DISCUSSION
Analyses of children and adolescents’ ALL cases at a single reference center in Northeast Mexico for the fifteen years between 2004 and 2018 provide evidence for seasonal variation in month of diagnosis with a peak in March. Our study contributes with a contemporary analysis of a homogeneous ethnic and socioeconomic group. Contrary to our findings, the single previous study addressing seasonality of diagnosis in a Hispanic population concluded that an ALL peak did not repeat periodically in their six-year time series 20. A study in a Middle Eastern country did not find a seasonal effect related to month of diagnosis either21. A reduced number of years was assessed in both reports, this could explain their lack of a trend in ALL seasonality. Conversely , our findings support those of a large 17-year French study that found seasonal variation in 1 to 6 years old males with an increase of the incidence in April, August and December.25
In 1934 Lambin and Gerard, the pioneers of studies to establish a relationship between leukemia and the season of year, concluded that there was a peak incidence from November to February in Belgium population 22. Studies from the United States26, Italy 27, and Denmark15 highlighted the elevated incidence during the winter months; contrarily, in England and Wales, the largest number of ALL cases occurred in summer 28. Additionally, one study conducted in Southern China including patients of all ages analyzed the monthly distribution for onset of ALL symptoms and found a peak in July.29 Contrary to these positive findings, a review of twenty-four reports from eleven countries in locations ranging from 35.05° South to 65.01° North found no pattern of seasonality, and the hypothesis of increasing ALL incidence as the latitude of the study population moved away from the equator was rejected19.
The precise etiology of ALL has not been established, only exposure to radiation in utero and Down syndrome have been recognized as risk factors associated with this malignancy; yet, these account for a very small part of cases.30 Environmental risk factors including infections, radiation, electric energy sources, and other causes have long been suspected to play an important role in the development of the disease 31–33. A multi-stage two-hit model has been proposed with the first hit of genetic susceptibility possibly occurring before conception or in the prenatal stage and the second hit ensuing in the extrauterine life through environmental exposure.34,35 Previous reports suggest that antigenic stimulation after community acquired infections may activate oncogenes or disrupt tumor suppressor genes36,37 and thus seasonal changes in incidence of ALL in the context of an infectious etiology have been studied, with mixed results 6,13,38. Our findings document the existence of a monthly seasonal pattern in the study group and appear to support the putative role of infections as a second hit influencing ALL development in Hispanic children.
The influence of risk-group on season of ALL diagnosis has not been previously reported; we assessed it and found that May was the month with the greater number of high-risk ALL diagnoses, while for the standard-risk group it was October. Remarkably, a distinctive peak of male adolescents with ALL was identified in July, while females had peaks in March and May. Seasonality in the diagnosis of ALL in adolescents and its conspicuous male predominance has not been previously reported, confirming that ALL in adolescents has a distinctive biologic behavior, evolution, and clinical characteristics, underscoring that specific research needs for this age group should be addressed. In this respect. a previous study in adolescents in the United States supports the existence of important seasonal variation in the cumulative risk of ALL among youthful populations; the possibility that seasonal factors, including environmental allergens and/or infectious agents, promote malignancy via indirect mechanisms was proposed 38. Hormonal fluctuations, especially during puberty, may play an important role in the increased cancer incidence, especially ALL, among male individuals. The influence of sex hormones in hematological diseases has been previously addressed39–41. In this context, sexual dimorphism in adolescents with ALL, with a global 2:1 male to female ratio in the second decade of life, has been recently reported 42.
In conclusion, ALL seasonal variation was found in our fifteen-year analysis, and March was identified as the peak month for its diagnosis in our study group of almost four-hundred consecutive children and adolescents. In male adolescents, a distinctive peak emerged in July, underscoring the need for further studies to identify particular risk factors in this group.