Chronic Lymphoproliferative Disorders II PDF

CHRONIC LYMPHOPROLIFERATIVE DISORDERS II Head of department Dr Mihaela Andreescu UTM – Faculty of Medicine  Pluripotent stem cell...

CHRONIC LYMPHOPROLIFERATIVE DISORDERS II Head of department Dr Mihaela Andreescu UTM – Faculty of Medicine  Pluripotent stem cell SCF Multipotent Multipotent myeloid IL3, GM-CSF IL3 lymphoid stem cell stem cell IL3, IL11,TPO IL3, EPO IL3, GM-CSF IL3, IL7 SCF Proerythroblast Mieloblast Limfoblast Megakaryoblast IL11, EPO TPO IL3, GM-CSF IL3, GM-CSF IL3, GM-CSF IL3, IL7 Basophilic erythroblast B. promyelocite N. promyelocite E. promyelocite Monoblast GM-CSF, IL4 GM-CSF, GM-CSF, Promegakryoblast G-CSF IL5 GM-CSF, EPO M-CSF IL6, TPO Polychromatic erythroblast B. myelocytes N. myelocytes E. myelocytes Prolymphocyte IL4 G-CSF Promonocyte IL5 IL2, IL7 Erythroblast oxyfill B. metamielocit N. metamyelocite E. metamyelocite M-CSF Megakaryocyte NK cell Small lymphocyte IL2, IL6, Reticulocytes IL4, TPO B. band N. band E. band IL7 B lymphocyte T-lymphocyte IL6 Platelets Erythrocytes Basophile Neutrophil Eosinophil Monocyte LTh LTc Macrophage Dendritic Dendritic Mastocyte myeloid cell Plasmocyte lymphoid cell  Monoclonal gammopathies  Multiple myeloma is a rare, complex and incurable neoplasia Number of people in the EU affected by Median age for diagnosis in the % of all cancers2 EU3 multiple myeloma1 Low life expectancy4 OS~5y5  Multiple myeloma Multiple myeloma (MM) is characterized MM is suspected in a patient who presents : by neoplastic plasma cell Bone pain with lytic lesions on X-ray/ proliferation, that produces a pathological bone fracture. monoclonal immunoglobulin. Increased concentration of total serum proteins with the presence of monoclonal protein (M) in This plasma cell clone proliferates in urine or serum. the bone marrow and produces Systemic suggestive signs or symptoms, such as frequently destruction of bone anemia with unknown cause. structure, causing osteolytic lesions, Hypercalcemia, that is either symptomatic (for osteopenia and/or pathological example, drowsiness) or discovered by chance. fractures. Acute renal failure, rarely associated with nephrotic syndrome. It also frequently causes kidney damage, which can cause kidney failure.  Multiple myeloma It is important to distinguish between MM and other plasma cells pathologies, in order to correctly assess the prognosis and treatment regimen in such patients, since in some cases there is no need for therapeutic intervention – MONOCLONAL GAMMOPATHY WITH UNDETERMINED SIGNIFICANCE. It is also very important to evaluate MM suspected patients in a time efficient manner, since a major delay in MM diagnosis is associated with a negative impact on the course of the disease. Normal protein electrophoresis and elctrophoretic migration variants  Monoclonal gammopathies The diagnosis of monoclonal gammopathy is made in the presence of monoclonal protein (M) in serum or urine. The vast majority have M-protein produced and secreted by malignant plasma cells, which can be detected by serum protein electrophoresis and/or urine electrophoresis (from 24-hour urine collection), and by immunofixation of light chains in serum and urine. Protein-M has a single narrow tip, in gamma, beta or alpha-2 region on the image of protein electrophoresis or as a dense strip, on the agarose gel (figure 1). Rarely, two M-proteins (biclonal gammapathy) can be distinguished. Immunofixation confirms the presence of M-protein and determines its type (Figure 2). Figure 1. Image representing the analysis of serum protein elctrophorrosis in graphical form (on top) and on agarose gel (bottom), with normal variant on the Figure 2. Serum protein electrophoresis (on top) left side and with monoclonal light chain immunofixation (bottom) in a case of gammopathy on the right side). multiple myeloma with IgG and kappa light chain Electrophoretic migration in monoclonal gammopathies  Monoclonal gammopathies Malignant plasmocyte can present itself in several forms: - cell that produces heavy chains of immunoglobulins, plus light chains, or free light chains, of various types of immunoglobulin, or, in some cases, does not produce protein-M. Type of monoclonal secretion Percentage (%) IgG 52 IgA 21 Kappa or lambda (Bence Jones) 16 IgD 2 Biclonal 2 IgM 0,5 Negative (non-secretory) 6,5  Monoclonal gammopathies  Monoclonal gammopathies About 3% of patients with MM do not have M protein in serum or urine on immunofixation at the time of diagnosis. In these cases, free light chains (FLC) detection may be used to detect monoclonal proteins in the absence of M protein. In about 60% of cases where serum and urine immunofixation is normal, monoclonal free light chains can be identified using FLC tests. Patients who do not have detectable M protein by any of these tests are considered to have "non- secretory myeloma." Hypogammaglobulinemia may be the only change identified in more than half of non-secretory myeloma cases. Myeloma patients who have normal immunofixation in serum and urine and normal light chain free chain analysis are considered to have non-secretory myeloma. Of these, the majority (85%) have M protein detected in the cytoplasm of neoplastic plasma cells by immunohistochemistry. Patients with non-secretory MM have no risk of kidney damage as long as light chains cannot be detected in the urine, but they are at risk for other complications. Patients with non-secretory myeloma should be monitored mainly on the basis of imaging tests and bone marrow studies if they were initially abnormal. Monoclonal gammopathies  Clinical findings Most patients with MM show signs or symptoms related to plasma cells infiltration into bones or other organs or kidney damage through excess light chains. Anemia - 73% Bone pain - 58% Increased creatinine – 48% Fatigue/weakness – 32% Hypercalcaemia – 28% Weight loss – 24% Symptoms and signs present in 5% of cases or less include: paresthesia, hepatomegaly, splenomegaly, lymphadenopathy and fever. Pulmonary effusion and diffuse pulmonary involvement due to plasma cell infiltration are rare and usually occur in advanced stages of the disease. Using laboratory tests in current work practice, patients are diagnosed earlier in the course of the disease.  Clinical findings Extramedullary plasmacytoma in 7% of patients with MM at the time of diagnosis. Spinal cord compression by an extramedullary plasmacytoma or a bone fragment due to pathologic fracture of a vertebral body occurs in about 5% of patients; it should be suspected in patients who present severe back pain, associated with fatigue or paresthesia in lower limbs or bladder, intestinal dysfunction or incontinence. CNS damage can occur due to intracranial plasmacytoma and represent extensions of skull myeloma lesions or plasmacytoma of clivus or at the base of the skull. Myeloma leptomemningeal involvement is associated with abnormal CSF examination and is more common in advanced stages of the disease. Sternal tumor-plamacytoma Thyroid, orbit infiltration Amyloidosis  Clinical findings Bone disease - bone pain, pathologic fractures, osteolysis, plasmacytomas. Bone pain is especially present in the lumbar or thoracic area and less often in extremities, it is present at the time of diagnosis in about 60% of patients. Pain is usually induced by movement and does not occur when the patient rests. Anemia: pallor, fatigue Kidney damage (Cr>2 mg/dl) (20% of patients at diganostic): tubular damage (myeloma cast nephropathy with deposits of cylinders formed mainly from precipitated light chains - Bence Jones protein or amyloidosis nephropathy) factors for renal failure: hypercalcemia, dehydration, hyperuricemia, use of nephrotoxic drugs or contrast substance in radiology. predictors for kidney failure recovery: Cr. Ser 100 mm/h in one third of patients with MM. there may be increases in clotting times, due to blockade of coagulation factors by monoclonal proteins- when they are in large quantity can induce an acquired coagulopathy  Investigations for diagnosis Anamnesis and clinical examination - should pay special attention to the following symptoms: bone pain constitutional symptoms neurological symptoms infections the physical examination must include a detailed neurological examination. CBC with peripheral blood smear Serum creatinine, urea, ionogram Calcium, serum albumin LDH, beta 2 microglobulin Serum viscosity Serum protein electrophoresis and monoclonal component dosing, serum protein immunofixation + Serum immunoglobulins, serum free light chains + Proteinuria/24 h, urinary protein electrophoresis, urinary proteins immunofixation  Evaluation of osteolytic lesions: Low dose CT scan /X-ray /MRI /PET-CT - MRI and PET/CT are useful to evaluate the degree of bone damage. Bone marrow aspiration and bone marrow biopsy Examen citogenetic/FISH (del 13,del 17p13 ,t(4;14),t(11,14),t(14,16), chromosome1 abnormalities Immunophenotyping Vertebral MRI - in case of persistent bone pain or in case of signs of bone marrow compression Tissue biopsy (tumor) + Abdominal fat biopsy –when light chain type amyloidosis is suspected  Multiple myeloma Multiple osteolytic lesions. Impending humerus fracture  MULTIPLE MYELOMA - bone marrow evaluation Mature myeloma plasma cells are oval, with abundant basophilic cytoplasm. The nucleus is round and located eccentrically with a perinuclear halo. The nucleus contains 'spoke wheel’ chromatin with prominent nucleoli and increased nucleus-cytoplasmic ratio. Cytoplasm of myeloma plasma cells may contain condensed immunoglobulin, resulting in the various specific morphological characteristics described, such as: grape shape accumulation, which give the appearance of mott cells (morula cells); round organelles of cherry color (Russell organelles); + glycogen granules rich in IgA (Flame cells).  MULTIPLE MYELOMA-Immunophenotyping The myeloma cell immunophenotype can be distinguished by immunohistochemical technique, but flow cytometry can detect specific markers and kappa or lambda ligh chains in the cytoplasm of plasma cells from bone marrow, since surface immunoglobulin is absent. The normal kappa/lambda ratio in the bone marrow is 2:1. A ratio greater than 4:1 or less than 1:2 is considered to meet the definition of monoclonality. Thus it can be distinguished monoclonal gammopathy of reactive plasmocytosis due to autoimmune diseases, metastatic cancer, chronic liver disease, acquired immunodeficiency syndrome (AIDS) or chronic infections, in which the plasma cells show kappa/lambda ratio within normal limits. Just like normal plasma cells, myeloma plasma cells express CD79a, CD138, CD38, but rarely express CD19 and do not express CD45, and about 70% express CD56, which is usually negative in normal plasma cells and plasma cell leukemia. Diagnosis and treatment criteria  Staging Stage Criterii Durie-Salmon: ISS criteria: R-ISS criteria: I All criteria : Beta-2 microglobulin ≤ 3,5 mg/l ISS I + standard -Hb >10 g/dl and serum albumin ≥ 3,5 g/dl cytogenetic risk + -Normal calcemia or ≤ 12mg/dl normal LDH -skeletal X-ray : normal bone structure or solitary plasmacytoma -Low CM: Ig G 5 g/dl;Bence Jones protein>12 g/25h Subdivision: A.Functie renala normala (Cr serica