Vol 43 # 2 June 2011 - Kma.org.kw

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120 Pattern of Chromosomal Abnormalities in Pediatric Acute Lymphoblastic Leukemia (ALL) June 2011 Table 2: Type of metaphase plates obtained in 31 cases of ALL Type of metaphase plates Abnormal & normal Abnormal only Normal / near normal No. of cases 17 10 04 (2n > 46), aneuploidy were seen in 10 (32.0%), and five (16.0%) patients respectively (Table 3). Hypodiploid blasts with modal chromosome number between 40 and 45 were observed in 9 / 16 patients whereas those with 31 to 39 were seen in five patients, and near haplodiploidy in only two (Fig. 2). The Chr 2, 10, 12,15,17,19 were commonly deleted in hypodiploid cell lines whereas gain of Chr 4, 8, 10, 14 and 20 was observed in hyperdiploid group. (Table 4, Fig. 3). A majority of patients (18 / 31, 58%) had no detectable structural abnormalities on conventional G- banding technique whereas thirteen (41.9%) showed chromosomal translocations. Translocation t (10; 14) was the commonest structural abnormality seen in four (12.8%) followed by t (9; 22) (Fig. 4 & 5), t (8; 22), t (2; 22) and t (4; 11) in three, two, two and one patient respectively. Stickiness (Fig. 6), fragmentation, and endomitosis (Fig. 7), as secondary chromosomal aberrations, were observed in significant proportion of our patients (Table 5). DISCUSSION ALL is the most common cancer diagnosed in children and represents 23% of cancer diagnoses among children younger than 15 years with a sharp peak among children aged 2 to 3 years [6] . The majority of patients in our series were male in the age group of 5 - 9 years with ALL-L2 predominant phenotype. Generalized malaise and fatigue was the most common presentation (100%) followed, in frequency, by fever with or without infection (77.4%), and bleeding manifestation (58%, mostly purpura). Four patients (13%) presented with predominant skeletal % 54.8 32.0 13.0 Table 3: Distribution of FAB* morphology according to numerical abnormalities in ALL † Numerical changes Hypodiploid (2n < 46) Hyperdiploid(2n > 46) Aneuploid L1‡ 07 05 L2§ 09 05 04 L3ε 00 - 01 Total cases 16 10 05 % 51.6 32.0 16.0 * French American British, † acute lymphoblastic leukemia, ‡ ALL-L1, § ALL-L2, ε ALL-L3 symptoms such as joint pain, swelling, and difficulty in walking which led to the misdiagnosis of juvenile rheumatoid arthritis, as has been described in the literature (Table 1) [7] . Clonal chromosomal abnormalities are found in upto 80% of patients with ALL. These are closely related to the biology of the disease and indicate the genes involved in leukemogenesis. Cytogenetic classification is based on the number of the chromosomes (ploidy), structural alterations (translocation), and immunophenotype which are important in both childhood and adult ALL to distinguish low from high risk patients [8-12] . The incidence of cytogenetic abnormalities detected by routine karyotype analysis have led to the following distribution in pediatric ALL; pseudodiploid (25 - 40%), normal karyotype (20 - 30%), hyperdiploid (10 - 25%), and hypodiploid (4 - 10%) [2,13,14] . Similar to our observation (51.6% hypodiploid Vs 32% hyperdiploid), various Indian studies have found opposite results, i.e., the chromosomal abnormalities associated with poorer prognosis have been observed more frequently from India than those associated with good prognosis. There has been a marked increased in prevalence of hypodiploid karyotype (30 - 40%) than hyperdiploidy (15%) among Indian ALL patients [15, 16] . Similarly, a higher percentage of adult ALL patients were found to be hypodiploid in another study from neighboring Pakistan [17] . Table 4: Age, FAB*subtypes and numerical changes in all cases of ALL † Type of numerical changes No of patients % Age range (yrs) ALL-L1 ALL-L2 ALL-L3 Chromosome gain (+) / loss(-) Hypodiploid (2n = 25 - 30) Hypodiploid (2n = 31 -39) Hypodiploid (2n = 40 - 45) Hyperdiploid (2n = 47 - 50) Hyperdiploid (2n = 51 - 60) Aneuploid 02 05 09 03 07 05 6.4 16.0 29.0 9.6 22.5 16.0 4 - 5 1 - 14 1 - 10 2 - 5 3 - 8 2 - 10 - 03 02 02 04 03 02 02 07 01 03 01 - - - - - 01 -6, -9, -13, -15, -17, -18, -20 -2, -10, -15, -17, -19, -20 -3, -10, -11, -18, -20 +14, +17 +4, +8, +10, +14, +20 -9, -10, -14, -17, +12, +19 * French American British, † acute lymphoblastic leukemia
June 2011 KUWAIT MEDICAL JOURNAL 121 Fig. 2: Blast morphology and numerical chromosomal abnormality in acute lymphoblastic leukemia (ALL). High hyperdiploid ALL is one of the most common malignancies in children. It is characterized by gain of chromosomes, typically +X, +4, +6, +10, +14, +17, +18, and +21 [18-21] . High hyperdiploidy (2n = 51 to 65) generally occurs in cases with clinically favorable prognostic factors (patients aged 1 - 9 years with a low WBC count) and is itself an independent favorable prognostic factor. Trisomy of Chr 4, 8, 10, 14 and 20 was noted among hyperdiploid group in our study. Inspite of adverse clinical and laboratory parameters in these patients (Table 1), good cytogenetic parameters were predictive of a favorable outcome following chemotherapy as has been described in the literature [21-23] . Compared to hyperdiploid group, progressively worse outcome is associated with a decreasing chromosome number (hypodiploidy). Cases with 24 to 28 chromosomes (near haploidy) have the worst outcome and those with fewer than 44 chromosomes have a worse outcome than patients with 44 or 45 chromosomes in their leukemic cells [2, 24, 25] . In the present study, hypodiploid cell lines of 40 - 45 were more common which were characterized by deletion of Chr 2, 10, 12, 15, 17, 19 (Fig. 3). Demonstration of near haploidy in two of our patients (age 3 & 4 years) was an example of ‘age restricted leukemia’ [26] and worst prognosis as both the patients died during their initial investigation work-up. Chromosomal abnormalities that cannot be resolved by G-banding may be detected by molecular Table 5: Structural abnormalities in all cases of ALL † Structural abnormalities A. No identifiable abnormalities B. With structural abnormalities I Primary chromosomal translocation 1. t‡ (10; 14) 2. t (9; 22) 3. t (4; 11) 4. t (2; 22) 5. t (8; 22) II) Secondary/additional aberration 1. Stickiness 2. Chromatid fragmentation 3. Pulverization † acute lymphoblastic leukemia, ‡ translocation No. of cases 18 13 04 03 01 02 02 21 19 17 % 57.6 41.6 12.8 9.6 3.2 6.4 6.4 67.0 60.8 54.5
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