T umor-Infiltrating Lymphocytes and Perforationin Colon Cancer
Predict Positive Response to 5-Fluorouracil Chemotherapy
Melinda Morris,1Cameron Platell,1,2and Barry Iacopetta1
Purpose: The major pathologic markers of prognosis in colorectal cancer include vascular
invasion by tumor cells, invasion of adjacent lymph nodes, and perforation of the serosal wall.
Recent work suggests that a high density of tumor-infiltrating lymphocytes (TIL) is associated
with good outcome independently of these established prognostic markers. The aim of the
present study was to investigate the prognostic significance ofTILs and other routinely reported
pathologic features in colon cancer, particularly in relation to the use ofadjuvant chemotherapy.
Experimental Design: Pathologic markers, disease-specific survival, and the use of adjuvant
chemotherapy were recorded in a retrospective, population-based series of1,156 stage III colon
cancer patients with a median follow-up time of 52 months.
Results: Inpatients treatedbysurgeryalone(n = 851), markerswithsignificantprognosticvalue
included poor histologic grade,T4 stage, N2 nodal status, vascular invasion, and perforation, but
not thepresenceofTILs. Inpatients treated with 5-fluorouracil^basedchemotherapy (n = 305),
TILs were associated with significantly improved survival [hazard ratio (HR), 0.52; 95%
confidence interval, 0.30-0.91; P = 0.02] and perforation with a trend for improved survival
(HR,0.67;95%confidenceinterval,0.27-1.05;P =0.16). PatientswithTILsorperforationseemed
to gain more survival benefit from chemotherapy (HR, 0.22 and 0.21, respectively) than patients
without these features (HR, 0.84 and 0.82, respectively).
Conclusion: The apparent survival advantage from 5-fluorouracil associated withTILs and
perforation requires confirmation in prospective studies. Because the presence ofTILs reflects
an adaptive immune response and perforation is associated with inflammatory response, these
results suggest that there may be interactions between the immune system and chemotherapy
leading to improved survivalof colon cancer patients.
Colorectal cancers (CRC) are commonly infiltrated by immune
cells along the invasive margin. The most frequent among these
are T and B lymphocytes; however, natural killer cells, dendritic
cells, macrophages,and neutrophils are also present (1). The sur-
vival advantage associated with pronounced tumor-infiltrating
lymphocytes (TIL) in CRC has been widely documented (2–9).
The density of TILs is highest in stage I and II CRC and lowest in
stage III to IV CRC; however, the favorable prognosis associated
with this feature seems to be independent of tumor stage (3, 4,
6, 7). Naito et al. (4) reported that cytotoxic CD8+cells located
within tumor cell nests were a strong prognostic factor and this
became more apparent after longer patient follow-up times.
Menon et al. (6) found that CD8+and CD57+stromal cells at the
advancing tumor margin were independent prognostic factors.
The excellent prognosis associated with infiltrating lympho-
cytes was particularly evident in tumors displaying the micro-
satellite instability phenotype (5, 7).
The above studies support the notion that immune surveil-
lance plays a significant role in determining CRC prognosis.
CD8+cells and other activated T lymphocytes might suppress
the metastasis rather than the growth of these tumors. High
levels of infiltrating memory CD45RO+cells were shown re-
cently in CRC that showed no signs of early metastatic invasion
(8). A follow-up study by the same group found that quanti-
tative analysis of the adaptive immune response (CD3+, CD8+,
and CD45RO+) could provide prognostic information that was
superior to and independent of the International Union Against
Cancer tumor-node-metastasis classification system (9). High
densities of adaptive immune cells correlated with a highly
favorable prognosis regardless of the extent of tumor invasion
through the bowel wall or the involvement of regional lymph
Robust prognostic markers would be especially useful for
the management of stage II CRC due to the uncertainty sur-
rounding the overall benefit of chemotherapy for patients with
this stage of disease (10). The ability to identify stage II CRC
patients with very good prognosis would allow them to be
spared the toxicity and inconvenience of adjuvant treatments.
Established tumor markers for poor prognosis are extramural
vascular invasion, peritoneal involvement, extent of extramural
Imaging, Diagnosis, Prognosis
Authors’Affiliations:1School of Surgery and Pathology, University of Western
Australia, Nedlands,Western Australia, Australia and2Colorectal Unit, St John of
God Hospital, Subiaco,Western Australia, Australia
Received 8/13/07; revised11/29/07; accepted12/5/07.
Grant support: Royal Australasian College of Surgeons Surgeon-Scientist
scholarship (M. Morris).
The costs of publicationof this articlewere defrayedinpart by the paymentof page
charges.This article must therefore be hereby marked advertisement in accordance
with18 U.S.C. Section1734 solely toindicatethis fact.
Requests for reprints: Barry Iacopetta, School of Surgery and Pathology M507,
University of Western Australia, 35 Stirling Highway, Nedlands,Western Australia
6009, Australia. Phone: 61-8-9346-2085; E-mail: firstname.lastname@example.org.
F2008 American Association for Cancer Research.
www.aacrjournals.orgClin Cancer Res 2008;14(5) March1, 20081413