Written in Blood
Understanding Familial Risk for
Hodgkin Lymphoma
Hodgkin lymphoma (HL) represents approximately 1 percent of
all de novo neoplasms worldwide
annually, with more than 65,000
new cases diagnosed globally
each year. Family history is a risk
factor for HL, though the rarity of
familial HL has hampered detailed
analyses of familial clustering. This
lack of data has likely contributed
to the variation in risk estimates
for first-degree relatives.
In a recent study published
in Blood, Elham Kharazmi,
MD, PhD, from the Division of
Molecular Genetic Epidemiology
at the German Cancer Research
Center in Heidelberg, Germany,
and colleagues characterized the
familial risk of HL based on relationship, histology, age at diagnosis, and sex.
“HL has few known risk
factors, but a family history is definitively one of them. Physicians
should ask about family history
when seeing patients,” Kari Hemminki, MD, PhD, of the Norwegian Cancer Registry in Oslo, Norway, the corresponding author of
the study, told ASH Clinical News.
“Awareness of risk among healthy
family members may help us to
recognize the symptoms early and
thus facilitate treatment.”
The researchers gathered
family-cancer data from five Nordic countries (Denmark, Finland,
Iceland, Norway, and Sweden)
to quantify the familial risk of all
concordant and discordant histologic subtypes of classical HL in
relatives of HL patients. 13,922 HL
patients (diagnosed between 1955
and 2009) and 57,475 of their firstdegree relatives were included,
making it the largest of its kind.
Standardized incidence ratios
(SIRs) were calculated using
histology-, age-, sex-, period-, and
country-specific incidence rates
as the reference. Patients were
followed from birth, immigration,
or the country-specific starting
year of cancer registration until
death, emigration, or the end of
the study.
The lifetime cumulative risk
was calculated based on the following formulas:
• Age-specific annual incidence rate
= number of cases for each 5-year
age group divided by personyears for that age group
• Age-specific cumulative rate =
5 x age group–specific annual
incidence rate
• Lifetime cumulative rate = sum of
all age-specific cumulative rates
• Lifelong cumulative risk = 1 –
lifelong cumulative rates
higher than the general population (95% CI 1.6-2.6). “Very high
risk of HL was found in only a few
subjects with multiple affected
first-degree relatives (2.8-8.4%,
a 13-fold increase) and for twin
brothers (13%, a 57-fold increase),”
Dr. Kharazmi and colleagues
stated. “The familial risk in sisters
was also higher than in brothers or
unlike-sex siblings (TABLE 2).”
“Awareness of
risk among
healthy family
members may
help us to recognize the
symptoms
early and
thus facilitate
treatment.”
—KARI HEMMINKI, MD, PhD
The overall cumulative risk of HL
in first-degree relatives of a patient
with HL was 0.6 percent, representing a three-fold increased risk
compared with the general population (SIR=3.3; 95% CI 2.8-3.9).
The risk among siblings was
the highest according to the analysis, increasing six-fold compared
with the general population (95%
CI 4.8-7.4), while the risk for
parents/children was only 2.1-fold
The authors also observed high
familial risks between certain concordant histologic subtypes of HL,
including lymphocyte-rich (an
81-fold increase; 95% CI 30-177)
and nodular sclerosis (a 4.6-fold
increase; 95% CI 2.9-7.0). Overall,
as seen in TABLE 2, the lifetime
risk of HL was higher when firstdegree relatives were diagnosed at
an early age (<30 years).
A number of factors could
explain the familial aggregation
of HL, Dr. Kharazmi and authors
noted, including genetic, environmental, or the interaction between
the two. The increased risks for
different histologic subtypes of
HL, though, suggests that a common oncogene pathway or environmental risk factor is associated
with various subtypes of HL.
“These findings are important
as relatives of cancer patients are
currently concerned about their
own risk of developing the same
cancer that occur in their family,”
the authors concluded. “These data
may potentially impact clinical
practice by increasing the awareness among relatives of patients
with incidental HL about potential HL symptoms.” For instance,
oncologists/hematologists might
inform their HL patients about
the familial risk and encourage
counseling for their first-degree
relatives to watch for signs of early
diagnosis, while relatives with a
lower, general population–level
risk may find reassurance in these
results.
There are limitations to these
findings, though, including the
long-term nature of the study, and
the possibility of a reporting bias.
Information from earlier years
may not be as accurate as more
recent years, which can also be
a source of bias toward underestimation of SIRs for concordant
histologic subtypes.
REFERENCE
Kharazmi E, Fallah M, Pukkala E, et al. Risk of familial
classical Hodgkin lymphoma by relationship, histology,
age, and sex: a joint study from five Nordic countries.
Blood. 2015 August 26. [Epub ahead of print]
Cumulative Risk of HL in First-Degree Relatives of HL Patients by Family Relationship and Age
at Diagnosis Compared to the Population Risk
TABLE 2.
HL patients in family
Relationship
Sibling
Parent/Child
≥2 First-degree
relatives
Same-sex twin
Population Risk
34
ASH Clinical News
95% CI and number (N) for
lifetime risk (0-79 years)
Cumulative risk in relatives by relative’s age
Age at
Diagnosis
0-9
years
0-19
years
0-29
years
0-39
years
0-49
years
0-59
years
0-69
years
0-79
years
95% CI
N
All
0.0%
0.1%
0.4%
0.5%
0.6%
0.7%
0.9%
0.9%
0.6-1.1
86
<30 years
0.0%
0.1%
0.4%
0.6%
0.7%
0.7%
1.1%
1.1%
0.3-1.8
49
30-59 years
0.0%
0.1%
0.3%
0.4%
0.6%
0.8%
0.8%
0.8%
0.5-1.2
36
All
0.0%
0.1%
0.2%
0.2%
0.3%
0.3%
0.3%
0.4%
0.3-0.5
61
<30 years
0.0%
0.2%
0.4%
0.5%
0.5%
0.6%
0.6%
0.6%
0.3-0.8
31
30-59 years
0.0%
0.1%
0.2%
0.2%
0.2%
0.3%
0.3%
0.4%
0.2-0.5
26
≥60 years
0.0%
0.0%
0.0%
0.0%
0.0%
0.1%
0.1%
0.1%
0.0-0.2
4
All
1.0%
2.8%
2.8%
2.8%
2.8%
2.8%
2.8%
2.8%
0.0-5.9
3
<30 years
3.0%
8.4%
8.4%
8.4%
8.4%
8.4%
8.4%
8.4%
0.0-17
3
All
0 .0%
0.0%
4.0%
4.0%
5.5%
5.5%
13%
13%
0.0-26
6
<30 years
0.0%
0.0%
6.5%
6.5%
6.5%
6.5%
6.5%
6.5%
0.1-12
4
0.0%
0.0%
0.1%
0.1%
0.1%
0.2%
0.2%
0.3%
0.3-0.3
28,732
October 2015