Enhanced TKTL1 expression in malignant tumors of the ocular adnexa predicts clinical outcome

Abstract

Purpose: Malignant tumors metabolize glucose to lactate even in the presence of oxygen via the pentose-phosphate pathway. The metabolic switch from oxidative glycolysis to nonoxidative fermentation in tumors has been associated with overexpression of the transketolase-like-1-gene (TKTL1), which encodes an essential and rate-limiting enzyme in the nonoxidative part of the pentose-phosphate pathway. This study investigates the role of TKTL1 in ocular adnexal tumors and analyzes how its expression correlates with the clinical outcomes against the background of tumor thickness and mitotic rate.

Design: Comparative case studies.

Participants: We included 89 subjects with malignant tumors of the ocular adnexa (44 squamous cell carcinomas, 26 lymphomas, 19 malignant melanomas) who had been treated at the University Eye Hospital Freiburg from 1994 to 2008. Sixteen subjects with conjunctival nevi, 19 with conjunctival papilloma, and 2 with conjunctival-reactive lymphoid hyperplasia were included as controls.

Methods: TKTL1 expression was assessed by reverse transcriptase-polymerase chain reaction and immunohistochemistry and semiquantitatively analyzed using an established immunoreactive score (IRS). The tumor recurrence rate, metastasis occurrence, and survival time of each patient were assessed retrospectively and correlated with the TKTL IRS using Kaplan-Meier and Cox regression analyses.

Main outcome measures: TKTL1 expression, mitotic rate within the tumor mass, and tumor thickness and its association with clinical outcome.

Results: We identified increased TKTL1 protein levels in malignant conjunctival tumors compared with control samples and detected an average IRS of 1.78 (standard deviation [SD], ± 0.46) for melanomas, 1.3 for lymphomas (SD, ± 0.79), and 1.22 for squamous cell carcinomas (SD, ± 0. 97) compared with 0.86 for conjunctival nevi (SD, ± 0.57) and 0.5 for conjunctival papilloma (SD, ± 0.83). Multifactorial survival analysis showed that TKTL1 overexpression correlated with the patient outcomes in malignant tumors (P = 0.045). In the squamous cell carcinomas, tumor thickness and mitotic rate correlated more strongly with prognosis compared with TKTL1 overexpression (P = 0.0061, P = 0.015, and P = 0.061, respectively).

Conclusions: TKTL1 is dysregulated in malignant tumors of the ocular adnexa, and enhanced expression seems to predict clinical outcome, especially the tumor recurrence rate.