Prognostic impact of FoxP3+ regulatory T cells in relation to CD8+ T lymphocyte density in human colon carcinomas.

BACKGROUND: T-lymphocyte infiltration into colon carcinomas can influence clinical outcome, and interactions among T cell subsets may be more informative than either subset alone. Our objective was to examine the prognostic impact of tumor-infiltrating FoxP3(+) regulatory T cells (Tregs) in relation to cytotoxic CD8(+) T lymphocytes in patients with colon carcinomas characterized by DNA mismatch repair (MMR) status who participated in adjuvant chemotherapy trials. METHODS: FoxP3(+) and CD8(+) densities in tumor epithelial and stromal compartments were analyzed by immunohistochemistry and quantified in resected, stage II and III colonic carcinomas (N = 216). Immune marker density was dichotomized at the median and categorized as high vs low. MMR status was classified as MMR deficient (dMMR) or proficient (pMMR). Cox models were adjusted for age, stage, and tumor grade. RESULTS: The density of FoxP3+ infiltration was similar in tumor stroma and epithelia, whereas CD8+ was higher in stroma. The prognostic impact of FoxP3+ and CD8+ T cell infiltration was stronger in stroma vs epithelia, and the density of each marker in stroma was independently associated with improved overall survival (OS). However, the impact of FoxP3+ on survival was dependent upon CD8+ density (P interaction = 040). Among CD8+(low) tumors, FoxP3+(high) cases had significantly improved OS compared to FoxP3+(low) cases after adjustment for covariates (hazard ratio 0.43; 95% confidence interval 0.19 to 0.95; P = .030). In contrast, FoxP3+ was not prognostic among CD8+(high) tumors. FoxP3+ remained prognostic in CD8+(low) tumors after further adjustment for MMR or BRAF(V600E) mutation status. Additionally, these immune markers identified a pMMR subgroup with a similarly favorable OS as for dMMR tumors. CONCLUSIONS: The prognostic impact of FoxP3+ and CD8+ T cell density are inter-dependent, whereby FoxP3+ exerts a favorable influence on survival only in colon cancers with low CD8+ infiltration.

INI1 and GLUT-1 expression in epithelioid sarcoma and its cutaneous neoplastic and nonneoplastic mimics.

The morphological features of epithelioid sarcoma may closely mimic those of epithelial neoplasms, such as squamous cell carcinoma, mesenchymal tumors, such as benign fibrous histiocytoma, and nonneoplastic lesions, such as granuloma annulare. Immunohistochemistry, particularly for epithelial markers and CD34, thus plays a valuable role in the differential diagnosis of epithelioid sarcoma. However, some epithelioid sarcomas may show very focal or even absent expression of such markers and may be difficult to distinguish from various morphological mimics. There is therefore continued interest in the development of new immunohistochemical markers of epithelioid sarcoma. Recently, loss of expression of INI1, a tumor suppressor gene/protein, and expression of GLUT-1, a glucose transporter protein, have been described in epithelioid sarcoma. We examined the utility of immunohistochemistry for INI1 and GLUT-1 in the diagnosis of epithelioid sarcoma and various cutaneous mimics. Twenty-four cases of epithelioid sarcoma, 13 cases of granuloma annulare, 10 cases of rheumatoid nodule, 19 cases of cutaneous squamous cell carcinoma, 7 cases of atypical fibroxanthoma, 9 cases of benign fibrous histiocytoma (dermatofibroma), and 3 cases of nodular fasciitis were immunostained for GLUT-1 and INI1 using commercially available antibodies, heat-induced epitope retrieval, and the Dako Envision detection system. Total or near-total loss of normal constitutive expression of INI1 protein was noted in more than 85% of epithelioid sarcomas, with 19 of 24 cases (79%) showing complete loss of INI1 expression. In contrast, all other cases studied showed uniformly retained expression of INI1. GLUT-1 was positive in 40%-50% of epithelioid sarcomas, all cases of granuloma annulare and rheumatoid nodules, 67% of benign fibrous histiocytomas, and in all squamous cell carcinomas. In contrast, atypical fibroxanthomas and cases of nodular fasciitis were consistently GLUT-1 negative. We conclude that immunohistochemistry for INI1 expression should be included as part of the routine immunohistochemical panel for the diagnosis of epithelioid sarcoma, along with established markers such as wide-spectrum cytokeratins, cytokeratin 5/6, p63, and CD34. In this clinical context, loss of INI1 expression seems to be an entirely specific marker of epithelioid sarcoma and this finding may be of great value in distinguishing CD34-negative epithelioid sarcoma from squamous cell carcinoma and in the distinction of rare cytokeratin-negative epithelioid sarcomas from necrobiotic processes, nodular fasciitis, and benign fibrous histiocytomas. In contrast, there does not seem to be a role for GLUT-1 immunohistochemistry in this differential diagnosis.