College of American Pathologists



Prognostic Significance of Macrophages in Newly-Diagnosed Classical Hodgkin Lymphoma

Posted October 4, 2012

Jennifer G. Pryor, MD

The March 11, 2010, issue of The New England Journal of Medicine (NEJM) contained an article co-authored by Dr. C. Steidl and colleagues from a number of international institutions entitled “Tumor-Associated Macrophages in Classic Hodgkin’s Lymphoma”. This article is of interest to hematologists, oncologists and hematopathologists for raising the question as to whether the initial clinical and pathological work-up of new cases of classical Hodgkin lymphoma (CHL) needs to be altered based on the presence or absence of tumor-associated macrophages.

The study proposes that the proportion of CD68-positive macrophages in lymph nodes involved by CHL at the time of initial diagnosis correlated significantly with worse primary and secondary treatment outcomes. Specifically, a greater number of tumor-associated macrophages is correlated with both shortened progression-free and disease-specific survival and failure of autologous stem cell transplantation in patients for whom primary treatment failed. In multivariate analysis, tumor-associated macrophages used as a biomarker outperformed the International Prognostic Score for predicting disease-specific survival in patients with advanced-stage disease. A very low percentage (<5%) of macrophages in patients with low tumor-burden could predict a long-term disease-specific survival of 100%.

The findings of this article are alluring to oncologists for a number of reasons. Initial management decisions for patients newly diagnosed with CHL are influenced by clinical prognostic variables, which are used to differentiate standard risk patients from those patients at higher risk. The International Prognostic Score, however, is only indicated for patients with advanced-stage disease and, therefore, is not useful for patients with a low tumor burden. Additionally, there is currently no reliable way to identify patients at higher risk of failing autologous stem cell transplantation. Immunohistochemical quantitation of macrophages in diagnostic lymph nodes could, at least in theory, easily be incorporated into a pathologist’s normal workflow in order to meet these clinical needs.

Classical Hodgkin lymphoma often can be recognized on hematoxylin-eosin stain due to its characteristic Reed-Sternberg cells, but typically an immunohistochemical panel is performed to confirm the immunophenotype of the neoplastic cells. While adding CD68 to the panel would be easy enough, interpretation of the results is problematic for a number of reasons. Perhaps most importantly, the NEJM study was done on tissue microarray cores and did not address the inherent variability of cellularity present in tissue sections. It is currently unknown whether it is more appropriate to examine multiple representative high-power fields and average the results or to score the area of highest macrophage density. Also not known is whether it is necessary to manually count the CD68-positive cells or whether a simple visual estimate is sufficient. With that said, there will be some straightforward cases of CHL with very few macrophages that can easily be scored as 1 (<5%), supporting a better prognosis, or cases with numerous macrophages that can easily be scored as 3 (>25%), placing the patient at higher risk. However, the majority of cases will likely fall in between these extremes; therefore, it is important that these technical issues be addressed prior to introducing CD68 immunohistochemistry into the standard prognostic algorithm for CHL.

In summary, increased tumor-associated macrophages are associated with worse outcomes in patients with CHL. Certain technical questions need to be answered from the pathology standpoint before a reliable and reproducible scoring of macrophage quantity is introduced to daily practice.


  1. Steidl C, Lee T, Shah SP, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362(10):875–885.

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NewsPath® Editor: Kyle L. Eskue, MD
This newsletter is produced in cooperation with the College of American Pathologists Public Affairs Committee and the NewsPath Editorial Board and may be reproduced in whole or in part as a service to the medical community. Copyright © 2012 by the College of American Pathologists.
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