Multiple Myeloma Analysis - Case Study Example

Assignment Case Study 2 Case history The summarized case history reads A 64 year old man has been feeling chronically tired and generally unwell with lower back pain. He has lost a substantial amount of weight in recent months. Although a non-smoker he had had several recent infections and was increasingly short of breath." From this history we should form a group of provisional differential diagnoses which need to be systematically investigated to arrive at the correct diagnosis. Chronic unwellness with low back pain in a 64 year old man should always make one suspicious of a neoplastic or malignant process that has affected or infiltrated his lower lumbar spine. The cause can be local, for instance cancer of the prostate or large bowel, which can give rise to low back pain. The substantial weight loss should also alert someone about a possible malignant process, as it is commonly associated. The possibility of inflammatory lower back disease also should not be ruled out, as diseases like rheumatoid arthritis or ankylosing spondylitis can be rarely localized to the spine as well. Weight loss can also be a non-specific finding. Thus inflammatory arthritis should be another group of disorders to be kept as part of the diagnosis. The addition of several recent infections and being short of breath despite being a non-smoker adds another layer of possibilities. Recurrent recent infections (not mentioned if they were chest infections or not) can be associated with immune suppression, which is seen in hematological illnesses. Shortness of breath can be due to a variety of causes including lung diseases, severe anemia and even heart failure, which should be investigated further. The substantial weight loss is seen in many chronic conditions and malignant conditions, which can be confirmed after making the diagnosis. The history is not classically suggestive of any illness in particular, and based on the differential diagnoses outlined in the history, clinical tests should be interpreted for accurately diagnosing the condition. Clinical chemistry In view of the bone pain, the clinical chemistry can be helpful if there is bone destruction. Calcium levels (3.48 mmol/L) are elevated, which is indicative of a possible bone destructive process, which can be seen in a variety of conditions. In addition, alkaline phosphatase is raised when there is new bone formation, as typically seen in classical hypercalcaemia seen with solid tumours invading bone. Moreover, phosphate levels are normal, which rules out hyperparathyroidism as a cause. Liver damage can also raise alkaline phosopahatase levels, but in light of the above history, is not one of our differential diagnoses. However, in this case, alkaline phosphatase is normal (94 IU/L) too , which raises the possibility that myeloma is the underlying cause. Few other causes of hypercalcaemia have normal phosphates and alkaline phosphate levels. The cause of hypercalcaemia in myeloma is however complex, and thought to be related to cytokine-driven increase in osteoclast activity. In this case we should also have done full serum creatinine and electrolytes, as renal insufficiency is common in myeloma as well as itself a cause of hypercalcaemia itself. The urea levels are increased ( 14.0 mmol/L) which is some cause for concern, as it could be associated with renal insufficiency. Infact hypercalcaemia itself can cause renal insufficiency, and up to this point that could be considered as the working hypothesis. Bone pain is seen in up to 70 % of cases of myeloma, and is an important consideration even at this stage. There are no clinical chemistry tests that can confirm the diagnosis of multiple myeloma, which can only be diagnosed with any certainty with the use of immunological markers as discussed below. Blood counts and film analysis The Hb level of 10.7 g/dL shows that there is mild anaemia, although Mean Corpuscular Volume (MCV) is normal (82 fl) (normochromic anaemia) and so is the White cell count (11.7 x 109/L). Mild anaemia rarely causes breathing difficulty, and therefore chest infections must be considered as a possible cause. The anaemia indicates that the possible cause of the normochromic anemia is bone marrow involvement by plasma cells ( to be discussed later). The blood film analysis showing high ( 20 per cent +) levels of plasma cells is highly characteristic of a plasma cell disorder, including myeloma, but at such high levels of cells, plasma cell leukaemia (PCL) must also be considered as a diagnosis. According to Alexania et al (1998) the group of plama cell related disorders is long ( Multiple myeloma (IgG, IgA, free light chains, IgD, IgE), Plasma cell leukaemia, Solitary plasmacytoma of bone , Extramedullary plasmacytoma, Waldenstrm's macroglobulinaemia (IgM), Chronic lymphocytic leukaemia, Malignant lymphoma, Primary amyloidosis, Heavy chain disease ), and from this point onwards, differential diagnoses within this group must be aimed to make specific diagnosis. High plasma viscosity is also seen as a characteristic feature of this group, and in particular rouleaux formation is quite common. Total albumin and protein Using chromatographic methods of assessment of absorptions of total protein and albumin, it has been established that total protein levels in plasma are high (153 g/L) , although albumin levels are lower than normal (27.1 g/L). This indicates a massive increase in the non-albumin protein component of plasma, which also explains the high viscosity of plasma and the associated rouleaux formation. The dimunition in albumin could be result of impaired hepatic function, often related to cytokines. Flow cytometry Immune studies using flow cytometry using markers have been in use for several years, and in this approach, plasma cell antibody receptors have been identified with several markers. Cellular differentiation (CD) proteins are proteins found on surfaces of cells developing in the bone marrow in particular, and can be used to differentiate the origins of cells e.g. T-cell, B-cells, etc. CD19 and CD21 are two of these markers. In the current case, only CD21 and CD19 results have been mentioned, though in practice results for quite a few markers together are considered as a group. San Migel et al (2006) found that the most consistent markers for plasma cells are CD38 and CD138 combined. They also found that less than 15 % of plasma cells retain the early markers like CD 19, and in this respect the loss of CD 19 is not surprising. CD21 is however expressed by both mature and immature plasma cells, and is a well-documented B-cell differentiation antigen. According to Huang et al (1995) since both plasma and myeloma cells are thought to very late maturing cells in the B-cell pathway, the CD21+ status confirms the B-cell lineage, bringing us a step closer to the final diagnosis of myeloma. In this respect it must be mentioned that Robillard et al (1998) found that CD28 can be a useful marker of expansion of myeloma cells in the bone marrow, which can also therefore encroach upon bone to produce bone lesions. According to the International Myeloma Working group (2003) criteria, myeloma cells are typically CD56, CD38, CD138 positive and CD19 and CD45 negative. This can be a useful criteria as it helps define the pattern of myeloma. Electrophoretic patterns Studying electrophoretic patterns from patients with myeloma, gamma band ( band 5) was shown to be extremely high, thus establishing the diagnosis of a monoclonal gammopathy. This is further elucidated by the presence of Bence Jones' protein in urine (Immunoglobulin Light Chain Lambda) which is practically diagnostic of a plasma cell disorder and rules out all the other causes of heavy chain plasma cell disorders we had mentioned above (heavy chain disease, plasmacytoma and Waldenstrom macroglobulinemia). On the basis of the current information we cannot be sure whether the diagnosis is monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), plasma cell leukemia, solitary plasmacytoma. However although it does not yet appear to be multiple myeloma as there are no multiple proteins on electrophoresis at present, in future it could easily change to so. About forty percent of patients with multiple myeloma develop plasma cell leukemia. Clinically overt multiple myeloma develops in 55 percent of patients with solitary plasmacytoma within three to four years. Disorders within this group are highly variable and mutable. In addition however, most myeloma patients secrete heavy chain proteins as well belonging to the category of Immunoglobulins - although Ig G, Ig M and Ig A are mentioned here to be negative, it is still possible that Ig E or Ig D could be positive, as these heavy chain M-proteins is what gives the plasma its high viscosity and causes the rouleaux formation that we mentioned above. In addition it must be remembered that the light chain lambda proteins in this case can precipitate and deposit in the kidney causing a huge variety of kidney disorders. Essentially they consist of a variety of symptoms due to tubular obstruction and glomerulonephritis and also diminished urine output. In the worst cases, they cause acute renal failure. The characteristic "myeloma kidney," caused by cast nephropathy, occurs in about 28 percent of patients with multiple myeloma. Dehydration and hypercalcaemia soon worsen the situation with renal function, and in our case, we have noted that the biochemistry showed both hypercalcaemia and high urea suggestive of dehydration. This patient has to be therefore carefully managed in terms of his kidney status. Microbiological Investigation The microbiological assay shows alpha-haemolytic lanceloate diplocccus sensitive to penicillin and optochin, which positively identifies the organism as Streptococcus Pneumonia, a common respiratory pathogen found in myeloma patients. Its presence on blood culture suggests bacteriaemia which is an indication for urgent intravenous antibiotic therapy. There are several factors accociated with streptococcus pneumonia - some important ones are polysaccharide capsule (prevents neutrophils from phagocytosis), pneumolysin (causes lysis of host cells), hydrogen peroxide (can damage host tissue), Pili or hair like projections on capsule (which can cause them to bind to the respiratory tract) and Protective antigen (PsPA) which can inhibit opsonization of pneumococci by host complement). Although this organism can be found in 10-20% of healthy adults and in up to 40 % of children, once it overcomes our immune system, can cause infection of the sinuses (sinusitis) and middle ears (otitis media). Thereafter it can infect the lungs causing pneumonia and can spread into the blood stream. The test results suggest this has already happened in the current case, and should be dealt with promptly. If not checked, it can spread to the meninges (meningitis), bones (osteomyelitis, particularly common in sickle cell anemia) and joints (arthitis) and can even produce brain abscesses. It can also cause death by septic shock. It must be mentioned that in multiple myeloma, our immune system is severely affected as the bone marrow is taken over by malignant plasma cells, and makes patients far more vulnerable to infections like streptococcal pneumonia. Its diagnosis depends on culturing the organism from sputum, or form the blood, as in this case. Pneumococci are gram positive cocci, seen under the microscope in pairs or chains. On blood agar plate culture in the laboratory with added optochin antibiotic disc disk, they demonstrate a pattern of alpha-hemolytic colonies (partial haemolysis). In addition, a clear zone is seen around the disk which show that the streptococci have died I the zone implying they are optochin sensitive. The other test called Quellung test is performed with India ink to identify polysaccharides in their capsules, although this is rarely done. Although vaccination is available, the only practical treatment of pneumococcal infections is treatment with antibiotics. Penicillin resistance is seen, and many cases require beta-lactam antibiotics, macrolides, cephalosporins. Bone Marrow analysis The bone marrow film analysis shows neoplastic plasma cells which confirms the diagnosis of myeloma. Flow cytometry could also be performed on these cells. At this stage we are certain of our diagnosis of a light chain gammopathy of plasma cells (B-cell origin). The plasma cells start proliferating within the bone marrow, causing expansion of the marrow cells, and invading bones in the cortex of the bones which contain marrow (e.g. skull, spine, long bones). In addition these myeloma cells also produce a cytokine called IL-6 which stimulate cells called osteoclasts which cause punched out lesions in the bone, by causing bone to break down. The effective treatment in most cases is chemotherapy to halt the progression of the dividing plasma cells, although radiotherapy to the affected bones has been used in some cases. The level of immunoglobulins in the system cause deposition in kidneys and casts, with respiratory infections, and most I these immunoglobulins are ineffective, predisposing patients to infections everywhere. The proliferating cells in the bone marrow also gradually weed out other cells like red blood cells, neutrophils, other lymphocytes and platelets, leading to anaemia, infections and bleeding ( due to platelet deficiency). Monoclonal antibody refers to the fact that they are produced by one type of immune cell only, namely the plasma cells derived from the B-cell system. In this case, the electrophoresis clearly shows that the antibodies are of monoclonal origin (gamma, Band 5). We can conclude that in this case there is monoclonal gammopathy possibly as a result of multiple myeloma. Other investigations We have outlined most of the tests, but in addition, for this patients a few more could be done. They are X-rays of spine and skull to detect any osteolytic lesions (full skeletal survey), CT/MRI of spine, renal function tests to assess kidney function. A general discussion of multiple myeloma Multiple myeloma is a cancer of the immune system, more specifically plasma cells within the bone marrow, that produce high levels of antibodies. Specific genetic mutations have been recently identified. It is characterized by four symptoms - high calcium levels in blood, kidney failure, anaemia and bone pain. In addition as the plasma cells grow within the bone marrow, they displace other cells, and causing anaemia, reduction in other white blood cells ( neutrophils, basophils, eosinophils, lumphocytes, monocytes) making us more vulnerable to infections, platelets (causing bleeding). The test used to diagnose them include a skeletal survey (x-ray of all bones in the body) to find out expanding lesions in the bones, supplemented sometimes by MRI and CT scans. Bone marrow biopsy is performed to estimate the proportion of marrow space occupied by myeloma cells, which is useful for staging the disease. Immunohistochemistry for cell-surface CD proteins is also carried out to delineate the cell origins and has been discussed earlier. Quantitative assays of immunoglobulins is also carried out. There is currently no curative treatment for myeloma, and all our treatment is aimed at suppressing and controlling the expansion of the disease. Steroids (dexamethasone) are commonly used, along with chemotherapy agents like thalidomide, cyclophosphamide, vincristine, adriamycin, melphalan. Facon et al (2007) has proved that the addition of thalidomide can prolong life significantly. Lenalinomide is a related new drug introduced more recently. Autologous stem cell transplantation is used in young patients, where patient's own stem cells are grown in the lab are administered after high dose chemotherapy to destroy bone marrow cells. This can be repeated more than once. Allogenic stem cell transplantation (from other bone marrow donors) is experimental, as 5-10 % people die as a result of side effects. Along the course of treatment, 'resistance' to standard therapy can occur, but can be reversed with newer forms of treatment. Renal failure can also require dialysis. References Alexanian R, Weber D (1998) Differential Diagnosis of Monoclonal Gammopathies. Archives of Pathology and Laboratory Medicine: Vol. 123, No. 2, pp. 108-113. International Myeloma Working Group (2003). "Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group". Br. J. Haematol. 121 (5): 749-57. San Miguel J F, Guttierez N et al (2006) Conventional diagnostics in multiple myeloma.European J of Cancer 2006 : (42) 1510-9. Huang N, Kawano MM, et al (1995) Expression of CD21 Antigen on Myeloma Cells and its Involvement in Their Adhesion to Bone Marrow Stromal Cells. Blood, Vol 85, No 12 (June 15). 1995: pp 3704-3712 George E D, Sadovsky R (1999) Multiple Myeloma: Recognition and Management. American Family Physician. Vol. 59/No. 7 (April 1, 1999) Facon T, Mary JY, Hulin C et al (2007). "Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial". Lancet 370: 1209-1218. Robillard N, Jego G et al ( 1998) CD28, a marker associated with tumoral expansion in multiple myeloma. Clinical Cancer Research, Vol 4, Issue 6 1521-1526, Copyright 1998 by American Association for Cancer Research Read More