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.