I. Symptoms and signs
Approximately 20% of patients with multiple myeloma may be completely asymptomatic and are detected by physical examination or hematological examination for other diseases. Most patients have non-specific symptoms such as fatigue, fatigue, weakness, weight loss or one or more symptoms and signs caused by abnormal proliferation of plasma cells affecting the corresponding organs and tissues, such as hematological manifestations, neuropathy, bone lesions, infection, abnormal function of various organs, etc.
(i) Hematologic manifestations.
At the time of diagnosis about 60% of patients have anemia, 15% have leukopenia, and 15% have decreased platelets. Nucleated erythrocytes and naive leukocytes are seen in the peripheral blood. The main cause of anemia is the inhibition of the growth of the erythroid lineage by the massive growth of tumor cells in the bone marrow. Other factors such as abnormal renal function, decreased erythropoietin, bleeding and the diluting effect of excess abnormal immunoglobulins in the blood aggravate the anemia. Patients have systemic symptoms such as dizziness and weakness, and a few have a tendency to bleed.
(ii) Abnormal renal function.
It is a serious complication of multiple myeloma. Both acute or chronic renal function abnormalities may occur. Renal function abnormalities account for 15-20% at diagnosis and develop to 50% during the course of the disease. Uremia is one of the leading causes of death in multiple myeloma. The causes of abnormal renal function are multiple, the most common being interstitial nephritis due to blockage of the renal tubules by light chains, the so-called myeloma kidney. Another major cause is pre-renal azotemia due to hypercalcemia causing osmotic diuresis and hypovolemia. Other causes of renal failure due to multiple myeloma include the application of nonsteroidal anti-inflammatory drugs for pain relief, hyperuricemia, toxicity of chemotherapeutic drugs to the kidney, intravenous use of radiographic contrast agents, calcium deposition in the kidney, and renal calculi.
(iii) Bone destruction.
Multiple myeloma shows multiple osteolytic changes in 70% of cases. Single osteolytic destruction or extensive bone thinning accounts for 15%. 15% of patients have no significant abnormal radioactive concentration in ECT. The most common sites of bone destruction are the skull, spine, ribs, pelvis, and proximal end of long bones. In contrast, the sites of fracture were vertebrae, ribs, femur, sternum, ilium, humerus, and clavicle, in that order. Compression fractures of the thoracolumbar spine are the main cause of paraplegia. It is currently believed that multiple myeloma bone destruction is caused by multiple factors, the main mechanism being the imbalance between osteogenesis and osteolysis. Tumor cells, stromal cells, osteolytic cells, osteoblasts and factors regulating the microenvironment such as IL-1b, TNF-β, lymphotoxin, IL-6, colony-stimulating factor, vascular endothelial growth factor, specific matrix metalloproteinases, as well as the recently discovered Osteoprogerin and its ligands TRANCE and RANK ligands all play a role in bone destruction. (d) Hypercalcemia: The osteolytic activity is increased and the osteogenic capacity is reduced, causing osteolytic destruction of multiple skeletal sites throughout the body.
(iv) Hypercalcemia.
Bone destruction and cytokine milieu in multiple myeloma can cause hypercalcemia. The incidence of hypercalcemia in Europe and the United States is 25%-50% in all stages of multiple myeloma. It is relatively uncommon in the Chinese. The severity of symptoms correlates with the level of free calcium in the blood and the rapidity of the onset of hypercalcemia. A rapid onset of moderate calcium elevation is associated with dullness of sensation and coma. Gradually elevated hypercalcemia, on the other hand, is only mildly symptomatic at calcium levels >3.8 mmol/L. Early signs of hypercalcemia include polyuria, nocturia, thirst, anorexia, fatigue, and weakness. Late symptoms include indifferent expression, irritability, depression, inattention, coma, muscle weakness, nausea and vomiting, abdominal pain, intractable constipation, increased gastric acid secretion, acute pancreatitis, pruritus, blurred vision, etc. Prolonged bed rest can aggravate hypercalcemia. Hypercalcemia is the main cause of renal failure in patients with multiple myeloma. It is also a tumor emergency and should be detected and treated early.
(V) Infection
Abnormal proliferation of monoclonal plasma cells in patients with multiple myeloma inhibits normal immunoglobulin production. Both humoral and cellular immunity are defective, and infection can easily occur. The high doses of corticosteroids used in the treatment of multiple myeloma increase the risk of infection. Pneumonia is the most common infection and previously Streptococcus pneumoniae, Staphylococcus, and Haemophilus influenzae were the most common pathogens. In recent years, gram-negative bacteria are more common. Infection is also a cause of death in multiple myeloma.
(vi) Neurological lesions
About 15% of patients have symptoms of spinal cord and nerve root compression due to epidural multiple myeloma. Vertebral compression fractures can lead to spinal cord compression, paraplegia, or spinal nerve root compression producing radicular symptoms. Intracranial and meningeal multiple myeloma is rare.
(vii) Hyperviscosity
Hyperviscosity is present in 5% of patients with multiple myeloma, with a high incidence in the IgA type and less frequently in the IgG type. Elevated blood viscosity causes tissue stasis and hypoxia, affecting neurological, renal, and pulmonary functions, resulting in corresponding symptoms, neurological disorders, visual impairment, and congestive heart failure.
(H) Amyloidosis
The incidence is 10-15%. Extensive deposition of light chain proteins and polysaccharide complexes in various organ tissues, involving tongue, parotid gland, heart, kidney, nervous system, skin. Causes heart failure, nephropathy, and giant tongue.
(ix) Coagulation disorders
Multiple myeloma has thrombocytopenia and damaged blood vessels. Mucosal skin bleeding with petechial ecchymosis. Death may occur in the late stage of the disease due to intracranial hemorrhage.
(J) Extramedullary plasmacytoma
Relatively uncommon. Masses in the upper respiratory tract, oropharynx, gastrointestinal tract, gonads, breast, spleen, skin, and soft tissues, confirmed by biopsy, and normal bone marrow examination. Extramedullary plasmacytomas rarely occur in the lymph nodes.
II. Examination methods and diagnosis
Multiple myeloma often has multiple organ involvement, so it has multiple non-specific manifestations. The diagnosis is often delayed. Multiple myeloma should be alerted in the presence of the following conditions, for example, an elderly male patient with recent onset of unexplained bone pain, recurrent pulmonary infections, urinary tract infections, anemia, and renal insufficiency.
(I) Clinical examination
Take a careful medical history, including the presence of dizziness, bone pain fracture, recurrent fever and cough, urinary urgency and frequency, drowsiness, thought disorder, hallucinations, anorexia, vomiting, constipation, and nerve root compression symptoms. Careful physical examination should mainly check for anemia, petechiae, petechiae, giant tongue, body masses, superficial lymph nodes, enlargement of liver and spleen, rales in both lungs, skeletal pressure, deformities, and percussion pain in the kidney area. Neurological examination should include the presence or absence of muscle weakness, loss of deep reflexes, nerve root compression symptoms and psychiatric symptoms.
(B) Laboratory tests
1.Hematological examination All patients have varying degrees of anemia, which becomes severe with the aggravation of the disease. Peripheral blood showed normal pigmentation and normocytic anemia. The red blood cells in the blood film were coin-like. White blood cells and platelets were normal or decreased. Blood sedimentation is increased. In plasma cell leukemia, plasma cells account for more than 20% of the total number of blood cells, or the absolute number of plasma cells is higher than 20*109/L.
2, monoclonal protein 80% of patients have a narrow peak of serum protein electrophoresis between β and γ as M protein or M component. Immunoglobulin electrophoresis can further typify multiple myeloma.
3. Serum biochemistry: There may be varying degrees of abnormal renal function. Hypoalbuminemia. Elevated LDH. Alkaline phosphatase is increased in pathological fracture healing.
4. β2 microglobulin The amount of urinary β2 microglobulin reflects the excretory function of renal function and the proliferation of tumor cells. The increase of β2 microglobulin in the case of normal renal function indicates poor prognosis.
5. Urine examination: 40%-70% of patients have positive urine Bence Jones protein (coaguloplasmin). This is a small molecule protein, filtered out by the glomerulus. pH 4.5-5 urine heated to 50-60 ℃ appears cloudy precipitate protein coagulation, continue to heat to 90 ℃, such protein will dissolve. When the urine is cooled to 50-60°C, protein coagulation will occur again.
Bone marrow examination: 2% plasma cells in normal bone marrow and 15% plasma cells in bone marrow smear is one of the bases to confirm the diagnosis of multiple myeloma. Multiple myeloma involves the bone marrow in a lamellar pattern. Plasma cells are unevenly distributed, diffuse, focal, mesenchymal or a mixture of these conditions. The bone marrow in plasma cell leukemia shows diffuse replacement of normal hematopoietic cells by plasma cells. The morphology of plasma cells may range from naive to mature. The degree of differentiation and diffusion of myeloma cells determines the prognosis. Those with poor differentiation have a poor prognosis and a short survival period. Multiple punctures at multiple sites or at sites with positive imaging may increase the positive rate.
(iii) Imaging examination
1.X-ray examination There are three main manifestations, namely diffuse osteoporosis, which mainly occurs in the spine, ribs, and pelvis. Typical worm-like, chisel-like changes, skull, pelvis, spine, ribs, long bones are more common. Pathologic fractures, long bones, ribs, and vertebrae are likely to occur.
MRI can accurately evaluate the tumor load, especially sensitive to detect isolated lesions in bone. 95% of multiple myeloma are abnormal in MRI examination.
PET can make a functional diagnosis of small lesions detected by X-ray and MRI.
4.Nuclide Since most of multiple myeloma has only osteolytic changes without osteogenic changes, the negative rate of nuclide bone scan is high. It can be positive at the site of fracture, so its role in diagnosis is limited.
Differential diagnosis
Multiple myeloma should be distinguished from the following three diseases.
1. Benign monoclonal immunoglobulinopathy: It is more frequent in elderly people, with M protein in the serum, but no bone destruction, 20% plasma cells in the bone marrow, and negative urine Benzo’s protein. Some patients may develop into multiple myeloma after several years.
Lymphoplasmacytic lymphoma is less common, accounting for 1.4% of all non-Hodgkin’s lymphomas. The median age of onset is 63 years. The proportion of males and females is similar. 73% have bone marrow invasion. Lymph node biopsy reveals a large number of plasmacytoid lymphocytes. Bone marrow aspiration shows lymphocytes.
3.Bone metastasis Multiple osteolytic or osteogenic changes, and cancer cells are seen on bone marrow aspiration. Most of the primary foci can be found. There is no M protein and urine is negative for Benzo’s protein.