Multiple Myeloma in the Elderly
Introduction
Introduction to multiple myeloma in the elderly Multiple myeloma is a malignant tumor characterized by uncontrolled proliferation of clonal plasma cells. Proliferating plasma cell infiltration and its products (M-protein, tumor necrosis factor, plasma cytokines, etc.) cause a series of organ dysfunction. . basic knowledge The proportion of the disease: the incidence of this disease in the middle-aged and elderly people over 50 years old is about 0.005%-0.007% Susceptible people: the elderly Mode of infection: non-infectious Complications: anemia, hypercalcemia, renal failure
Cause
The cause of multiple myeloma in the elderly
Application of ionizing radiation and certain chemicals (30%):
The etiology of multiple myeloma is unclear. Possible risk factors include ionizing radiation and the use of certain chemicals, such as pesticides and herbicides. Epidemiological studies have found that ionizing radiation is the most evidenced MM risk factor. The special proto-oncogenes on DNA and DNA may be the main targets of oncogenic ionizing radiation. In the larger dose radiation survivors after the atomic bombing, the MM incidence increases after long-term incubation, and the radiation worker's MM The occurrence of long-term low-dose exposure is associated with a 2-fold increase in the risk of MM compared with the normal population.
Chemicals such as insecticides, benzene and other organic solvents also have a certain relationship with the incidence of MM. Smoking and drinking are considered to be unrelated to the onset of MM.
Genetic factors (20%):
There have been reports of the incidence of twins and family MM, but there is no evidence that MM is a hereditary disease. Many studies have focused on HLA, chromosomal abnormalities, oncogenes and environmental changes related to MM. Studies have shown that HLA- B5, some antigens of HLA-C point, such as: HLA-CS, C2 may also be related to MM. In terms of chromosomal abnormalities, more specific 14q+ abnormalities account for about 32% of MM diseases, and other chromosomal abnormalities are Non-specific, in addition, activation of oncogenes such as N-ras, c-myc, etc., and defects or loss of tumor suppressor genes such as Rb, P53, etc. have a certain relationship with the onset of MM, especially in recent years against apoptosis. The study of the gene bcl-2 has made a further understanding of the onset of MM.
Other factors (10%):
Chronic antigenic stimulation of the immune system such as bacteria and viral infection may play an important role in the pathogenesis of MM, but the results of various studies are inconsistent, further epidemiological studies are needed, and there are reports of MM in high-risk populations of AIDS, but The relationship between the two is unclear.
Pathogenesis
Recent studies have indicated that about 80% of patients have aneuploid myeloma cell population, expressing pre-B common acute lymphoblastic leukemia antigen (CMLLA), and Ruiz Angulles reports that two cases of multiple bone marrow CALLA-positive cells express early to late stages. B cell-associated antigens, such as HL-A-DR, CD20, CD21. and OKT10 surface immunoglobulins; studies using direct bone marrow specimens and cultured bone marrow specimens revealed that the anterior B malignant cell population of myeloma patients co-expressed cytoplasmic , CMLLA, terminal deoxynucleotidyl transferase (TDT) and plasma cell antigen (PCA-2, PC-1), heavy chain and light chain immunoglobulin gene rearrangement confirmed the monoclonality of these cells, immunophenotype and Marker index double labeling indicates that the proliferative activity of B-cells in the past exceeds myeloma cells and may represent stem cells of myeloma. The above results suggest that all blood-based tumors originate from a common tumor-progenitor cell.
Many growth factors are known to be involved in the growth and differentiation of B cells. Interleukin 4 (IL-4) stimulates resting B cells to enter DNA synthesis, IL-5 promotes cell proliferation, and IL-6 induces B cells to finally differentiate into maturity. IL-6 is the most important growth factor for myeloma cells, and IL-6 levels are elevated in advanced patients. The content of C-reactive protein is regulated by IL-6, so it can be reflected indirectly. The amount of IL-6 is simple and easy to observe.
Other growth factors affect myeloma cells through the IL-6 pathway. For example, granulocyte-macrophage colony-stimulating factor (GM-CSF) increases the response of tumor cells to IL-6, thereby increasing the proliferation rate, IL-1, IL-1. And tumor necrosis factor (TNF) can induce the proliferation of myeloma cells to secrete IL-6, stimulate the growth of myeloma cells, and inhibit the factors of myeloma cells with gamma interferon.
Osteolytic damage is one of the important manifestations of this disease. It is believed that osteolytic damage of myeloma is not caused by tumor cell infiltration, but osteoclast activation by osteoclast activating factor (OAF). In the vicinity of myeloma infiltrating lesions, local bone resorption is stimulated, and osteogenic activity is inhibited. OAF activity is IL-1. Lymphatic toxin, TNF-mediated, corticosteroid or gamma interferon can prevent the formation of these cytokines.
The causes of kidney disease are comprehensive, with hypercalcemia, direct infiltration of tumor cells, free light chain and other protein components causing renal amyloidosis, increased production of uric acid, precipitation of uric acid crystals in the interstitial, large amounts of light chain and uric acid It can block the lumen of the renal tubule, resulting in obstructive atrophy of the nephron; the light chain can also directly damage the renal tubular epithelial cells to affect the concentration function, resulting in increased loss of amino acids, sugar, phosphorus, potassium and other electrolytes, namely adult Fanconi syndrome, individual Cases may be associated with nephrotic syndrome. Among the many factors mentioned above, hypercalcemia and light chain injury are most important.
Prevention
Multiple myeloma prevention in the elderly
Multiple myeloma has a high incidence in the elderly, and the specific cause is not very clear, but there are many risk factors that need to be prevented to reduce the incidence.
Ionizing radiation
It is the most important risk factor. For example, almost one-third of the survivors of the atomic bombing area in Hiroshima, Japan, died of multiple myeloma and should be protected against leakage by nuclear facilities and some radioactive materials.
2. Environmental factors
Harmful gases in the atmosphere, exposure to benzene and organic solvents, the working environment is a high risk factor for this disease.
3. Some chronic inflammatory stimuli may cause proliferation or mutation of B-lymphocytes, leading to disease, so it is necessary to actively control infection, improve the body's immunity, and promptly remove foreign antigens.
Complication
Multiple myeloma complications in the elderly Complications anemia hypercalcemia renal failure
Complications include anemia, infection, hypercalcemia, and renal failure.
Symptom
Symptoms of multiple myeloma in the elderly Common symptoms Weak bone destruction Osteoporosis Back pain Inability to bone metastases Thrombocytopenia Repeated unhealed vision Obstructive disorder Bone pain
1. Bone pain is the most common symptom of this disease, the incidence rate is 70% to 80%, the back and rib pain are the most, can be aggravated by activity, persistent local pain or tenderness may have pathological fracture, osteolytic The damage is more common in vertebrae, skull, ribs, clavicle, scapula and pelvis. X-ray shows multiple lesions, bone sparse and pathological fractures.
The bone destruction of this disease is rarely accompanied by new bone formation, so the detection rate of radionuclide bone scan is low. If there is bone pain and the X-ray is abnormal, CT or magnetic resonance imaging can be performed. In order to improve the detection rate, osteolytic damage may cause hypercalcemia, and when the myeloma infiltrates the bone, it may locally bulge and form a mass.
2. Immunodeficiency
The incidence of infection in this disease is significantly increased. Common pathogens include pneumococci, staphylococcus, Escherichia coli and Haemophilus influenzae. The mechanism of immunodeficiency is multifaceted, such as reduced antibody production and reduced granulocyte lysosomes. The granulocyte migration is lower than normal and the complement function is abnormal. In addition, although some patients have normal T cell function, the CD4+ cell subset is decreased, the CD4/CD8 ratio is decreased, and the infection may be accompanied by an increase in C-reactive protein (IL-6 is elevated). It causes tumor cell proliferation and promotes disease progression, so infection is the main cause of death of this disease.
Viral infections have also increased, and herpes zoster is common.
3. Kidney damage
90% of patients may have proteinuria, characterized by no hypertension, almost all light chain, only a small amount of albumin, the positive rate of proteinuria detected by immunoelectrophoresis or immunofixation electrophoresis is 80%, about 50 % of patients had elevated serum creatinine at the time of diagnosis. A total of 130 cases of multiple myeloma were analyzed in Shanghai. Among them, 86 cases were associated with different degrees of renal damage, accounting for 66.2%, and 32 cases were chronic renal insufficiency, acute kidney. The incidence of insufficiency is 1% to 2%, which can occur in the case of normal renal function. The triggering factors are dehydration, acute infection, intravenous pyelography, hypercalcemia, and application of nephrotoxic drugs.
4. Monoclonal immunoglobulin (M-protein)
Serum protein electrophoresis showed that M peak accounted for about 80%, which may be the earliest abnormality found, 10% showed hypogammaglobulinemia, 10% electrophoresis was found to be abnormal, and some 440 cases of multiple bone marrow were collected in some hospitals in China for the past 10 years. The distribution of tumor M-protein typing was as follows: IgG type accounted for 49.3%, IgA type accounted for 20.5%, light chain type (BJ type) accounted for 17.5%, IgD type accounted for 6.6%, double clone type accounted for 1%, and 3% M-protein was not detected at the time of diagnosis, and the remaining 2.1% of patients were not stereotyped. The positive rate of M-protein was 80% in immunoelectrophoresis and concentrated urine samples, and the ratio of : was 2:1. Among IgG and IgA patients 2/3 can appear this week proteinuria, due to different types of M-protein, clinical manifestations are also different, such as IgG, IgA type M-protein has a higher viscosity, high concentration can occur high viscosity syndrome Light chain type has a short course of disease, poor prognosis, and renal insufficiency; IgD myeloma is younger than other types, more common in under 50 years old, urinary light chain is dominated by , short survival time, and easy to merge with bone Cell tumors or extramedullary plasmacytoma, it is reported that China's IgD myeloma is significantly higher than Western countries (1% to 3%).
5. Anemia and thrombocytopenia
80% of patients with this disease may be associated with anemia, usually positive cells are positive pigmentation, thrombocytopenia may also occur, anemia and thrombocytopenia are replaced by normal bone marrow by proliferating tumor cells, but the two are not proportional, so far no confirmed hematopoiesis The presence of inhibitors, recent studies suggest that erythropoietin levels in patients with myeloma anemia are significantly lower, resulting in poor erythropoiesis, effective treatment with recombinant human erythropoietin, neutropenia is extremely rare; coagulopathy may be due to platelet dysfunction or M- Protein and clotting factor interactions.
6. Neurological symptoms are only seen in a small number of patients
Such as spinal cord compression caused by sputum, nerve root pain and defecation disorder; amyloidosis infiltrating peripheral nerve caused carpal tunnel syndrome; high viscosity caused headache, weakness, visual impairment and retinopathy.
7. Others If M-protein forms cryoglobulin, Raynaud's phenomenon, circulatory disorder and gangrene may occur. The incidence of amyloidosis is only about 7% in China. It is characterized by giant tongue, heart enlargement, cardiac arrhythmia, arrhythmia, kidney. Insufficient function, lymph nodes or hepatosplenomegaly are rare.
Examine
Examination of multiple myeloma in the elderly
Blood around
Anemia is generally moderate, normal cells, normal pigmentation, red blood cell size can be seen, there may be a small amount of young particles in the blood, young red blood cells, white blood cells and platelets are normal early, lymphocytes and eosinophils are slightly increased, late often There is a reduction of whole blood cells, multiple bone marrow infiltration and inhibition of chemotherapy drugs. Due to the significant increase of plasma globulin, the red blood cells on the smear are often arranged in a shape of money, and the erythrocyte sedimentation rate is significantly increased. The Weiss method can be as high as 100-150 mm/ h, this is rare in other diseases and causes difficulties in red blood cell count and blood type identification.
2. Bone marrow examination
It has the significance of specific diagnosis. In the early stage of the disease, the bone marrow lesions can be focal and nodular. Therefore, the negative test can not rule out the disease. It should be used for multiple sites. Because the sternum is easy to accumulate, if necessary, the sternum puncture should be Important diagnostic steps, puncture in the site of bone tenderness or X-ray film found lesions, more positive chances, bone marrow nucleated cells are mostly active or active, when the plasma cells are more than 10%, accompanied by morphological abnormalities, should be considered Myeloma may be similar to plasma cells, but the cell size and shape are different, the maturity is also different, the diameter is generally 15 ~ 30m, round to elliptical; the diameter of the core is 5 ~ 7m, biased On the side, there are 1 or 2 nucleoli, the nuclear chromatin is fine, loose, rarely arranged in a wheel-like shape, the light-dyed ring around the nucleus disappears, the cytoplasm is rich or medium, basophilic, dark blue, opaque Foamy, some pulp may have a small amount of azuramide blue particles, acidophilic globular inclusion bodies (russell body), vacuoles of different sizes (such as mulberry cells, morula cells or Mott cells) or rod-shaped bodies, if fine The plastid is filled with large, light blue vacuoles and has a three-dimensional sense. It is called a grape cell. In the myeloma of IgA, flaming plasma cells and thesaurismosis, cytoplasm are also seen. More than a network structure, and can be seen 2 nucleus, 3 nucleus and a few multinucleated myeloma cells, myeloma cells are unevenly distributed in the smear, often into small heaps.
A small number of patients have difficulty in bone marrow puncture because the bone marrow tissue is jelly-like and has a large viscosity. Because the bone marrow tissue is mixed with hyperplasia of tumor cells and poor hematopoietic cells, it is not easy if the needle is located in a poorly proliferated area. Get bone marrow tissue.
Electron microscopy revealed that the rough endoplasmic reticulum of myeloma cells is very rich and pleomorphic; ribosomes are generally reduced, Golgi is developed; mitochondria are generally larger, the number is increased, sputum is high and swells, and the cytoplasm of myeloma cells contains many forms. The inclusion body of the mutated bounded membrane, the inclusion body surrounded by a single layer of membrane, or the bundle-shaped body arranged in parallel with filaments may be the accumulation of storage proteins.
3. abnormal globulin
(1) hyperglobulinemia and M protein appearance: about 95% of patients, serum total protein exceeds normal, globulin increases, albumin is normal or decreased, white/globulin ratio is inverted, on paper or cellulose acetate membrane electrophoresis An abnormal electrophoresis pattern, ie, M globulin, can be seen as an immunoglobulin band with a dense and dense monomodal protrusion. A few bimodal peaks can be distinguished from normal human immunoglobulin light-dyed uniform patterns. In paper electrophoresis analysis, the monoclonal IgG type M globulin can move at the same speed as the gamma protein, the monoclonal IgA type is in the region, the monoclonal IgM, and the IgE type are between the and regions, due to normal IgD and IgE. The concentration is very low, their monoclonal immunoglobulin should be more than 10 times higher than the normal concentration. In the electrophoresis, the peak of the single plant moves in the or region. The application of immunoelectrophoresis can be divided into the following types according to the difference of the M component. :
1 IgG type accounts for 50% to 60%;
2IgA type accounts for 20% to 25%;
3 coagulating protein or light chain type accounts for 20%;
4IgD type accounts for 1.5%, often accompanied by light chain;
5IgE and IgM are rare, accounting for only 0.5% and <0.1%, respectively. In addition, 1% of patients with multiple myeloma can not isolate M protein in serum, called "non-secretory" myeloma, a few Cold globulin is still present in the patient's serum, which self-precipitates at 4 ° C but re-dissolves at 37 ° C.
(2) This week (coagulation) protein: This week, the protein is composed of excess light chain, the molecular weight is small, can be discharged from the urine through the mesangial membrane, 50% to 80% of myeloma patients can be positive, when urine When the liquid is gradually warmed to 45-60 ° C, the protein begins to solidify this week, and then re-dissolved when heated to the boiling point; precipitation occurs again after cooling to below 60 ° C. Protein electrophoresis can be in the region or in the and regions. There are 1 to 2 protein bands in this week. This week, the protein comes from the blood. Because of the large amount of leakage in the urine, the peak of the serum protein electrophoresis can not be measured. In the early stage of the disease, the protein often appears intermittently in this period. Frequently appear, so this week protein negative, can not rule out the disease, should check urine repeatedly, it is best to check 24h urine or 300 times the urine concentration, in order to improve the positive rate of protein detection this week, in addition, this week protein is not the disease Specific, such as chronic leukemia, bone metastases, multiple sarcoma, polycythemia, senile osteomalacia and fibrocystic tumors, can also be positive.
4. Other
Due to extensive destruction of bone, a large amount of calcium enters the blood circulation, and hypercalcemia occurs. Blood phosphorus is mainly excreted by the kidneys. Therefore, when the renal function is normal, blood phosphorus is normal, but in advanced patients, especially renal insufficiency, blood phosphorus can be significant. Elevated, because myeloma is mainly bone destruction, and no new bone formation, serum alkaline phosphatase is mostly normal or slightly increased, which is significantly different from bone metastasis, due to the decomposition of tumor cells, nuclear protein damage, Hyperuricemia can occur, causing uric acid stones in severe cases. About 70% of patients suffer from nephron destruction and renal dysfunction due to protein binding to free calcium in the renal tubules, sedimentation and protein accumulation in glomerular capillaries. Proteinuria, tubular urine and hematuria, serum urea nitrogen and serum creatinine may increase, and blood cholesterol levels may be significantly reduced in some patients, which may increase after treatment.
Imaging examination: multiple myeloma occurs in the spine, ribs, skull, sternum and pelvis and other parts containing red bone marrow, which is the most active part of adult hematopoiesis, so the spinal cord has the most opportunities, long bones such as the femur and tibia The end is usually only affected in the late stage. It is rare to involve the knee and elbow. About 10% of the patients have X-ray positive findings.
Skeletal X-ray performance can be of the following three types:
Diffuse osteoporosis
Early patients are prone to diffuse osteoporosis in the spine, ribs and pelvis. For example, microscopic radiographs have been shown to reduce and destroy trabecular bone, and some have osteosclerosis.
2. Osteolytic destruction
Multiple circles are visible, and the edges are clear, such as drill-like or rat-bite-shaped bone defect shadows, commonly found in the skull, pelvis, spine, femur, humeral head and ribs.
3. Pathological fracture
Often located in the ribs and spine, the spine can be a compression fracture.
Diagnosis
Diagnosis and diagnosis of multiple myeloma in the elderly
Diagnostic criteria
Diagnostic criteria: bone marrow plasma cell infiltration >10% or tissue biopsy confirmed as plasmacytoma, plus any of the following:
1 serum M-protein> 30g / L;
2 urine detected M-protein;
3 osteolytic lesions must be excluded from bone metastases, connective tissue disease, chronic infection or lymphoma.
A new perspective on the diagnosis of this disease: multiple myeloma is difficult to diagnose early, and is easily misdiagnosed. It is often misdiagnosed as orthopedic disease, nervous system disease and kidney disease. Most patients are diagnosed in the late stage and lose the opportunity of early treatment.
If there is unexplained fatigue, anemia, increased erythrocyte sedimentation rate, back pain, osteoporosis or osteolytic lesions or pathological fractures, immunoglobulin abnormalities, hypercalcemia, proteinuria, nephrotic syndrome or renal function this week Incomplete, repeated unhealed infections, peripheral neuropathy, carpal tunnel syndrome, large and hard liver and refractory congestive heart failure should be thought of.
Differential diagnosis
Bone metastases
The bone damage of multiple myeloma is characterized by typical osteolytic destruction. It is more common in the hematopoietic flat bone, the osteogenic activity is low, the bone metastasis is characterized by osteolysis, and the osteotic mixed bone structure is destroyed, so the radionuclide bone Scanning shows mostly in radioactive concentration zones; cancer cells are found by bone marrow puncture or biopsy.
2. Asymptomatic myeloma (SMM)
M-protein>30g/L, bone marrow plasma cells>10%, no clinical symptoms, no osteolytic damage, 3H-TDR labeling index <0.4%, stable for 5 years without development.
3. Reactive plasma cell increase
Found in chronic hepatitis cirrhosis, connective tissue disease, chronic infectious diseases, rheumatoid arthritis, malignant tumors, etc., plasma cells generally do not exceed 10%, the morphology is more mature, the cause can be reduced after removal.
