الفهرس 
MULTIPLE MYELOMAOnly 14 pages are availabe for public view
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Abstract
Multiple myeloma (MM) is one of the plasma cell dyscrasia (PCD). It is an incurable, but treatable hematological disorder, characterized by accumulation of malignant PCs within the BM. The MM accounts for 10-15% of all hematological malignancies, and 1 - 2% of all cancers. The extrapolated incidence rate of MM in Egypt is 17.630 in estimated population of 76.117.4212 (US Census Bureau, IDB, 2004). Mortality rates are consistently higher among men than women in each age group.
The MM is characterized by a clinical pentad: (a) anemia, (b) a monoclonal protein in the serum, or urine, or both, (c) abnormal bone radiographs and bone pain, (d) hypercalcemia, and (e) renal insufficiency or failure.
Regarding the standard diagnostic and prognostic modalities, a CBC, PB smear, CRP and chemistry screen (including, calcium and creatinine, β2M and LDH) are essential. In addition, serum protein electrophoresis (SPEP), immunofixation (IFX), Ig quantification and measurement of serum free light chains (FLCs) are mandatory. A BM aspiration with immunophenotyping and cytogenetic analysis are required. The BM plasma cell labeling index, if available, may be of additional value. A radiological skeletal bone survey is necessary. MM is diagnosed according to IMWG (2003) and (Kyle, 2009). Staging of MM is estimated according to the Durie-Salmon Staging System and the International Staging System.
It has been reported that, all MM patients harbor cytogenetic abnormalities, sometime during the course of the disease. Frequent chromosome abnormalities in MM include 14q32 rearrangements, 13q deletion/monosomy 13, 1q duplication, 1p, 6p, 11q and 17p deletions.
Chromosomal 14q32 region containing the IgH locus has been identified as a recurrent hotspot of translocations in MM. They are associated with translocations involving the IgH locus at chromosome 14q32, and one of several partner genes including CCND1 (11q13), MMSET (4p16), CCND3 (6p21), CMAF(16q32) and MAFB (20q11). It provides important information that may assist in the diagnostic and prognostic assessment of such cases.
Although conventional cytogenetics is becoming a major parameter in MM, it is hampered by hypoproliferative nature of PCs. The FISH is probably the best method, so far, for cytogenetic assessment in MM, but it requires the identification of the malignant cells. The FICTION technique combines IF to detect cellular antigen (CD138 on PCs) and FISH to detect chromosomal abnormalities (14q32 rearrangements). It is an attractive alternative approach for evaluation of chromosomal changes in MM, owing to its capacity to improve the efficacy of result interpretation, resulting from the combination of more than one technique on the same sample.
This study was conducted at the Clinical Pathology Department of Ain-Shams University Hospitals, in the period from February 2008 to August 2010 (after procuring the approval of the Scientific and Ethical Committee of Ain-Shams University). The study was carried on 25 MM patients to detect rearrangements of IgH locus on chromosome 14q32, on CD138 positive cells, using FISH analysis combined with simultaneous IF by CD138 (FICTION), on archival BM slides. The study aimed to determine the frequency of these rearrangements in MM patients; and to correlate the prognostic value of these rearrangements with other known prognostic factors (CBC, SPEP, BJP in urine, IFX, serum calcium level, LDH, BUN and serum creatinine, serum β2M, CRP and BM PCs percentage).
The percent of PCs was estimated using CD138 immunostained BM slides of MM patients under low-magnification power microscope, and was compared to their traditional differential count of BM PCs. This IF slide technique gave higher percent of positive cases compared to that estimated by morphological assessment of Leishman-stained smears. Additionally, this technique was found to be simple, rapid, not requiring extensive training or experience, and it provided a more accurate estimate of BM PCs as it makes it possible to recognize PCs under low-magnification microscopy, when their numbers can be better judged, in relation to other cells of the marrow.
The 14q32 rearrangements were detected in 32% of MM patients by means of FICTION technique, versus 12% by FISH alone. There was an association between the presence of the translocation and low Hb levels, higher monoclonal bands and higher percent BM PCs using IF staining for CD138.
Patients with lower serum albumin levels and those with positive CRP had significantly shorter OS. However, there was no association between OS and the presence of 14q32 rearrangements, age, gender, stage, serum creatinine, or Ig isotype.
Finally, FICTION technique (fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasm) was found to be applicable on archived and fresh BM aspirate samples for assessment of newly diagnosed, and follow up of treated or relapsed MM patients. It is extremely valuable in the detection of low-level disease, minimal residual disease, or composite tumors. It is a more sensitive tool for establishing clonal PC infiltration of BM aspirates at lower BM PC count. It is potentially very useful due to its easy applicability, rapidity and amenability to automation. This justifies the routine application of FICTION in the work-up of all newly diagnosed and relapsed myeloma patients for a more precise prognostic classification and therapeutic management focused on the molecular genetics of every patient. Moreover, the use of FICTION technique is recommended for the simultaneous detection of other clinically relevant chromosomal abnormalities in other hematological malignancies.