Potential Use of Quantitative Tissue Phenotype to Predict Malignant Risk for Oral Premalignant Lesions

Abstract

The importance of early diagnosis in improving mortality and morbidity rates of oral squamous cell carcinoma (SCC) has long been recognized. However, a major challenge for early diagnosis is our limited ability to differentiate oral premalignant lesions (OPL) at high risk of progressing into invasive SCC from those at low risk. We investigated the potential of quantitative tissue phenotype (QTP), measured by highresolution image analysis, to identify severe dysplasia/ carcinoma in situ (CIS; known to have an increased risk of progression) and to predict progression to cancer within hyperplasia or mild/moderate dysplasia. We generated a nuclear phenotype score (NPS), a combination of five nuclear morphometric features that best discriminate 4,027 ''normal'' nuclei (selected from 29 normal oral biopsies) from 4,298 ''abnormal'' nuclei (selected from 30 SCC biopsies). This NPS was then determined for a set of 69 OPLs. Severe dysplasia/CIS showed a significant increase in NPS compared with hyperplasia or mild/moderate dysplasia. However, within the latter group, elevated NPS was strongly associated with the presence of high-risk loss of heterozygosity (LOH) patterns. There was a statistical difference between NPS of hyperplasia or mild/ moderate dysplasia that progressed to cancer and those that did not. Individuals with a high NPS had a 10-fold increase in relative risk of progression. In the multivariate Cox model, LOH and NPS together were the strongest predictors for cancer development. These data suggest that QTP could be used to identify lesions that require molecular evaluation and should be integrated with such approaches to facilitate the identification of hyperplasia or mild/moderate dysplasia OPLs at high risk of progression. [Cancer Res 2008;68(9):3099-107]

Translation of an STR-based biomarker into a clinically compatible SNP-based platform for loss of heterozygosity

“…LOH is a common somatic genetic abnormality in solid tumors and many precancerous conditions [8, 9, 15, 17, 22, 27, 28, 33] The TP53 and CDKN2A/ARF loci are two of the most common targets for inactivation in human cancers associated with LOH [32, 43, 47, 48]. In addition to 17p and 9p LOH in BE, several longitudinal studies have reported that detection of selected LOH in premalignant tissues can identify patients at increased risk for future progression to cancer, providing a window for early detection and prevention.…”

Targeting of chemoprevention to high-risk potentially malignant oral lesions: Challenges and opportunities

“…The association of DNA quantity and risk has been reproducibly demonstrated by several groups using independent cohorts 39–42 , with evidence that combining such analysis with dysplasia grading gives a higher predictive value than either technique alone. In 2008, Guillaud et al ., 43 reported on the use of an algorithm (nuclear phenotype score, NPS) for identifying textural changes in oral lesions (such as heterochromatin versus euchromatin organization) and nuclear morphology changes (diameter, radius, and nuclear boundaries) that strongly associated with progression risk in a set of 69 PMLs. Individuals with a high NPS had a 10-fold increase in relative risk of progression.…”

“…Studies with the OCPL cohort have shown that a combination of TB staining and LOH increases the capacity to delineate mucosal areas with high molecular risk, compared to each test alone 28 . Finally, the combination of LOH (3p/9p markers) and QTP increases the ability to detect lesions with both high molecular risk and the subtle histological change associated with outcome, thus enhancing overall predictive value against either approach alone 43 . Analysis of a validation of the latter approach has just been completed in a new group of patients in the OCPL study.…”

High throughput image cytometry for detection of suspicious lesions in the oral cavity

“…28 Our previous quantitative histology work showed that the quantification of the many facets of heterochromatin condensation and hyperchromatism is predictive of cancer development and is strongly associated with genetic level alterations within oral tissue. [5][6][7]34 Thus it was not unexpected that the training process for the LDFs resulted in the selection of features that are known to be measures of nuclear hyperchromasia.…”

“…4 We have previously reported that the organization of DNA within nuclei is predictive of progression of dysplasia to cancer 5,6 and highly correlated with other indices of genetic alteration, such as measured loss of heterozygosity (LOH) and array comparative genomic hybridization. 7 The combination of DNA content and subtle alterations in DNA organization have been used to improve the detection of cervical and bronchial cancers and precancers from cytological samples and has demonstrated clinical utility.…”