen every day, and replaced by newborn red blood cells, so as to maintain the number of red blood cells at a constant level to perform normal physiological functions.In MDS, the bone marrow red blood system is increased, and sometimes the pathological hematopoietic phenomenon is very obvious, with a slight increase in reticulocytes, which is similar to that of hemolytic anemia.In MDS, the chromosomal karyotype abnormality can be found, while hemolytic anemia does not have it. MDS may have chromosomal karyotype abnormalities, whereas hemolytic anemia does not. In addition, hemolytic anemia may have corresponding etiological findings, such as positive Coombs test, positive Ham test, etc., while in MDS, it is mostly negative. reticulocytes firstly rise and then hemoglobin rises after treatment of MDS, while in hemolytic anemia, reticulocytes firstly fall and then hemoglobin rises after treatment.
4. Idiopathic thrombocytopenic purpura (ITP)
Due to the massive reduction of platelet caused by skin, mucous membrane petechiae, hemorrhage, epistaxis, bleeding gums and menorrhagia, children and young people are more common, male to female ratio is 1:2. MDS bone marrow megakaryocytes increase (small megakaryocytes), ITP megakaryocytes are also increased, so sometimes the two are confused, but relying on the clinical treatment of prednisone is effective or not, whether there is a significant pathology in bone marrow, chromosomal abnormalities can be differentiated. However, the two diseases can be distinguished by the effectiveness of clinical treatment with prednisone, the presence of significant hematopoiesis in the bone marrow picture and the presence of chromosomal abnormalities.
5. Bone marrow
Acute myeloid leukemia (AML): AML is the most important differential diagnosis for progressive MDS. Although the peripheral blood and/or bone marrow primitive cell ratio of 0.20 is used as the threshold for determining MDS and acute leukemia, it is easy to confuse MDS and AML from the clinical manifestations and bone marrow diagnosis alone, such as chromosome -7 abnormalities strongly suggesting that MDS, even if the ratio of primitive cells > 0.30, may not be a true primary AML. In patients with cytogenetic evidence for the diagnosis, a repeat bone marrow examination in 2 weeks is recommended. AML is considered a diagnosis in patients with an increase in the number of primitive cells to 0.30 or more, and AML is usually diagnosed in patients with a markedly enlarged liver and spleen, especially with elevated leukocytes.
Complications
1. Bleeding
Severe internal bleeding, such as urinary tract, gastrointestinal tract, respiratory tract and central nervous system bleeding, especially intracranial hemorrhage often endanger the life of children; if repeated blood transfusion can lead to ferrous hemosiderosis.
2.Infection
In mild cases, there may be persistent fever, weight loss, loss of appetite, recurrent oral mucosal ulcers, necrotizing stomatitis and pharyngitis, and sepsis may occur, and the infection may aggravate the hemorrhage and lead to death.
3.Other
Growth retardation in young children and adolescents with severe anemia.
Treatment
Determination of the treatment program needs to be carried out after a clear diagnosis, such as without a clear diagnosis that is hastily carried out treatment will bring great difficulties to the subsequent diagnosis. The goal of treatment for pediatric MDS patients is to achieve a cure, which poses a higher demand and a more difficult challenge to the goal of prolonging life with adult supportive therapy. Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for progressive MDS in children. Before choosing a treatment regimen, it is important to identify patients with AML with chromosome 7, which may not be true primary AML, even if the proportion of primitive cells is >0.30. These patients have features of MDS rather than primary AML, and this group of patients responds well to drug therapy. HSCT after 1st remission is not required.
Given that the subtypes are different stages of development of a disease, treatment should vary according to the stage of the disease. Generally, the principle of administering treatment according to stage should be followed.
1. Supportive treatment
Children with MDS are highly susceptible to complications related to hematopoiesis, so active supportive therapy should be emphasized at all stages of the disease, including component blood transfusion and anti-infection. Stanozolol, glucocorticoids, recombinant interleukin 3, androgens and anabolic hormones, colony-stimulating factors, etc. can also be used.
2. Induction of differentiation
Cis or all-trans retinoic acid, interferon alpha, indocyanine, tritiated alkaloids, vitamin D3, etc. or combined drugs can be used.
3.Chemotherapy
Small-dose cytarabine, azulene, idarubicin, etoposide, small-dose trichostatin, pedunculated glycosides and combined chemotherapy can be used.
4. Hematopoietic stem cell transplantation
HSCT is the only cure for the disease, and its 3-year disease-free survival rate is close to 50%. Immunosuppressants such as leucovorin, cyclophosphamide, melphalan and HSCT with all-matched related or unrelated donors are the mainstay of treatment for MOS in children. However, they are rarely used in China because problems such as bone marrow sources have not yet been fully resolved. Umbilical cord blood and placental blood stem cell transplantation, will replace bone marrow transplantation. In patients with MDS secondary to cancer treatment, it is recommended that transplantation should be performed at the early stage of RAEB or RAEB-T. Children with RC with chromosome 7 monosomy or complex chromosome karyotype abnormality should undergo HSCT as early as possible after diagnosis if they have HLA-matched sibling donors or unrelated donors, and other children with RC should undergo HSCT as early as possible after diagnosis if they have HLA-matched sibling donors. children with progressive MDS (RAEB and RAEB-t) should undergo HSCT as early as possible after diagnosis with HLA-exactly matched sibling donors and unrelated donors or 1-locus-mismatched unrelated donors, and haploinsufficiency HSCT may be considered if the disease progresses.
Prognosis.
In pediatric MDS, thrombocytopenia and >5% primitive cells suggest low survival. Complex chromosomal karyotype abnormalities are the most significant factor affecting the prognosis of progressive MDS in children. MDS progresses to MDR/AML at varying rates, but retains the biological characteristics of MDS, is insensitive to chemotherapy, and has a very poor prognosis. Most patients with MDS die from a variety of complications related to abnormal bone marrow hematopoiesis before progressing to leukemia. Spontaneous remission of MDS in children has occasionally been reported and has been limited mainly to young children with chromosome 7 abnormalities. MDS in children progresses rapidly from RAEB to RAEBT and leukemia, and has a poor prognosis, with some children dying from infections and bleeding. The prognosis of MDS in children is related to many factors. For all children with MDS, gender and age have no prognostic significance, but for CMML, the younger the age, the better the prognosis, and the survival of those younger than 2 years old is significantly longer than those older than 2 years old. Platelet counts, blood HbF levels and cytogenetic alterations that are evident at the time of initial diagnosis affect the prognosis of MDS in children.The FAB phenotypes of MDS, i.e., RA, RAS, RAEB, and RAEB-T, are stages of the disease rather than separate phenotypes, with some cases of RA evolving into RAEB, then RAEB-t, and then leukemia; and some cases of death due to hemorrhage or infection while in RA or RAEB. MDS evolves into acute granulocytic leukemia except for a few acute lymphoblastic leukemias, which are seen from M1 to M6, with M1 and M2 being the most common. Because of the different types, there are more treatment measures, so the efficacy is not good, comprehensive treatment may improve the prognosis. The incidence of MDS in children is low, the risk of progression to leukemia is high, and a high degree of heterogeneity exists. Despite the fact that there are many treatments applied to MDS in children, the therapeutic effect is not satisfactory. In the future, it is necessary to conduct multicenter joint research on the nature of MDS, pathogenesis and diagnostic typing criteria, especially for progressive MDS with poor therapeutic efficacy, in order to provide a more effective diagnostic basis and treatment for clinical diagnosis and treatment.
Prevention
Avoid contact with various chemical substances, ionizing radiation, viruses and other harmful factors that cause leukemia, avoid environmental pollution, especially indoor environmental pollution, and use cytotoxic drugs cautiously, such as POTOX, chlorpromazine chloramphenicol. Do a good job of eugenics to prevent certain congenital diseases, such as trisomy 21, Fanconi anemia.
If there is pallor, bleeding, fatigue, fever, bone pain, should go to the hospital in time, should follow the doctor’s instructions for blood tests, if necessary, follow the doctor’s advice to do bone marrow examination and bone marrow biopsy, in order to be able to diagnose and treat in time.MDS is closely and intimately related to the emotions, the emotional optimism, mental happiness is extremely meaningful to prevent the disease.