Multiple myeloma is a hematological tumor with a high incidence, but many friends and medical workers do not know much about this disease. The author summarizes our oncology department’s experience in the diagnosis and treatment of multiple myeloma over the years, and introduces its clinical manifestations here in the hope that you can improve your understanding of it, reduce misdiagnosis and take less detours.
Infiltration of myeloma cells into various tissues
(1) Infiltration of bones. The most frequently invaded bones are the skull, ribs, sternum, vertebrae and the proximal ends of the long bones of the limbs. As the tumor cells proliferate indefinitely in the bone marrow cavity, it leads to diffuse osteoporosis or limited bone destruction. Bone pain is the most common early symptom, most often in the lumbar region, followed by the sternum, ribs and extremity bones. The pain may be intermittent or wandering at the beginning, and then gradually worsen and become persistent. There is localized pressure, elevation or fluctuating sensation; it may be accompanied by pathological fractures, often not in weight-bearing areas, and often several fractures occur simultaneously. X-ray examination can be problematic to find typical multiple osteolytic lesions, diffuse osteoporosis, pathological fractures, etc., which can help in the diagnosis.
②Infiltration of bone marrow. Tumor cells proliferate heavily in the bone marrow, causing marked changes in the bone marrow picture, hypoproliferative, active or markedly active. Characteristically, myeloma cells account for 10-90% of the total number of cells. The cells vary in size from 15 to 30 μm in diameter, are ovoid or round, have abundant cytoplasm, are dark blue or bright blue, may have vacuoles, and have inconspicuous paranuclear hyaline areas. The nucleus is round or oval, on one side of the cell, with coarse reticulation of chromatin, containing one to two nucleoli, large and obvious. Sometimes 2 to 3 nuclei are seen in one cell, and mature red blood cells are often arranged in a money string pattern. In the peripheral blood picture, there is a progressive normocytic, normopigmented anemia. In the smear, the red blood cells are in the shape of strings of money. White blood cell and platelet counts may be normal or low, with advanced manifestations of complete cytopenia.
(iii) Infiltration of other organs. 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 may cause neuralgia, abnormal sensation, or even paralysis. The infiltration of tumor cells throughout the body can cause liver, spleen, lymph nodes and, more often, liver enlargement. Other organs may also be invaded, causing the corresponding clinical group manifestations. Due to bone destruction and bone resorption, a large amount of calcium enters the blood, and the combination of M protein and calcium increases the bound calcium, which can lead to hypercalcemia.
Clinical manifestations related to M protein
There are various manifestations as follows.
(1) Urinary protein, about 40-70% of myeloma patients have light chains of Ig in the urine, called Bence-Jones protein, because the Ig molecules synthesized by tumor cells have more light chains than heavy chains, and the light chains are small and can appear in the urine by glomerular filtration.
(2) Blood sedimentation increases rapidly, to more than 100mm in the first hour.
(③) Bleeding tendency, thrombocytopenia and M protein-induced blood flow retardation, vascular wall damage, platelet and coagulation factor dysfunction, patients often have a bleeding tendency, and the treatment appears as mucosal oozing blood, resulting in serious consequences.
④ Renal failure, due to the deposition of light chains in the renal tubules, hypercalcemia and hyperuricemia so that the function of renal tubular reabsorption suffers, the infiltration of tumor cells into the kidney and other reasons, domestic chronic renal insufficiency is one of the significant features of the disease becomes.
⑤ susceptible to infection, the reduction of normal Ig content often leads to immune dysfunction.
⑥High viscosity syndrome, a large number of monoclonal Ig to improve blood viscosity, causing microcirculatory disorders, retina, brain, kidney and other organs are particularly vulnerable to damage, causing dizziness, numbness in the hands and feet and other symptoms. This syndrome is mostly seen in IgM-type myeloma and macroglobulinemia.
(7) Raynaud’s phenomenon, the monoclonal Ig in some patients is cold precipitated globulin, when cold globulin agglutination precipitation, causing microcirculatory disorders, appearing hand and foot cyanosis, cold, numbness or pain, etc., the symptoms are relieved when hot.
8 amyloidosis, abnormal nerve function and other clinical manifestations.
1.Bone pain
Bone pain is one of the main symptoms of the disease. The pain varies in severity and is often mild and temporary in the early stage, but can become persistent and severe as the disease progresses. The pain is severe or suddenly increases, often suggesting the occurrence of pathological fractures. 64,0% of patients have bone pain as the main complaint, and the most common site of bone pain is the lumbosacral region (28,0%), followed by the thoracic ribs (27,0%), and the long bones of the extremities are less common (9,0%), and a few patients have shoulder or limb joint pain. The vast majority (90-93%) of patients have symptoms of bone pain to varying degrees throughout the course of the disease, but a small number of patients do remain free of bone pain. In addition to bone pain and pathological fracture, skeletal masses may also appear, with tumor cells infiltrating outward from the bone marrow and invading the bone cortex, periosteum and adjacent tissues to form masses.
2.Anemia and bleeding tendency
Anemia is another common clinical manifestation of this disease. According to the analysis of 125 cases in our hospital, the majority (90%) of patients had anemia of varying degrees during the course of the disease, and some of them (10 or 4%) were seen with anemia as the main complaint. The main cause of anemia is malignant proliferation and infiltration of tumor cells in the bone marrow, which crowd out the hematopoietic tissue and affect the hematopoietic function. In addition, factors such as renal insufficiency and recurrent infections can also cause or aggravate anemia.
Bleeding tendency is also not uncommon in this disease. Eight out of 125 cases in Peking Union Medical College Hospital were seen with bleeding as the first symptom, and the bleeding tendency can occur in 10%-25% of cases during the course of the disease. The degree of bleeding is generally not serious, mostly manifested as mucosal oozing and skin purpura, common sites are nasal cavity, gums, skin, and in the late stage may occur visceral bleeding and intracranial bleeding. The causes of bleeding are thrombocytopenia and coagulation disorders. Thrombocytopenia is due to the suppression of bone marrow hematopoietic function, while coagulation disorders are caused by a large amount of monoclonal immunoglobulins covering the surface of platelets and coagulation factors (fibrinogen, prothrombin, factors V, VII, VIII, etc.), affecting their function and causing coagulation disorders. The abnormal increase of immunoglobulins increases blood viscosity, slows blood flow and damages capillaries, which may also cause or aggravate bleeding.
3.Recurrent infections
Patients with this disease are prone to infections, especially pneumococcal pneumonia, followed by urinary tract infections and sepsis. Viral infections such as herpes zoster and peripheral chickenpox are common. Among 125 cases in Peking Union Medical College Hospital, 18 cases (14, 4%) were seen with fever and infection as the main complaints, most of which were pulmonary infections. Some patients were hospitalized for recurrent pneumonia, and further examination confirmed the diagnosis of MM complicated by pneumonia. In patients with advanced MM, infection is an important cause of death. This disease is susceptible to infection because the proliferation, differentiation and maturation of normal polyclonal B cells – plasma cells are inhibited, the production of normal polyclonal immunoglobulins is reduced, and abnormal monoclonal immunoglobulins lack immune activity, resulting in reduced immunity of the body and the entry of pathogenic bacteria. In addition, the number and function of T cells and B cells are abnormal, as well as the application of chemotherapy drugs and adrenocorticotropic hormones, which also increases the chance of infection.
4.Renal damage
Renal lesions are the more common and characteristic clinical manifestations of the disease. Due to the excessive production of abnormal monoclonal immunoglobulin and the imbalance between the synthesis of heavy chain and light chain, too much light chain is produced, and the light chain with a relative molecular mass of only 23,000 can be filtered from the glomerulus and reabsorbed by the renal tubules. In addition, hypercalcemia, hyperuricemia, hyperviscosity syndrome, amyloidosis and tumor cell infiltration can cause renal damage. Patients may have proteinuria, Bence-Jones proteinuria, and microscopic hematuria, which may be misdiagnosed as “nephritis”. Eventually, renal insufficiency develops. Renal failure is one of the leading causes of death in MM. In most cases, renal failure is chronic and progressive, but in a few cases, acute renal failure can occur, mainly due to hypercalcemia and dehydration, which can be reversed if treated properly.
5. Hypercalcemia
Elevated blood calcium is the result of bone destruction causing blood calcium to escape into the blood, reduced renal tubular exocrine secretion of calcium, and monoclonal immunoglobulin binding to calcium. The incidence of hypercalcemia is reported differently, and the incidence of hypercalcemia in MM patients in Europe and the United States is 10% to 30% at diagnosis, and up to 30% to 60% when the disease progresses. The incidence of hypercalcemia in MM patients in China is about 16%, which is lower than that in western countries. Hypercalcemia can cause headache, vomiting, polyuria, constipation, and in severe cases, cardiac arrhythmia, coma and even death. Calcium deposition in the kidneys causes kidney damage, and in severe cases can cause acute renal failure, which is life-threatening and therefore requires emergency treatment.
6.High viscosity syndrome
The abnormal increase of monoclonal immunoglobulin in blood, one wraps red blood cells, reducing the repulsive force between the negative charge on the surface of red blood cells and lead to the aggregation of red blood cells, the other makes the blood viscosity, especially serum viscosity increases, blood flow is not smooth, resulting in microcirculatory disorders, causing a series of clinical manifestations called hyperviscosity syndrome. Common symptoms include dizziness, headache, blurred vision, visual impairment, numbness of limbs, renal insufficiency, and can lead to impaired consciousness, seizure-like epilepsy, and even coma when cerebral blood circulation is seriously affected. Funduscopic examination reveals dilated retinal veins in the form of pouch-like dilatation resembling “sausage”, accompanied by blood leakage and hemorrhage. Because immunoglobulin wrapped platelets and coagulation factors surface, affecting their function, coupled with slow blood flow damage capillary wall, so there is often a tendency to bleeding, especially mucosal bleeding (nasal cavity, oral cavity, gastrointestinal tract mucosa) is common. In elderly patients, increased blood viscosity, anemia, and blood volume expansion can lead to congestive heart failure. Raynaud’s phenomenon can also occur.
The occurrence of hyperviscosity syndrome is related to both the blood immunoglobulin concentration and the type of immunoglobulin. When the blood viscosity (plasma or serum viscosity) exceeds three times normal and the blood monoclonal immunoglobulin concentration exceeds 30 g/L, hyperviscosity syndrome is likely to occur. Among the various immunoglobulin types, IgM has a large relative molecular mass, asymmetric shape, and a tendency to aggregate, so it is most likely to cause hyperviscosity syndrome. Next, IgA and IgG3 are easy to form multimers, so they are also more likely to cause hyperviscosity syndrome.
7.Hyperuricemia
Elevated blood uric acid >327μmol/L is common in MM. Among 91 cases of MM in Peking Union Medical College Hospital, 61 cases (67%) had hyperuricemia. Elevated blood uric acid is the result of increased production of uric acid by tumor cell breakdown and decreased uric acid excretion by the kidneys. Although elevated blood uric acid rarely causes obvious clinical symptoms, it can cause kidney damage and should be prevented and treated.
8.Nervous system damage
Tumor cell infiltration, tumor mass compression, hypercalcemia, hyperviscosity syndrome, amyloidosis and mechanical compression caused by pathological fracture can be the cause of neurological lesions and symptoms. Neurological symptoms are diverse and can manifest as both peripheral neuropathy and nerve root syndrome, as well as central nervous system symptoms. Compression pathological fractures of the thoracic and lumbar spine can cause paraplegia. Among 125 cases in Peking Union Medical College Hospital, 12 cases had neurological lesions, 3 cases of peripheral neuropathy, 3 cases of nerve root damage, 2 cases of intracranial damage, and 4 cases of paraplegia due to spinal cord compression.
9. Amyloidosis
Amyloidosis is a disease in which the light chains of immunoglobulins and polysaccharide complexes are deposited in tissues and organs. The involved tissues and organs are often extensive, including tongue, parotid gland, skin, cardiac muscle, gastrointestinal tract, peripheral nerve, liver, spleen, kidney, adrenal gland, lung, etc. It can cause tongue hypertrophy, parotid gland enlargement, skin mass or moss disease, cardiac hypertrophy, heart enlargement, diarrhea or constipation, peripheral neuropathy, liver and spleen enlargement, renal insufficiency, etc. The diagnosis of amyloidosis relies on tissue biopsy pathology, including morphology, Congo red staining and immunofluorescence examination. The incidence of amyloidosis in MM is reported to be 10%-15% in Europe and the United States, while the incidence in China is 1.6%-5.6%. Carpal tunnel syndrome caused by amyloidosis damage to the median nerve is common in Western countries, but has not been reported in China.
10. Hepatosplenomegaly and others
Hepatosplenomegaly is caused by infiltration of tumor cells and amyloidosis. Hepatomegaly is seen in more than half of the patients, and splenomegaly is seen in about 20% of the patients, usually with mild enlargement of liver and spleen. The lymph nodes are usually not enlarged. A small number of patients may have joint pain or even swollen joints and rheumatoid nodules, which are signs of amyloid degeneration of the bones and joints. Skin lesions such as pruritus, erythema, gangrenous pyoderma, and hypertrichosis are only seen in a few patients. Individual patients have xanthomatosis, which is thought to be the result of monoclonal immunoglobulin binding to lipoproteins.