Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability

doi:10.1016/j.humpath.2004.01.022

Human Pathology

Volume 35, Issue 7, July 2004, Pages 808-816

https://doi.org/10.1016/j.humpath.2004.01.022 Get rights and content

Abstract

Previous studies have identified high numbers of intraepithelial T lymphocytes to be associated with good prognosis in various types of cancer. Few studies addressing this issue have been published for colorectal cancer. In a simulated prospective approach (“phase II prognostic factor study“), all nonmetachronous International Union Against Cancer (UICC) stage III colorectal cancers that were accessioned in the years 1994 to 1999 were included in the study (152 cases). Follow-up information as to vital status and occurrence of metachronous metastases could be obtained for all patients in the years 2001 and 2002. CD8+ intratumoral lymphocytes were quantified after immunostaining and referred to tumor cell area (CD8+ densities). Microsatellite status was determined by using the Bethesda panel of microsatellite markers. CD8+ densities ranged from 0 per square millimeter to 1436 per square millimeter of tumor area in a nonnormal distribution that was skewed toward low values. Univariate survival analyses revealed the 66th percentile as a stringent cutoff (CD8+high versus CD8+low), with CD8+high cases taking a significantly better clinical course. This prognostic impact appeared even more pronounced in the subset of patients with colon carcinomas who were receiving 5-fluouracil/leucovorin as adjuvant treatment (79 patients). Seventeen patients had carcinomas with high microsatellite instability (MSI-H). MSI-H-CD8+high cases (n = 11) showed an excellent prognosis, with tumor-free survival for 9 of the 11 patients. The prognostic effect of CD8+high was retained in Cox regression analyses when including UICC substages (IIIA to IIIC). Our results identify CD8+ tumor-infiltrating lymphocytes as a promising candidate for further evaluation in the ongoing search for prognostic and predictive factors of colorectal cancer, particularly if combined with microsatellite status.

Section snippets

Patient material and clinical data

All patients who underwent a resection of a colorectal carcinoma in the years 1994 to 1999 in the Department of Surgery, University of Rostock, Rostock, Germany were identified. After review of the histopathologic reports and the clinical charts for the results of the clinical staging (clinical examination, abdominal imaging, chest roentgenogram, surgeon’s report), all patients for whom a UICC TNM stage III nonmetachronous primary colorectal cancer (adenocarcinoma or mucinous carcinoma) that

Densities of intratumoral CD8+ lymphocytes

CD8+ densities ranged from 0 per square millimeter of tumor area to 1436 per square millimeter; the mean was 106 per square millimeter, and the median was 28 per square millimeter. The histogram in Fig 2A represents the distribution of the densities, which was skewed toward low values. Associations of CD8+ densities with patient age, anatomic location of the tumor, UICC substage, microsatellite status, and adjuvant therapy are supplied in Table 1.

The determination of CD8+ densities proved to

Discussion

This study was designed as a confirmatory one, addressing CD8+ densities in colorectal carcinomas as a prognostic factor. To ensure sufficient statistical power, the study was made on UICC stage III cases; thus, selection was made for the stratum of potentially curatively resected patients with maximum likelihood of metachronous recurrence, that is, a maximum number of events. On the basis of a consecutive series of 152 cases that were resected in the years 1994 to 1999, standardized

Acknowledgements

The expert technical assistance of Ms. Silvia Stegemann and Ms. Marianne Thiemann is gratefully acknowledged by the authors.

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Original contributionPrognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability

Abstract

Section snippets

Patient material and clinical data

Densities of intratumoral CD8+ lymphocytes

Discussion

Acknowledgements

Eur J Cancer

Am J Pathol

Am J Pathol

The prognostic inhomogeneity of colorectal carcinomas Stage IIIA proposal for subdivision of Stage III

Cancer

Adjuvant chemotherapy in colon cancerWhat is the evidence?

Intern Med J

Specific immune recognition of autologous tumor by lymphocytes infiltrating colon carcinomasAnalysis by cytokine secretion

Cancer Immunol Immunother

Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes

Science

Lymphoid hyperplasiaA major prognostic feature in 519 cases of colorectal carcinoma

Am J Pathol

Assessment of invasive growth pattern and lymphocytic infiltration in colorectal cancer

Histopathology

Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma

Cancer

Dendritic cell infiltration in colon cancer

J Immunother

Proliferative activity of intratumoral CD8+ T-lymphocytes as a prognostic factor in human renal cell carcinomaClinicopathologic demonstration of antitumor immunity

Cancer Res

Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer

N Engl J Med

Original contribution
Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability