Multiple myeloma

Introduction to multiple myeloma Multiple myeloma (MM) is the most common type of malignant plasma cell disease, also known as myeloma, plasma cell myeloma or Kahler disease. It was not until 1889 that Kahler reported cases in detail that multiple myeloma Generally known and recognized by people. Multiple myeloma is characterized by malignant proliferation of monoclonal plasma cells and secretion of a large number of monoclonal immunoglobulins. The incidence rate is estimated to be 2~3/100,000, and the ratio of male to female is 1.6:1. Most patients are >40 years old, and black patients are 2 times white. basic knowledge The proportion of illness: 0.002% Susceptible people: no specific people Mode of infection: non-infectious Complications: hypercalcemia, disturbance of consciousness

Multiple myeloma etiology

(1) Causes of the disease

The etiology of MM has not yet been fully clarified. Clinical observations, epidemiological investigations and animal experiments suggest that ionizing radiation, chronic antigen stimulation, genetic factors, viral infections, genetic mutations may be associated with the pathogenesis of MM, and MM is affected by atomic bombs. And the incidence of occupational or therapeutic radiation in the population is significantly higher than normal, and the higher the dose of radiation, the higher the incidence, suggesting that ionizing radiation can induce the disease, its incubation period is longer, sometimes up to 15 years the above.

Therefore, genetic factors, ionizing radiation, chronic antigen stimulation, etc., may be related to the occurrence of this disease.

(two) pathogenesis

Although it is believed that MM tumor cells mainly express the characteristics of B cells-plasma cells, their origin is malignant transformation of hematopoiesis precursor cells earlier than the pre-B cells.

As for the mechanism of malignant transformation of hematopoietic progenitor cells, it has not yet been fully elucidated. There is a lot of evidence that the occurrence of MM is related to oncogenes.

The relationship between lymphokine cytokines, growth factors, interleukins, colony-stimulating factors and myeloma has been paid attention to in recent years. The process of proliferation, differentiation and maturation of B cells is related to various lymphokines. The abnormal regulation of lymphocyte secretion may be related to the pathogenesis of MM. Based on this, some people have tried IL-6 antibody to treat MM, and the efficacy has yet to be evaluated.

Osteolytic lesions are one of the important features of MM. It is currently believed that osteolytic lesions are not caused by the direct erosion of bone by tumor cells, but by the secretion of some factors by tumor cells to activate osteoclasts. These factors include IL- 1, lymphocyte toxin, tumor necrosis factor (TNF) and osteoclast activating factor (OAF), OAF activity is mediated by IL-1, lymphotoxin, TNF, these factors can activate osteoclasts, leading to bone Loose, bone destruction, another study pointed out that the long arm loss of chromosome 6 can promote the increase of TNF, OAF, aggravation of osteolytic lesions, interferon gamma and adrenocortical hormone can inhibit the production of these factors.

The diverse clinical manifestations of MM are caused by the uncontrolled proliferation, infiltration and secretion of a large number of monoclonal immunoglobulins by malignant clonal plasma cells: excessive proliferation of bone marrow in the primary site of the tumor cells, leading to inhibition of bone marrow hematopoietic function; Extensive infiltration of tumor cells may involve lymph nodes, spleen, liver, respiratory tract and other parts, causing dysfunction of affected tissues and organs: some factors secreted by tumor cells cause osteolytic lesions and related symptoms; a large number of monoclonal immunoglobulins secreted by tumor cells Protein appears in the blood to cause increased blood viscosity and clotting factor dysfunction, while excessive light chain excretion from the kidney causes kidney damage, light chain deposition in tissues and organs causes amyloidosis damage, while normal polyclonal plasma cell proliferation and polyclonal immunity The synthesis of globulin is inhibited, and the immunity of the body is reduced, which is easy to cause secondary infection.

MM most commonly invades bones, and the trabecular bone of the diseased bone is destroyed. The bone marrow cavity is filled with grayish white tumor tissue. The cortical bone is thinned or damaged by corrosion. The bone becomes soft and brittle. It can be cut with a knife and the tumor tissue is cut. Gray-white gelatinous sample, if it is bleeding, it is dark red. The tumor tissue can penetrate the cortical bone, infiltrate the periosteum and surrounding tissues. Under the microscope, the tumor cells are diffusely distributed, with low mass, composed of slender fibrous tissue and thin-walled blood vessels. A small number of tumors can be rich in reticular fibers. The tumor cells are plasma cells with different degrees of differentiation. Those with good differentiation resemble normal mature plasma cells. The poorly differentiated cells resemble tissue cells, with large cell bodies, irregular shape, and cytoplasmic blue staining. The paranucleus is not obvious, the nucleus is large and the chromatin is fine. It contains 1 or 2 nucleoli. It can be seen in binuclear or multinuclear tumor cells. There are also tumor cells in the focal distribution. Extramedullary infiltration is more common in the liver, spleen, lymph nodes and others. Reticuloendothelial tissue, also found in kidney, lung, heart, thyroid, testis, ovary, digestive tract, uterus, adrenal gland and subcutaneous tissue. In some cases (8% to 15%), the tumor tissue and organs have amyloid Substantial deposition, ie immunoglobulin light chain deposition, stained with Congo red, showing special green and dichroism under ordinary light microscope and optical microscope, respectively, can be identified as light chain by immunofluorescence, in this amyloid There are foreign body giant cell reactions around the material deposition. Commonly affected organs are tongue, muscle, digestive tract, kidney, heart muscle, blood vessels, joint capsule and skin.

Multiple myeloma prevention

The occurrence of this disease is related to the environment, diet and other factors, so prevention of the disease, enhance the patient's physical condition, actively treat chronic diseases, avoid contact with radiation and chemical poisons, and have important significance for the prevention and treatment of diseases.

First of all, contact with carcinogenic factors should be avoided. If there is suspicious contact history or symptoms, regular physical examination should be carried out for early detection and timely treatment. Patients should participate in appropriate regular activities to reduce decalcification, pay attention to personal hygiene and prevent infection, especially Pay attention to the cleansing of the oral mucosa and skin to prevent colds.

Multiple myeloma complications Complications, hypercalcemia, disturbance of consciousness

1. Fracture: pathological fracture, common in skull, pelvis, ribs, spine bone fractures.

2. Hypercalcemia: The incidence of myeloma with hypercalcemia in European and American patients can reach 30% to 60%, clinical manifestations of loss of appetite, nausea, vomiting, polydipsia, polyuria, coma.

3. Renal damage: It is a common and important complication of MM, and it is also one of the main causes of death. Acute and chronic renal failure is one of the important complications of multiple myeloma, and it is also an important clue in diagnosis. Occurs at any stage of multiple myeloma.

4. High-viscosity syndrome: The incidence rate is 10% in MM patients, often showing decreased vision, disturbance of consciousness, central nervous system disorder, heart failure and so on.

5. Hematological complications: anemia, bleeding, thrombosis.

6. Infection: Recurrent infections, fever, such as skin infections, lung infections, etc. during the course of the disease.

7. Amyloidosis: cause corresponding clinical manifestations, including tongue hypertrophy, parotid swelling, cardiac hypertrophy, heart enlargement, diarrhea, peripheral neuropathy, hepatosplenomegaly and so on.

8. Nervous system damage: The incidence of MM with neurological damage is 28.6% to 40%, including spinal cord compression, nerve root spinal cord compression and so on.

Multiple myeloma symptoms Common symptoms Chisel-like changes in skull destruction Urine protein Bone pain Osteoporosis Diffuse Osteoporosis Bone destruction Joint pain Skeletal mass Joint swelling Heart stab amyloid

Clinical manifestation

Slow onset, some patients can be asymptomatic for a long time, but serum protein electrophoresis found a monoclonal immunoglobulin (IG) peak, or urine light chain positive, called "pre-myeloma", this period can be up to 3 ~5 years. The main clinical manifestations are divided into the following two categories:

Myeloma cells infiltrate various tissues

1 Infiltration of bones: The most frequently invaded bones are the proximal ends of the skull, ribs, sternum, spine and long bones of the extremities. Due to the infinite proliferation of tumor cells in the bone marrow cavity, diffuse osteoporosis or limited bone destruction, Bone pain is the most common early symptom, the most common in the waist, followed by the sternum, ribs and limb bones. The pain can be intermittent or migratory at the beginning, and it is persistent and persistent, with local tenderness. Uplift or fluctuating; can be associated with pathological fractures, often not in the weight-bearing part, often several fractures occur simultaneously, X-ray examination can find typical multiple osteolytic lesions, diffuse osteoporosis, pathological fractures, etc. Helps diagnose.

2 Infiltration of bone marrow: tumor cells proliferate in the bone marrow, causing significant changes in bone marrow, decreased proliferation, active or significantly active, characterized by myeloma cells accounting for 10 to 90%, cell size varies, diameter 15 ~ 30m Oval or round, cytoplasm rich, dark blue or bright blue, may have vacuoles, the nucleus transparent area is not obvious, the nucleus is round or elliptical, on one side of the cell, the chromatin is coarse mesh , containing 1 to 2 nucleoli, large and obvious, sometimes 2 to 3 nuclei can be seen in a cell. Mature red blood cells are often arranged in a string, in the peripheral blood, it is characterized by progressive normal cells, normal pigmented anemia, In the smear, the red blood cells are in a string shape, the white blood cell and platelet counts are normal or low, and the late stage is a complete blood cell reduction.

3 Infiltration of other organs: due to the fracture of the spine or the compression of the spinal nerve roots by the myeloma itself or the infiltration of the brain and spinal cord, it can cause neuralgia, paresthesia, and even paralysis, due to the infiltration of tumor cells throughout the body, the liver, Spleen, swollen lymph nodes, more common in the liver, can also invade other organs, causing the corresponding clinical group performance, due to bone destruction and bone resorption, a large amount of calcium into the blood, combined with M protein and calcium to bind calcium Increased, can cause hypercalcemia and increased urinary calcium.

The clinical manifestations associated with M protein have the following manifestations:

1 urinary protein, about 40 to 70% of patients with myeloma, Ig light chain appears in the urine, called Bens Jones protein, because the Ig molecule synthesized by tumor cells has more light chains than heavy chains, light chain molecules Small, can appear in the urine from the glomerular filtration, when the light chain is small, it is not easy to detect, and the concentrated urine is electrophoresis, the positive rate is high.

2 ESR increased, increasing to 100mm or more in the first hour.

3 bleeding tendency, thrombocytopenia and M protein-induced blood flow stagnation, vascular wall damage, platelet and clotting factor function disorders, patients often have bleeding tendency, table treatment is now mucosal oozing, skin purpura, late can have viscera or Intracranial hemorrhage has serious consequences.

4 renal failure, due to the deposition of light chain in the renal tubules, hypercalcemia and hyperuricemia, the function of renal tubular reabsorption is impaired, the infiltration of tumor cells into the kidney, etc., the domestic chronic renal insufficiency is the disease One of the salient features is that in the advanced stage of the disease, uremia can be the cause of many deaths.

5 susceptible to infection, the reduction of normal Ig content often leads to the award of immune dysfunction, patients often have repeated infections, lung and urinary tract infections are more common.

6 high viscosity syndrome, a large number of monoclonal Ig improve blood viscosity, slow blood flow, cause microcirculatory disorders, retinal, brain, kidney and other organs are particularly vulnerable to damage, causing dizziness, visual impairment, hand and foot numbness and other symptoms It can cause coma when it seriously affects brain function. This syndrome is more common in IgM type myeloma and macroglobulinemia.

7 Reynolds phenomenon, part of the patient's monoclonal Ig is cryoprecipitated globulin, in the case of cold globulin agglutination precipitation, causing microcirculatory disorders, the occurrence of hand and foot cyanosis, cold, numbness or pain, and symptoms relieved after heat.

8 amyloidosis, a small number of patients with amyloidosis, amyloid deposits widely in tissues, organs and tumors, causing peripheral nerve, kidney, heart, liver, spleen lesions leading to liver, splenomegaly, joint pain, nerve Clinical manifestations such as dysfunction.

1. Bone pain : bone pain is one of the main symptoms of this disease. The degree of pain is different. The early stage is often mild and temporary. As the disease progresses, it can become persistent and severe, and the pain is severe or sudden, often It was suggested that pathological fracture occurred. According to the analysis of 125 cases of MM initial symptoms in Peking Union Medical College Hospital, 80 cases (64.0%) were mainly complained of bone pain. The most common part of the lumbosacral region was the lumbosacral region (28.0%), followed by the thoracic rib (27.0). %), less limbs and long bones (9.0%), a small number of patients have shoulder or limb joint pain, the vast majority (90% ~ 93%) patients have varying degrees of bone pain symptoms throughout the course of the disease, but there are a few The patient has no bone pain at all times.

In addition to bone pain and pathological fractures, bone masses can also appear. The tumor cells infiltrate from the bone marrow, invade the cortical bone, periosteum and adjacent tissues, forming a mass. In multiple myeloma, this bone mass is often multiple. Common parts are thoracic ribs, clavicle, skull, nasal bone, mandible and other parts. Unlike solitary plasmacytoma, the lesions are not only multiple, but the bone marrow has already been violated, and there are a large number of monoclonal immunoglobulins. Secretion of protein.

2. Anemia and bleeding tendency : Anemia is another common clinical manifestation of this disease. According to the analysis of 125 cases of Peking Union Medical College Hospital, the vast majority (90%) of patients have varying degrees of anemia in the course of the disease, some of which (10.4%) The patient is treated with anemia symptoms, and the degree of anemia varies. The general course of disease is mild in the early stage and heavier in the late stage. Hemoglobin can be reduced to <50g/L. The main cause of anemia is malignant hyperplasia, infiltration and exclusion of tumor cells in the bone marrow. Hematopoietic tissue affects hematopoietic function. In addition, factors such as renal insufficiency, repeated infection, and malnutrition can also cause or aggravate anemia.

Bleeding tendency is not uncommon in this disease. Among the 125 cases of Peking Union Medical College Hospital, 8 cases are treated with bleeding as the first symptom, and the bleeding tendency in the course of the disease can reach 10% to 25%. The degree of bleeding is generally not serious. For mucosal oozing and skin purpura, common parts are nasal cavity, gums, skin, visceral hemorrhage and intracranial hemorrhage may occur in the late stage. The cause of bleeding is thrombocytopenia and coagulopathy. Thrombocytopenia is caused by bone marrow hematopoietic function, and coagulopathy Because a large number of monoclonal immunoglobulins cover the surface of platelets and the surface of blood coagulation factors (fibrinogen, prothrombin, factor V, VII, VIII, etc.), affecting its function, causing coagulopathy, abnormal increase of immunoglobulin increases blood viscosity Slow blood flow, damage to capillaries, can also cause or aggravate bleeding.

3. Repeated infection: patients with this disease are prone to infection, especially pneumococcal pneumonia, followed by urinary tract infection and sepsis, viral infection with herpes zoster, common varicella is common, 125 cases of Peking Union Medical College Hospital 18 cases (14.4%) were treated with fever and infection. Most of them were pulmonary infections. Some patients were hospitalized for repeated pneumonia. Further examination was confirmed as MM complicated with pneumonia. For patients with advanced MM, the infection was One of the important causes of death is that the cause of infection is that the normal polyclonal B cells, plasma cells, are proliferated, differentiated, matured, and normal polyclonal immunoglobulin is reduced, while abnormal monoclonal immunoglobulins lack immunological activity. As a result, the body's immunity is reduced, and pathogenic bacteria are taken advantage of. In addition, the abnormal number and function of T cells and B cells, as well as the application of chemotherapy drugs and adrenocortical hormones, also increase the chance of infection.

4. Renal damage: Kidney disease is a common and characteristic clinical manifestation of this disease. Due to the abnormal production of abnormal monoclonal immunoglobulin and the imbalance of the synthesis of heavy and light chains, excessive light chain formation, relative molecules The light chain with a mass of only 23,000 can be filtered from the glomerulus, reabsorbed by the renal tubules, and excessive light chain reabsorption causes damage to the renal tubules. In addition, hypercalcemia, hyperuricemia, hyperviscosity syndrome , amyloidosis and tumor cell infiltration, can cause kidney damage, patients may have proteinuria, Ben-Ben (Bence- Jones) proteinuria, microscopic hematuria, easily misdiagnosed as "nephritis", and eventually developed into renal insufficiency Renal failure is one of the causes of death of MM. In most cases, renal failure is chronic and progressive, but in rare cases acute renal failure can occur. The main cause is hypercalcemia and dehydration. When treated promptly, this acute renal failure can also be reversed.

5. Hypercalcemia : elevated blood calcium is due to bone destruction, blood calcium escapes to the blood, renal tubular reduction of calcium exocytosis and the binding of monoclonal immunoglobulin to calcium, the incidence of hypercalcemia In different cases, the incidence of hypercalcemia in patients with MM in Europe and America is 10% to 30%, and when the disease progresses, it can reach 30% to 60%. The incidence of hypercalcemia in MM patients in China is about 16%. Lower than Western countries, hypercalcemia can cause headache, vomiting, polyuria, constipation, severe arrhythmia, coma and even death, calcium deposition in the kidneys cause kidney damage, severe cases can cause acute renal failure, threat Life, so urgent treatment is needed.

6. High viscous syndrome : abnormal increase of monoclonal immunoglobulin in blood, one wrapped red blood cells, reduced the repulsive force between the negative charges on the surface of red blood cells, resulting in aggregation of red blood cells, and secondly increased blood viscosity, especially serum viscosity, blood Poor flow, causing microcirculatory disorders, causing a series of clinical manifestations called high-viscosity syndrome, common symptoms such as dizziness, headache, vertigo, visual impairment, limb numbness, renal insufficiency, severely affecting cerebral blood circulation can lead to Consciousness disorder, epileptic seizures, and even coma, fundus examination showed retinal vein dilatation like a bag-like expansion like "sausage", accompanied by oozing, hemorrhage, due to immunoglobulin wrapping platelets and clotting factor surface, affecting its function, plus blood Flow stagnation damages the capillary wall, so there is often bleeding tendency, especially mucosal oozing (nasal cavity, oral cavity, gastrointestinal mucosa). In elderly patients, blood viscosity increases, anemia, blood volume expansion can lead to congestive heart When exhaustion occurs, the Raynaud phenomenon can also occur.

The occurrence of hyperviscosity syndrome is related to the concentration of immunoglobulin in blood and to the type of immunoglobulin. When the blood viscosity (plasma or serum viscosity) is more than 3 times normal, the concentration of monoclonal immunoglobulin in blood exceeds 30g. /L, prone to high viscosity syndrome, in various immunoglobulin types, IgM relative molecular mass, shape asymmetry, and aggregation tendency, it is most likely to cause high viscosity syndrome, and second, IgA and IgG3 is prone to form multimers, so it is also more likely to cause hyperviscosity syndrome.

7. Hyperuricemia: elevated blood uric acid>327mol/L is common in MM, 61 cases (67%) of Peking Union Medical College Hospital have hyperuricemia, elevated blood uric acid is due to the decomposition of tumor cells As a result of increased uric acid and decreased renal uric acid, elevated blood uric acid rarely causes obvious clinical symptoms, but can cause kidney damage and should be prevented and treated.

8. Nervous system damage : tumor cell infiltration, tumor block compression, hypercalcemia, high viscosity syndrome, amyloidosis and mechanical compression caused by pathological fractures can all cause neurological diseases and symptoms. Symptoms of the nervous system can be manifested as peripheral neuropathy and nerve root syndrome, and can also be manifested as central nervous system symptoms. Chronic and pathological fractures of the thoracic vertebrae and lumbar vertebrae can cause paraplegia. 12 of 125 patients in Peking Union Medical College Hospital have Nervous system lesions, 3 cases of peripheral neuropathy, 3 cases of nerve root damage, 2 cases of intracranial damage, 4 cases of paralysis caused by spinal cord compression.

9. Amyloidosis : The complex of the light chain and polysaccharide of immunoglobulin is precipitated in tissues and organs, which is the amyloidosis of the disease. The affected tissues and organs are often extensive, tongue, parotid gland, skin, heart muscle, gastrointestinal tract. Peripheral nerve, liver, spleen, kidney, adrenal gland, lung, etc. can be involved, can cause tongue hypertrophy, swollen parotid gland, skin mass or bryophyte, cardiac hypertrophy, heart enlargement, diarrhea or constipation, peripheral neuropathy, hepatosplenomegaly Large, renal insufficiency, etc., the diagnosis of amyloidosis depends on tissue biopsy pathology, including morphology, Congo red staining and immunofluorescence, European and American countries report the incidence of amyloidosis in MM 10% to 15% However, the incidence rate in China is 1.6% to 5.6%. The "carpal tunnel syndrome" caused by amyloidosis damage to the median nerve is more common in Western countries, but no report has been reported in China.

10. Hepatosplenomegaly and other: tumor cell infiltration, amyloidosis leads to hepatosplenomegaly, liver is more common in more than half of patients, spleen is found in about 20% of patients, usually liver, mild splenomegaly, lymph nodes are generally not Swelling, a small number of patients may have joint pain, even joint swelling, rheumatoid nodules, amyloidosis of the bones and joints, skin damage such as itching, erythema, gangrenous pyoderma, hairy only found in a small number of patients, Individual patients have xanthomatosis, which is believed to be the result of binding of monoclonal immunoglobulins to lipoproteins.

Multiple myeloma examination

Laboratory tests are important for the diagnosis, classification, clinical stage and prognosis of MM.

1. Peripheral blood : Anemia is seen in the vast majority of patients, and it is aggravated with the progress of the disease. It is generally positive cell anemia, but there may be large cell anemia with macroscopic changes of bone marrow erythrocytes, or may be manifested by blood loss. Small cell hypochromic anemia, red blood cells are often arranged in a money-like manner, and the erythrocyte sedimentation rate is also obviously accelerated, often reaching 80-100 mm/h or more. This is caused by abnormal globulin wrapping the surface of red blood cells to reduce the repulsive force between the negative charges on the surface of red blood cells. As a result, red blood cell aggregation may count red blood cells, making blood type examination difficult.

White blood cell count is normal or decreased, leukopenia is associated with impaired bone marrow hematopoietic function and the presence of leukocyte lectin. White blood cell differential counts often show a relative increase of lymphocytes to 40% to 55%, and individual tumor cells can be seen in peripheral blood smears. A large number of tumor cells should be considered as plasma cell leukemia.

The platelet count is normal or decreased. The cause of thrombocytopenia is the inhibition of bone marrow hematopoietic function and the presence of platelet agglutinin. When the surface of platelets is covered by abnormal globulin, the function is affected and it can be one of the causes of bleeding.

2. Bone marrow : The appearance of myeloma cells is the main feature of MM. The number of tumor cells varies, generally accounting for more than 5% of nuclear cells, and more than 80% to 95%. The bone marrow is generally hyperplastic. The proportion of each system is related to the number of tumor cells. When the proportion of tumor cells is small, the ratio of granulocytes and red blood cell lines can be roughly normal, and the number of megakaryocytes can also be in the normal range; when the number of tumor cells is large, the proportion is larger. At the time, the granulocyte cell line, erythroid cell line and megakaryocyte can be significantly reduced. It is worth mentioning that in some patients, especially in the early stage of the disease, myeloma cells may be focally distributed, and bone marrow puncture in a single site may not detect myeloma cells. At this time, multi-site bone marrow puncture or bone marrow biopsy should be performed to find the tumor cells. The tumor cells are easily located at the tail of the smear. The tail of the smear should be checked.

The morphology of myeloma cells is diverse. The well-differentiated cells are similar in morphology to normal mature plasma cells. The poorly differentiated cells are in the form of typical myeloma cells, and most of the tumor cells are in the shape of young plasma cells or plasmablasts. There are different types of myeloma cells. The typical myeloma cells are larger than the mature plasma cells. The diameter of the cells is 30-50 m. The shape of the cells is irregular. There may be pseudopods, cytoplasmic blue staining, and the paranuclear halo disappears or is not obvious. It can be seen that the vesicle contains ribonucleic acid, the vacuole containing the neutral nucleoprotein in the bubble, and the rod-like body containing the native-peripherin, and the outer layer containing immunoglobulin, and the glycoprotein-containing Russell Small body (Ruseu body), large nuclear, fine nuclear chromatin, one or two nucleoli, a few tumor cells with binuclear or multinuclear, but nuclear division is not common, IgA myeloma cells cytoplasm can be stained by Reiter It is flaming, which is due to the substitution of basophilic glycoprotein by eosinophilic glycoprotein. It is observed that the morphology of tumor cells is similar to that of mature plasma cells, and the progression of tumor cells is slow.

Under transmission electron microscopy, the prominent feature of tumor cells is the increase and enlargement of the endoplasmic reticulum. The Golgi body is highly developed. The enlarged rough endoplasmic reticulum contains amorphous substances, elliptical bodies, and these substances and serum. In the M protein, the developed Golgi contains dense bodies and vacuoles, and the mitochondria also increases, increases, and is rich in sputum. It is often seen that there are vacuoles in the cytoplasm, Russell bodies, crystals, inclusion bodies, and nuclei. Large and round, often on one side, the nuclear chromatin is coarser, the nucleolus is large and polymorphic, and sometimes the inclusion bodies in the nucleus are visible. The nuclear and cytoplasmic maturity are disproportionate. The tumor cells are under transmission electron microscope. Important features.

Using anti-immunoglobulin heavy chain antibody and anti-immunoglobulin light chain antibody, immunofluorescence examination can be found to be positive for myeloma cells, but only contains one heavy chain and one light chain, and its serum M protein (M protein) heavy chain, light chain type is consistent.

3. Serum abnormal monoclonal immunoglobulin : hyperglobulinemia caused by abnormal monoclonal immunoglobulin is one of the important characteristics of this disease, serum albumin is reduced or normal, A/G ratio is often inverted, abnormal monoclonal At the same time that the amount of immunoglobulin is increased, the normal immunoglobulin is often significantly reduced. The methods for detecting abnormal monoclonal immunoglobulin in serum are as follows:

(1) Serum protein acetate fiber membrane electrophoresis: The abnormally increased monoclonal immunoglobulin exhibits a concentrated narrow band, and the image drawn by the density scanner shows a narrow bottom peak with a peak height at least larger than the peak width. More than 2 times, that is, M component (or M protein), which is due to the relative molecular mass of the monoclonal immunoglobulin, the amino acid composition, and the charged charges are completely the same, so that the electrophoresis speed of the electric field is completely the same, M The components may be present in the gamma region (IgG, IgM), beta or alpha 2 region (IgA), depending on the type of monoclonal immunoglobulin, and when the M component is significantly increased, other immunoglobulins and serum albumin are often significantly reduced.

(2) Immunoelectrophoresis: Monoclonal immunoglobulin exhibits an abnormal precipitation arc on immunoelectrophoresis. In the presence of an abnormal heavy chain precipitation arc and an abnormal light chain precipitation arc, another light chain and other types are heavy. The chain is often significantly reduced. According to the results of immunoelectrophoresis, the type of monoclonal immunoglobulin can be determined, and the multiple myeloma can be classified, namely IgG type, IgA type, IgM type, IgD type, IgE type, light chain type, double clone. Or polyclonal, not secreted.

(3) Polymerase chain reaction (PCR): In recent years, PCR technology was used to detect the rearrangement of immunoglobulin heavy chain gene as a marker for malignant proliferation of monoclonal B cells, which is used for the diagnosis and benign reactivity of this disease. The differential diagnosis of immunoglobulin increase, after the detection of monoclonal immunoglobulin by the above method, still needs to be quantified, and currently the rate nephelometry is used to determine the concentration of immunoglobulin.

4. Urine: routine examination often found proteinuria, microscopic hematuria, but the tube type is rare, sometimes visible to the pulp (tumor) cells, the diagnostic significance is the presence of this week's protein in the urine, also known as gelatin protein, The protein coagulates when heated to 50-60 ° C in acidified urine, but is further dissolved by heating. The peri-protein is the immunoglobulin light chain excreted from the kidney. In multiple myeloma, the tumor cells are not only synthesized and Secretion of a large number of monoclonal immunoglobulins, and the ratio of heavy chain to light chain synthesis is imbalanced, often with excessive light chain formation, so the concentration of light chain in blood is significantly increased, the relative molecular mass of light chain is only 23000, can pass the small kidney The bait base membrane is excreted, so the present-period proteinuria occurs. Since the monoclonal plasma (tumor) cytometer can synthesize a light chain ( or chain), the peri-protein is only a light chain, and the immunization is applied. Electrophoresis can determine the light chain of this-week protein. In recent years, the rate-scattering turbidimetric method is used to quantitatively determine the light chain content in urine, which significantly improves the sensitivity and accuracy of urine light chain detection. - The positive rate of weekly protein is 30% 60%, and there is a false positive, and the positive rate of urine light chain quantitative method is nearly 100%, and there is no false positive. Normal humans have two light chains of and in the urine, the content is low, and there is urine. A large number of single light chains, while the other light chain content is reduced or even undetectable, is one of the characteristics of MM.

5. Renal function : Renal function is often impaired, especially in the middle stage, late stage, serum creatinine, urea nitrogen, endogenous creatinine clearance rate determination, phenol red excretion test, radionuclide kidney map and other tests can determine whether kidney function is affected Damage and damage, uremia can occur in the late stage, which is one of the causes of death. When patients have a large amount of this-week proteinuria, intravenous pyelography should be avoided, because the contrast agent may react with this-week protein to cause acute kidney. Functional failure.

6. Blood biochemical abnormalities : blood calcium is often elevated, foreign reports of hypercalcemia in MM incidence rate of 30% to 60%, domestic reported incidence rate of 15% to 20%, blood phosphorus is generally normal, renal insufficiency Reduced phosphorus excretion can cause elevated blood phosphorus, cholesterol can be normal, elevated or decreased, hypercholesterolemia is more common in IgA myeloma, hypocholesterolemia is more common in IgG-type myeloma, alkaline phosphatase can be normal, reduced or Elevated, it was thought that this disease has bone destruction and no osteogenic process, so alkaline phosphatase does not rise, and this is one of the identification points of this disease and hyperparathyroidism, bone metastases, but In recent years, studies at home and abroad have shown that not all MM patients have no osteogenic activity. Some patients may have higher alkaline phosphatase levels than normal. Therefore, the disease cannot be ruled out by elevated alkaline phosphatase levels. Hyperuricemia is The disease is common and can be complicated by urinary calculi.

7. X-ray and other imaging examinations : X-ray examination is of great significance in the diagnosis of this disease. The X-ray manifestations of this disease are as follows: 1 diffuse osteoporosis: tumor cell infiltration and activation of tumor cell secretion Osteoblast factors (IL-1, lymphotoxin, TNF, OAF) cause generalized osteoporosis, vertebrae, ribs, pelvis, skull often show obvious, also seen in the long bones of the extremities, 2 osteolytic lesions: bone Further development of loose lesions results in osteolytic lesions, multiple round or oval, sharp and sharp edges like perforated osteolytic lesions are typical X-ray signs of the disease, common in skull, pelvis, ribs, vertebrae Occasionally in the bones of the limbs, 3 pathological fractures: fractures occur on the basis of bone destruction, most commonly in the lower thoracic and upper lumbar vertebrae, mostly as compression fractures, followed by ribs, clavicle, pelvis, occasionally in the limbs 4 bone sclerosis: this type of lesion is rare, generally manifested as localized bone sclerosis, appearing around osteolytic lesions, diffuse osteosclerosis is rare, IgD type myeloma is more likely to be complicated with osteosclerosis -bone imaging is one of the methods used to examine bone abnormalities in recent years. In this disease, osteolytic lesions show radiation concentration in the lesions. This method can show the bones of the body at one time and is more sensitive to X-rays. X-rays can only show lesions when the bone decalcification is more than 30%, while -bone imaging can show signs of radiation concentration in the early stage of the lesion, but it is worth noting that -bone imaging is sensitive. High, but the specificity is not high, any increase in bone metabolism can lead to radiation concentration signs, so should pay attention to identification, CT and magnetic resonance imaging (MRI) are also used for the diagnostic examination of this disease, especially when Myeloma invades the central nervous system or spinal fractures. In the spinal cord and nerve roots, CT and/or MRI can provide important information for diagnosis.

8. B-ultrasound: renal function damage, urinary stones, cardiac hypertrophy can be prompted.

9. Radionuclide : A renal map can determine the extent of renal impairment.

Diagnosis and diagnosis of multiple myeloma

diagnosis

The main basis for the diagnosis of this disease are: M protein peaks appearing in serum protein electrophoresis; bone X-ray examination shows multiple osteolytic changes; a large number of myeloma cells are found in bone marrow smears, if two of the three are positive, combined with clinical manifestations , you can make a diagnosis.

The clinical manifestations of multiple myeloma are diverse, multivariate, easy to be confused with other diseases, and the incidence of misdiagnosis and missed diagnosis is high. Therefore, the development of diagnostic criteria for multiple myeloma has important clinical significance, multiple myeloma The diagnosis should be based on a comprehensive analysis of the patient's clinical symptoms, signs and related laboratory tests (focusing on bone marrow, M component and bone lesions). When the diagnosis of multiple myeloma is determined, in order to develop the correct The treatment strategy needs to further clarify the classification and clinical stage of multiple myeloma and evaluate its prognostic factors.

The World Health Organization (WHO) organized relevant experts in 2001 to review the diagnostic criteria for multiple myeloma (MM) after reference to existing diagnostic criteria for multiple myeloma.

1.WHO diagnostic MM standard

(1) Diagnostic MM requires at least one primary criterion and one secondary criterion, or has at least three secondary criteria and must include one and two, and the patient should have progressive disease symptoms associated with the diagnostic criteria.

(2) Main criteria:

1 Increased plasma cells in the bone marrow (>30%).

2 tissue biopsy confirmed plasmacytoma.

3M components: serum IgG>3.5g/dl or IgA>2.0g/d1, urinary-peripheral protein>1g/24h.

(3) Secondary criteria:

1 Increased plasma cells in the bone marrow (10% to 30%).

The 2M component is present but the level is below the above level.

3 have osteolytic lesions.

4 normal immunoglobulin decreased by more than 50%: IgG <600mg / dl, IgA <100mg / dl, IgM <50mg / dl.

2. China's domestic MM diagnostic criteria

Chinese hematologists are based on domestic clinical research results and with reference to foreign diagnostic criteria.

(1) Plasma cells in the bone marrow > 15% with abnormal plasma cells (myeloma cells) or tissue biopsy confirmed as plasmacytoma.

(2) A large amount of monoclonal immunoglobulin (M component) appears in serum: IgG>35g/L, IgA>20g/L, IgD>2.0g/L, IgE>2.0g/L, IgM>15g/L, or The monoclonal immunoglobulin light chain (pre-week protein) in urine is >10g/24h. In a few cases, double-cloning or triple-cloning immunoglobulin can occur.

(3) osteolytic lesions or extensive osteoporosis without other causes.

If the above 3 items are met or the items (1)(2) or (1)(3) are met, the diagnosis is MM, but in the case of diagnosing IgM type MM, in addition to items (1) and (2), Typical clinical manifestations of MM and multi-site osteolytic lesions, only those with (1) and (3) are non-secretory MM, further identification of non-synthetic or synthetic but not secretory, only (1 And (2) (especially those without bone marrow in the bone marrow, young plasma cells), except for reactive plasma cell enlargement and unexplained monoclonal immunoglobulinemia (MGUS).

Looking at the domestic and foreign MM diagnostic criteria, it can be summarized into three aspects: 1 abnormal proliferation of plasma cells in the bone marrow, it must be emphasized that not only the number of plasma cells is increased, but also myeloma cells (primary pulp, young plasma cells) must appear. Because the plasma cells in the bone marrow of reactive plasmacytosis may be >10% and reach 20% to 30%, but no myeloma cells will appear, and the monoclonal immunoglobulin or its light chain appears in the blood and urine. 3 bone changes, namely diffuse osteoporosis and multiple osteolytic lesions, can be diagnosed as MM if they meet the above 3 lesions or meet the 1+2 or 1+3 lesions.

3. Classification

Using serum protein electrophoresis, immunoelectrophoresis, and light chain quantification methods, it can be determined whether myeloma cells secrete monoclonal immunoglobulins and the type of monoclonal immunoglobulin secreted. According to whether the myeloma cells secrete and secrete monoclonal immunoglobulins. Multiple myeloma can be divided into the following eight types depending on the type of protein:

(1) IgG type: the heavy chain of its monoclonal immunoglobulin is chain, the light chain is chain or chain, IgG type is the most common MM subtype, accounting for about 50% of MM, this type has MM Typical clinical manifestations, in addition, normal immunoglobulin reduction is particularly pronounced in this type, with secondary infections being more common.

(2) IgA type: the heavy chain of its monoclonal immunoglobulin is chain, the light chain is chain or chain, and the IgA type accounts for 15%-20% of MM. In addition to the general performance of MM, there are Myeloma cells are flaming, IgA is easy to aggregate into multimers and cause hyperviscosity, and is prone to hypercalcemia and hypercholesterolemia. In serum protein electrophoresis, the M component formed by monoclonal IgA Often in the 2 region rather than the region.

(3) Light chain type: the monoclonal immunoglobulin is a monoclonal kappa chain or a monoclonal chain, and the heavy chain is absent. This type accounts for about 15% to 20% of MM, and the molecular weight of the light chain is only 23,000. It is much smaller than serum albumin (molecular weight 69,000), so there is no M component in serum protein electrophoresis. It is necessary to use immunoelectrophoresis and light chain quantitative determination to detect the presence of a large number of monoclonal light chains in the blood and urine of patients (urine-week Protein-positive), this type of tumor cells often poorly differentiated, rapid proliferation, more common bone damage, and more severe renal damage.

(4) IgD type: the heavy chain of its monoclonal immunoglobulin is chain, and the light chain is chain or chain. It is reported that this type only accounts for 1% to 2% of MM, but this type accounts for about MM in China. 8% to 10%, and it is not uncommon. In addition to the general performance of MM, this type has the characteristics of relatively young age, extramedullary infiltration, and relatively common bone sclerosis.

(5) IgM type: the heavy chain of its monoclonal immunoglobulin is chain, and the light chain is chain or chain. This type is rare, accounting for only about 1% of MM, except for the general clinical manifestations of MM. Its high molecular weight (molecular weight 950,000) and easy formation of pentamers increase blood viscosity, so it is easy to occur high viscosity syndrome.

(6) IgE type: the heavy chain of its monoclonal immunoglobulin is chain, and the light chain is chain or chain. This type is rare. There are only a few reports in the world, and there are no reports in China. According to foreign reports, The serum IgE in this type of patients can be as high as 45 ~ 60g / L, the light chain is mostly chain, osteolytic lesions are rare, but the peripheral blood plasma cells increase, can show signs of plasma cell leukemia.

(7) Double-cloning or polyclonal: This type is rare, accounting for less than 1% of MM. Double-cloning is often monoclonal IgM combined with monoclonal IgG, or monoclonal IgM combined with monoclonal IgA, double-cloning immunoglobulin Most of the chains belong to the same type ( or chain), and even two light chains, kappa chain and chain, and double cloned light chain MM (ie, monoclonal kappa chain combined with monoclonal chain) have case reports, but Rarely, polyclonal (triple or quad clone) MMs are rare, and double-cloned immunoglobulins can be derived either from the secretion of single clonal (tumor) cells or from the secretion of two clonal (tumor) cells.

(8) Non-secretory type: This type accounts for about 1% of MM. The patient has bone marrow cytoplasmic (tumor) cell proliferation, bone pain, bone destruction, anemia, normal immunoglobulin reduction, prone to infection, etc. Clinical manifestations, but no M component in serum, no monoclonal light chain in urine (urinary-peripherin negative), this type of myeloma can be further divided into non-synthetic and non-secretory by immunofluorescence, the former tumor cells are not Synthetic immunoglobulins, the latter's tumor cells have monoclonal immunoglobulin synthesis, but they are not secreted.

Because the classification of MM is related to the clinical diagnosis of MM, and also to the treatment and prognosis of MM, when the diagnosis of MM is determined, the classification should also be clarified.

4. Clinical staging

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Differential diagnosis

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