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FOXP3+ cell density in lymphoid follicles from histologically normal mucosa is a strong prognostic factor in early stage colon cancer

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Abstract

There are few clearly established prognostic factors available to guide the use of adjuvant chemotherapy in early stage colon cancer patients. Some of the most promising candidates include the invasion of extramural blood vessels by tumour cells and the densities of FOXP3+ T regulatory cells (Tregs) in tumour and adjacent normal colonic mucosal tissue. The aim of our study was to evaluate the prognostic significance of these markers in AJCC stage II colon cancer, with particular reference to lymphoid follicles in the mucosa. Histopathological review for the presence of vascular and serosal invasion was conducted on a series of 165 stage II colon cancers treated by surgery alone. Immunohistochemical staining for FOXP3 was performed on tumour tissue and histologically normal colonic mucosa from the surgical margin. Image analysis software was used to evaluate the density of FOXP3+ cells in the tumour core, invading margin and lymphoid follicles from the colonic mucosa. For survival analysis, cases were classified into high- or low-density of FOXP3+ cells according to the median value. The mean density of FOXP3+ Tregs in lymphoid follicles was twofold and fivefold higher than in the invading margin and tumour core, respectively. Multivariate analysis identified extramural vascular invasion (HR, 2.47; 95% CI: 1.00–6.07; P = 0.05) and high FOXP3+ cell density in lymphoid follicles (HR, 4.22; 95% CI: 1.49–11.91; P = 0.007) as independent factors for worse survival, whereas a high frequency of lymphoid follicles in histologically normal colonic mucosa was associated with better survival (HR, 0.31; 95% CI: 0.12–0.79; P = 0.014). Our data suggest that host factors related to the immune system have major prognostic significance in early stage colon cancer. The density of FOXP3+ cells within lymphoid follicles and the frequency of these structures in normal colonic mucosa represent novel and independent prognostic factors.

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Acknowledgments

Paul Salama was supported by a Sir Walter Gibbon Postgraduate Research Award from the University of Western Australia and by a grant from the Colorectal Surgical Society of Australia and New Zealand Foundation. The authors acknowledge the facilities and scientific and technical assistance of the Australian Microscopy & Microanalysis Research Facility at the Centre for Microscopy, Characterisation & Analysis, University of Western Australia. This facility is funded by the University of Western Australia and state and Commonwealth Governments. The authors gratefully acknowledge the assistance of Dr Tim Threlfall from the Western Australian Cancer Registry and Ms Lisa Spalding for technical assistance with immunohistochemistry. This work was funded by the Cancer Council of Western Australia and St John of God Hospital, Subiaco.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands, 6009, Australia

    Paul Salama, Cameron Platell & Barry Iacopetta

  2. Department of Histopathology, King Edward Memorial Hospital, Subiaco, Australia

    Colin Stewart

  3. Department of Histopathology, Fremantle Hospital, Fremantle, Australia

    Cynthia Forrest

  4. Colorectal Cancer Unit, St John of God Hospital, Subiaco, Australia

    Cameron Platell

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  1. Paul Salama
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  2. Colin Stewart
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  3. Cynthia Forrest
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  4. Cameron Platell
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  5. Barry Iacopetta
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Correspondence to Barry Iacopetta.

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Salama, P., Stewart, C., Forrest, C. et al. FOXP3+ cell density in lymphoid follicles from histologically normal mucosa is a strong prognostic factor in early stage colon cancer. Cancer Immunol Immunother 61, 1183–1190 (2012). https://doi.org/10.1007/s00262-011-1191-3

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  • DOI: https://doi.org/10.1007/s00262-011-1191-3

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