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 first-degree 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 person-years 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

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 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).”

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 the TABLE, the lifetime risk of HL was higher when first-degree 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]

TABLE. Cumulative Risk of HL in First-Degree Relatives of HL Patients by Family Relationship and Age at Diagnosis Compared to the Population Risk
HL patients in family Cumulative risk in relatives by relative’s age 95% CI and number (N) for lifetime risk (0-79 years)
Relationship 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
Sibling 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
Parent/Child 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
≥2 First-degree relatives 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
Same-sex twin 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
Population Risk 0.0% 0.0% 0.1% 0.1% 0.1% 0.2% 0.2% 0.3% 0.3-0.3 28,732

SHARE