Indian Journal of Cancer Medknow Publications on behalf of Indian Cancer Society ISSN: 0019-509X EISSN: 1998-4774 Vol. 48, Num. 3, 2011, pp. 310-315

Indian Journal of Cancer, Vol. 48, No. 3, July-September, 2011, pp. 310-315

Original Article

Time trend in frequency of occurrence of major immunophenotypes in paediatric acute lymphoblastic leukemia cases as experienced by Cancer Institute, Chennai, south India during the period 1989-2009

KR Rajalekshmy¹, AR Abitha¹, N Anuratha¹, TG Sagar²

¹ Department of Haematology, Cancer Institute, Chennai, India
² Department of Medical Oncology, Cancer Institute, Chennai, India
Correspondence Address: K R Rajalekshmy, Department of Haematology, Cancer Institute, Chennai, India, rajalekshmykraghavan@yahoo.in

Code Number: cn11084

PMID: 21921330

DOI: 10.4103/0019-509X.84932

Abstract

Keywords: Adayar, Cancer Institute, immunophenotype, pediatric acute lymphoblastic leukemia, time trend

Introduction

Pediatric acute lymphoblastic leukemia (ALL) is a biologically heterogeneous disease. ^[1],[2],[3] Incidence rates of childhood ALL varied worldwide. Madras Metropolitan Tumor Registry has recorded Crude incidence rate per 100,000/population in Chennai during 1989-2009 as 2.3-3.7. Age standardized rate per 100,000/population during this period was 2.4-4.0.

Childhood acute lymphoblastic leukemia

T and B precursor subtypes have been identified in different geographic and ethnic settings. ^[4],[5],[6] A comparison of relative frequencies of major immunosubtypes shows striking differences between developed and developing countries. ^{[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18]}

Developed countries showed predominance in common acute lymphoblastic leukemia (C-ALL) cases, whereas in developing countries a relative predominance in T-cell acute lymphoblastic leukemia (T-ALL) and a selective deficit in C-ALL were reported. Socioeconomic and environmental factors are considered to be important determinant of major immunophenotype in pediatric ALL cases in a particular geographic setting. ^[16],[19] We aim to study the time trend in the frequency of the occurrence of major immunophenotypes in our pediatric ALL cases studied at the Institute during 1989-2009 against this back drop. Socioeconomic and environmental profiles were also evaluated for these patients. Socioeconomically patients were categorized into low, middle, and high income groups based on annual income, educational status and occupation of the parents, housing and sanitary conditions, food habits, and source of water. Analytical data on this study group form the basis of this paper.

Materials and Methods

A total of 639 new pediatric ALL cases (<15 years), originally diagnosed by standard morphological and cytochemical assessment, were immunophenotyped by the flow cytometric method during the period 1989-2009, as detailed earlier. ^[13],[14] The study population comprised of 417 males and 222 females. 246 were up to 5 years, 186 were in 6-10 age group, and 207 were in the 11-15 age group. Age- and gender-specific distribution of various immunophenotypes among pediatric ALL cases during different time intervals are shown in [Table - 1], [Table - 2] and [Table - 3]. Panel of monoclonal antibodies used comprised of CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD13, CD14, CD19, CD20, CD22, CD33, CD34, immunoglobulins, HLA-DR, and Tdt. The phenotype of a given case was determined according to its reactivity with various monoclonal antibodies as T-ALL, precursor B, C-ALL, pre B, B, hybrid, and unclassified. When the percentage of blasts in test sample exceeded 90%, a positive reaction is recorded if 20% or more of the cells reacted with a given monoclonal antibody. In cases with lower percentage of blasts, the proportion of positive cells in the population required for the sample to be called positive was based on the percentage of blasts, to ensure that reactivity of admixed normal cells did not lead to any erroneous conclusion regarding the phenotype of leukemic cells.

Results

639 new pediatric ALL cases were immunophenotyped during 1989-2009. Minor subtypes have been pooled for analysis, males and females also have been combined. Frequency of the occurrence of pediatric ALL immunophenotypes at various time intervals during 1989-2009 and their socioeconomic profile during those time intervals are shown in [Table - 4] and [Table - 5].

During the period 1989-1992, a total of 72 pediatric ALL cases were immunophenotyped. Frequencies of the occurrence of T-ALL and C-ALL were 52.8% and 25%, respectively. Around 60% of pediatric T-ALL cases and 18% pediatric C-ALL cases had their origin from the lower socioeconomic group.

During 1993-2000, 195 cases were immunophenotyped. 34.4% were T-ALL and 35.4% were C-ALL. Around 40% of T-ALL and 18.2% of C-ALL cases were from the lower socioeconomic group.

During 2001-2009, a total of 195 cases were subjected to study. 29.5% were T-ALL and 45.7% were C-ALL. 32.3% of T-ALL and 37.2% of C-ALL case were from the lower socioeconomic group.

Over a period of 20 years, we observed a steady fall of 23.2% in the frequency of the occurrence of T-ALL cases and a proportionate increase of 20.7% in the frequency of the occurrence of C-ALL cases. Predominance of T-ALL cases originating from the lower socioeconomic group found in early periods of study disappeared toward the end of the study, which coincided with the fall in the frequency of the occurrence of T-ALL.

Discussion

In our earlier publications in 1990s, ^[13],[14] we concluded that T-ALL and C-ALL were the major immunophenotypes among our patients, which was in agreement with the reported data from all the world over. Frequencies of the occurrence of T-ALL (52.8%) were in excess with a selective deficit in C-ALL cases (25%), which was in contrast to Western data where C-ALL was the predominant subtype. Our finding was in agreement with other Eastern and African data. ^{[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18]} There was a distinct male predominance among T-ALL cases which conforms to the experience of all other workers. C-ALL cases showed a sharp early age peak at 2-6 years, which is in agreement with other reported data. T-ALL was more common among older children as experienced by other workers. 90% of pediatric T-ALL cases had their origin from more mature intrathymic compartments II and III, which was in agreement with other Eastern and African data, but was in variance with reported Western data. 60% of pediatric T-ALL cases had their origin from the lower socioeconomic group.

Predominance of T-ALL and a selective deficit in C-ALL cases among pediatric ALL cases in early 1990s in our locality may be attributed to several interpretations, but most favored one attributes these differences primarily to environmental factors linked to socioeconomic status and patterns of infections in infancy. ^{[6],[20],[21],[22],[23],[30]} The comparison of the relative frequencies of major subtypes indicates similar picture in other developing Asian and African countries during this period. ^{[10],[11],[12],[13],[14],[15]}

A comparison of national incidence rates in developed countries gives etiological clues to ALL subtypes. ^{[16],[19],[30]} Incidence rates of childhood ALL varied worldwide with the lowest rates among black African children. ^{[4],[16],[24]} This variation was mostly found in the 2-5 year group. The apparent increase in childhood ALL and appearance of typical 2-5 year age peak of incidence rate that was documented for the period 1930-45 for USA and UK and later in 1960s in Japan and other epidemiological data have suggested a possible link between the risk of ALL and socioeconomic factors. ^{[18],[20],[21],[22],[23],[25],[26],[30]} A study conducted in UK ^[27] on different ethnic groups including Caucasian, Asian, and African suggests that both the overall incidence of ALL and relative frequencies of T- and B-precursor cell subtypes approximately same arguing strong for factors linked to socioeconomic status as a primary determinant of low incidence rate of ALL in India and Africa. Other studies conducted in UK. ^{[28],[29],[30],[ 31]} suggested that Asian children in Britain experienced a pattern of incidence of ALL similar to that of Caucasian children. Overall worldwide incidence figures of ALL also suggest that the variable incidence rate may be associated with socioeconomic status of communities. ^{[32],[33],[ 34]} Increased levels of hygiene and altered patterns of infection could be contributing to the increased risk of C-ALL. In our study group we experienced a gradual increase in the frequency of the occurrence of C-ALL cases in the 2-6 year group and a corresponding fall in the incidence of T-ALL cases along with the disappearance of predominance of lower socioeconomic background for T-ALL cases, during the period 1989-2009 [Table - 4] and [Table - 5].

An international collaborative group study conducted on different geographic and ethnic settings conducted by MF Greaves et al. in 1985 has reported that C-ALL was less frequent in black African children of Nigeria, Kenya, and South Africa and that T-cell ALL was correspondingly more frequent among them. ^[6] Their earlier data suggested that 2-5 year maximum incidence peak of pediatric leukemia was missing in Africa. ^[5] Since this peak was a characteristic feature of C-ALL, C-ALL was less frequent in African children. Other Asian and African data also documented similar experience. ^{[12],[13] [14],[16],[23],[35]}

Even though some underdiagnosis of ALL cases might occur and a genetic component might contribute to risk, selective deficit in C-ALL cases in developing countries at a particular point of time reflects a reduced risk for this subset of leukemia in the socioeconomic conditions that existed in these settings, which used to prevail earlier this century in Western countries and Japan. Time trend in ALL subtypes experienced by us in two decades also is indicative of association of major subtype with socioeconomic development. This finding is consistent with the hypothesis of Ramot and Magrath based on time trends in leukemia/lymphoma cases in Gaza strip, suggesting that the risk of C-ALL might be associated with socioeconomic development. ^[23]

Unusual exposure to common infectious agents precedes overt ALL. Community characteristics such as improvement in hygiene and living standards, immunological isolation, etc result in delayed infectious disease. Incidence of C-ALL arises as a consequence of a rare response to common infection. It is a disease linked to socioeconomic development which may reduce or delay exposure to common infectious agents. ^[33] This explains socioeconomic and geographic associations in incidence of ALL subtypes.

Paucity of C-ALL and relative excess of T-ALL in early phase of our study could be due to the socioeconomic status which prevailed in our locality during that period of time. Low incidence of C-ALL resulting from underdiagnosis is unlikely as the age distribution of our C-ALL cases was essentially identical to that of C-ALL in other study groups. If this possibility was correct, one would have expected a difference in age distribution curve with loss of early age peak.

Low incidence of C-ALL in developing countries due to high mortality rate from infections in young children is also unlikely because infectious deaths are mostly seen in the first year of life and would therefore not reduce the incidence of C-ALL in 2-5 year group unless the same children are more susceptible to both early infection and C-ALL. In addition, high birth rates in developing countries should add much greater proportion of young children in the population, such that the overall frequency of C-ALL in the population might be expected to be higher than in Western countries, if the incidence rate of the disease was the same. Hence the deficit experienced during early part of our study was a true deficit.

Sharing of similar high or low incidence rates of C-ALL by unrelated ethnic groups rules our genetically determined risk factors. The appearance of 2-5 year peak in several Eastern and African countries strongly support that its deficit in these ethnic groups is not primarily genetic.

It is interesting to note that during 1989-92 when T-ALL cases were predominant, 60% of them originated from the lower socioeconomic group. During 92-2000, when both subtypes were codominant, 40% of them originated from lower strata. During 2000-2009, when C-ALL cases were dominating, only 32% of them had their origin from the lower socioeconomic group. This also indicates the impact of socioeconomic status in determining the major immunophenotype in a particular geographic setting.

Being a regional cancer centre, most of our patients are referred by other physicians and hospitals. Cancer awareness among public has improved considerably due to cancer awareness programs conducted by the Institute and other centers. This has been reflected in the increase in incidence rate as recorded by Madras Metropolitan Tumor Registry from 2.4 in 1989 to 4.0 in 2009. As a matter of policy, we accept all pediatric ALL cases attending our institute for treatment and offer them the full protocol treatment.

During the period 1989-2003, pediatric ALL cases were treated at the institute under MCP841 protocol. Intensive multicycle induction and intensification regimen was followed by six 13-week maintenance cycles. Intratherapeutic complications such as severe myelosuppression, febrile neutropenia, tumor lysis, gastrointestinal morbidity, and intercurrent infections have adversely affected long-term survival. During 1989-1998, 5 year event-free survival and relapse-free survival were respectively 30.2% and 33.4%. 10 year event-free survival and relapse-free survival were respectively 28.3% and 32.1%.

During 2004-2005, childhood ALL cases were treated under INTCR 02-04 protocol comprising of intensive induction cycles, repeat induction cycles, interim maintenance cycle, repeat induction-consolidation followed by total of six maintenance cycles.

During the period 2006-2009, pediatric ALL cases were treated under the BFM85 protocol consisting of intensive protocol induction, high dose methotrexate consolidation, and prolonged maintenance cycles. 3 year event-free survival and relapse-free survival for the period 2004-2006 for Institute patients were respectively 56% and 60%. We did not find any statistically significant difference in the survival rates of T- and C-ALL patients. Average 5 year and 10 year survival rates among childhood ALL cases in Chennai during the period 1990-2001 as recorded by Madras Metropolitan Tumor Registry were 38.7% and 35.3%, respectively. ^[36]

Conclusion

We conclude, with time progression, the shift in the socioeconomic profile, urbanization, and industrialization in our geographic setting has influenced the frequency of the occurrence of major immunophenotype of pediatric ALL cases. We plan to study the effect of socioeconomic and environmental factors in determining the major immunophenotype of pediatric ALL cases for a longer period of time.

Acknowledgements

We thank Mrs. M.S. Kalyani and Ms. Suneetha for their help in typing the manuscript and submission process.

References

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