Pediatric Cancers Are Infiltrated Predominantly by Macrophages and Contain a Paucity of Dendritic Cells: a Major Nosologic Difference with Adult Tumors

Abstract

Purpose: Adult cancer is frequently preceded by a period of prolonged chronic inflammation caused by infectious microbial agents or physical or chemical irritants. By contrast, an association between the classic pediatric neoplasias and inflammatory triggers is only rarely recognized. We hypothesized that the difference could be reflected in the inflammatory cell infiltrates of pediatric and adult cancer. Experimental Design: Three investigators retrospectively studied 27 pediatric and 13 adult cancers at first diagnosis by immunohistochemistry. Inflammatory cells were identified and counted, and their location in relation to tumor tissue was analyzed. Results: A majority of tumor-associated leukocytes (TAL) in adult tumors were located at the edges of tumor islands forming inflammatory foci between the supporting stroma and the malignant infiltrate. In contrast, TALs in pediatric tumors were scattered within the malignant tumor islands. In adult tumors, TALs were composed of diverse leukocyte types; but in pediatric tumors, the infiltrating cells were predominantly macrophages that accumulatedin areas ofnecrosis within the tumors. The most striking feature in the pediatric tumors was the virtual absence of dendritic cells.The proportion of intratumoral dendritic cells in pediatric samples was 4.1%;whereas in adult tumors, they formed 36.9% ofTALs within the tumor islands and 25.1% around the tumors. Conclusions: We conclude thatTALs in pediatric cancers are composed mainly of macrophages and largely devoid of dendritic cell. The findings may provide a major nosologic difference reclassifying pediatric and adult tumors based on nominal inflammatory and noninflammatory etiologies.Immunohistochemical analysis of adult cancers often reveals a significant infiltration of leukocytes, either intratumoral or peritumoral, at the edges of the tumor tissue between the tumor islands and their stromal component (1). Heavier infiltration of leukocytes is commonly associated with a better prognosis, such that in patients with ovarian cancer, the 5-year overall survival rate is 38% in patients whose tumors contained T cells and 4.5% in those patients whose tumors contain no T cells within the islands, making this one of the most important of all prognostic factors in this disease (2). Similarly, in patients with gastric cancer, the 5-year survival rates for patients with high natural killer (NK) or dendritic cell infiltration were 75% and 78%, respectively; whereas in patients with low numbers of infiltrating cells, the respective survival figures were only 50% and 43% (3).Adult cancer is frequently preceded by a period of prolonged chronic inflammation caused by infectious microbial agents (Hepatitis B or C, human papillomavirus, EBV, Helicobacter pylori) or other physical agents or irritants (repeated solar exposure, prolonged exposure to tobacco smoke, or asbestos fibers; ref. 4). Such preneoplastic inflammatory periods may persist for several decades before a state of genomic instability, and the full neoplastic p...

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