Abstract
Up to 50% of oral squamous cell carcinomas (OSCCs) recur following surgical resections with conventional "histologically-negative" margins. Three members of the SIBLING family of proteins: dentin sialophophoprotein (DSPP); bone sialoprotein (BSP); and osteopontin OPN are upregulated in OSCCs. In this study, we aimed to correlate the expression of DSPP, OPN and BSP as well as three SIBLING-partners, matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-3 (MMP-3), and matrix metalloproteinase-9 (MMP-9), at histologically-negative margins of OSCCs with tumor recurrence. Immunohistochemical analyses of the SIBLINGs and MMP expressions at histologically-negative margins of OSCC was carried out in a retrospective study of 20 patients, and the results correlated with tumor recurrence. Each protein was dichotomized as "present" (≥10% staining) or "absent" (more than 10% staining). The Sensitivity, Specificity, Positive Predictive Value(PV+) and Negative Predictive Value (PV-) for recurrence was calculated for each protein, along with their overall diagnostic accuracy, calculated as: (number of true positives + number of true negatives)/ number of patients. OSCC recurred in 9 of 20 patients (45%), a ratio not significantly different from the estimated population recurrence rate of 50% (p = 0.664). Among the SIBLINGs, DSPP and OPN showed the greatest Accuracy with DSPP being more Sensitive (89%) and OPN more Specific (64%). MMP-9 showed the greatest overall Accuracy (80%), slightly less Sensitivity (67%) and more Specificity (100%), than either DSPP or OPN. MMP-9 showed a superior positive PV than either DSPP or OPN. The negative PVs of OPN and MMP-9 were almost identical, and inferior to DSPP. We conclude that DSPP, OPN, or MMP-9 expressions at histologically-negative surgical margins predict OSCC recurrence with MMP-9 being the preferred predictor. These proteins may identify patients who could benefit from more extensive resection, or from adjunct treatments such as radiotherapy.
Highlights
Most mortality in oral squamous cell carcinoma (OSCC) patients is due to local recurrent disease and regional spread following surgical treatment failure at the primary site [1,2,3,4,5]
Recent studies explored the utility of molecular markers, independently or as complementary to the histologic parameters, to define functionally better resection margins that result in recurrence-free status (RFS) for patients treated for primary OSCCs as well as other head and neck cancers [4,5,6,7,8,9]
A total of 200 histologically negative surgical mucosal margin sections, obtained at several consecutive levels, from the 20 cases of OSCCs were each subjected to immunohistochemistry analysis for the expressions of each of the Small Integrin-Binding LIgand N-linked Glycoprotein (SIBLING) (BSP, dentin sialophophoprotein (DSPP), OPN), and matrix metalloproteinases (MMPs) (MMP-2, matrix metalloproteinase-3 (MMP-3), MMP-9)
Summary
Most mortality in oral squamous cell carcinoma (OSCC) patients is due to local recurrent disease and regional spread following surgical treatment failure at the primary site [1,2,3,4,5]. Up to 50% of OSCCs recur following surgical intervention even with “adequate tumor-free” (histologically-negative) margins, usually within 2 years of initial surgical intervention [3, 5] This high recurrence rate at primary tumor sites suggests malignant transformation at the molecular level that may precede the phenotypic histologic changes observed. The practical aspects of histologically defined negative margins are inadequate in determining recurrence-free status following surgical treatment in OSCC patients [6]. Recent studies explored the utility of molecular markers, independently or as complementary to the histologic parameters, to define functionally better resection margins that result in recurrence-free status (RFS) for patients treated for primary OSCCs as well as other head and neck cancers [4,5,6,7,8,9]. Most markers reported to date lack the sensitivity and/or ease of applicability required for routine clinical use [4,5,6]
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