Friday, March 24, 2023

heI am frequently asked about clusters—the occurrence of cancer cases in a given neighborhood or building or other population thought to be unusually high and perhaps due to some local etiologic factor. A recent cluster that has gained some attention has been a number of brain tumors at a high school in Colonia, New Jersey. The vast majority of the time, such clusters are purely the operation of chance and can be safely ignored, but they sometimes precipitate action by local health departments or epidemiologists. The question is, what should the proper follow-up be, and what makes a cluster more significant?

A description of how one such cluster was handled may be a good way to see what can be done. A 1971 paper in the Lancet by Nicholas Vianna and colleagues of the New York State Department of Health describes their investigation of a cluster of Hodgkin lymphoma (HL) at Albany High School, in Albany New York. HL is uncommon, only 3,000 cases annually in the U.S., but increased in adolescents and the elderly. Two members of the class of 1954, which had 317 students, died of HL, while one member of the class of 1955 and one member of the class of 1953 who were acquaintances also developed HL. Three other cases were traced to nearby schools through one link to the index cases over the next 15 years—how much weight to give to these cases is a question.

As you may imagine, this cluster raised considerable alarm in the Albany community and more broadly as well. That particular high school became unpopular for a while. There is reasonable evidence to suggest that HL is caused by a virus (Epstein-Barr virus) so the idea of person-to-person transmission is not far-fetched. But what to do further?

One way to think about this is to realize that a cluster is an a posteriori event and so calculating its probability is not very worthwhile. It is like, after flipping a coin and getting six heads in a row, you say how improbable that is. But it just happened. The real question is, how should you bet on the next flip? If there is indeed some predisposition to heads, then you should flip the coin another six times and test your hypothesis in an a priori fashion.

Likewise here, now that we have a hypothesis that HL may be transmitted among adolescents in high schools, we can test that in an a priori experiment. This experiment was conducted by Vianna and the New York State Department of Health and published in 1973 in the New England Journal of Medicine. They identified eight high schools in Nassau and Suffolk Counties on Long Island that had cases of HL diagnosed at them during the time frame of 1960-1964, and matched them to 16 high schools by size but without HL. Using the New York State Cancer Registry, they then looked at the 1965-1969 time frame and found that five of the eight HL-exposed schools had new cases of HL while none of the 16 control schools did.

This study created an uproar on Long Island—children with HL were shunned and avoided. The affected schools, as in Albany, were also shunned. The Long Island newspaper Newsday made it a cause celebre. But the story does not end there. A pediatrician, Seymour Grufferman, in his doctoral dissertation in epidemiology at the Harvard School of Public Health, published in the New England Journal of Medicine in 1979, undertook to repeat Vianna’s Long Island study in Boston using the identical study design. He used all the high schools in the greater Boston area, and identified those with HL cases during the 1960-1964 time frame, matched them to control high schools with no HL cases in a 2 to 1 ratio, and then looked at the 1965-1969 time frame for follow-up cases. In his study, he found that the number of HL cases during 1965-1969 was elevated in both the HL-exposed and the control high schools to a similar degree. Thus, his study showed no evidence for HL clustering.

How are we to interpret this discrepancy? Most experts believe that the Grufferman study was superior in methodology and conduct, and that there were some significant flaws in the Long Island study that led to the observed difference between the exposed and control high schools. Chief among them, the control schools were closer to the Nassau-Queens border, so any HL cases from those schools might have been more likely to cross the border into New York City and to be diagnosed and treated there and not counted in the follow-up period. (In the 1960s, the five boroughs of NYC were not included in the NYS Cancer Registry, the source of identification of the cancer cases for this study, so any Hodgkin case diagnosed in Queens or Manhattan would not be included.) Therefore, Hodgkin lymphoma ascertainment was likely to be more complete and accurate in Grufferman’s study.

The bottom line is that most experts don’t believe that person-to-person transmission is a serious risk for HL.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

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