Abstract
Objective
Requirements of an NCI contract examining a novel treatment for leukoplakia were to compare standard bi-dimensional measurement of oral lesions to examine for correlation with Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and to examine the feasibility of digital image analysis for automated measurements.
Study design
Retrospective review.
Methods
We examined 13 patients by bi-dimensional measurement and compared these measurements to 1) RECIST criteria, 2) scalar digital measurements using a standardized measuring device within the photograph, and 3) pixel number.
Results
RECIST criteria correlated (r-squared = 0.8535, p < 0.0001) with bi-dimensional measurements. Digitized measures in photographs correlated with bi-dimensional measurements (r-squared = 0.6661, p = 0.0007), but were time consuming. There was minimal to no correlation between pixel number in Adobe Photoshop and the other measures.
Conclusion
Bi-dimensional measurement of oral leukoplakia and RECIST criteria are highly correlated. Digital photography measurements, though highly correlative, are very cumbersome. We recommend bi-dimensional or longest length measurement and a simple photograph as standard of documentation for leukoplakia lesions.
1
Introduction
As defined by the World Health Organization, oral leukoplakia is a white patch or plaque that cannot be characterized clinically or pathologically as any other disease . It has been identified as a precursor of oral squamous cell carcinoma. The prevalence varies from less than one to more than 5% . Leukoplakia is seen most frequently in middle-aged and older men, with an increasing prevalence with age . It is associated with alcohol and tobacco use and chronic inflammation, although idiopathic forms are not uncommon . This disease process can occur throughout the oral cavity with the most common sites being the buccal mucosa, alveolar mucosa and lower lip. Lesions of the floor of mouth are at highest risk for malignant or dysplastic change, whereas the lateral tongue and lower lip are also considered high risk sites . The incidence of malignant transformation has been estimated to range from less than 1 to 17% .
Prevention of malignant transformation is particularly important in view of the poor prognosis associated with oral squamous cell carcinoma. Modalities that have been considered for the treatment of oral leukoplakia include observation, surgical resection, and topical or systemic medical therapies , none of which have been shown to be effective in preventing malignant transformation . Leukoplakias are not morbid or lethal in and of themselves, and their risk of transformation is relatively low. However, there is no definitive or reliable method to identify those lesions that will undergo malignant transformation . Thus, proposed treatments should have minimal adverse effects in terms of incidence and severity .
Additionally, since leukoplakia lesions can have a variety of appearances in terms of hue (amount of leukoplakia and erythroplakia), degree of homogeneity, and thickness, reliable methods of documentation of leukoplakia size and sites of involvement are vital for use as a standard surrogate lesion for any studies. Currently, we are conducting a National Cancer Institute (NCI)-sponsored clinical trial for treatment of oral leukoplakia. This is a phase IIa study that has as its principal objective to assess the clinical efficacy of a PPAR-gamma agonist in the treatment of upper aerodigestive leukoplakia. As part of the NCI contract, we investigated 3 separate modalities of documentation of lesion size to better understand if any method is more easily employed reliably in preneoplastic lesions.
2
Methods
This study was approved by the University of Minnesota Institutional Review Board and is also in compliance with HIPAA (Health Insurance Portability and Accountability Act) guidelines. Thirteen patients with oral dysplastic leukoplakia were evaluated. Patients were enrolled into the study if they had at least one lesion of histologically dysplastic leukoplakia as determined by biopsy. At the time of enrollment, patients underwent history, physical examination, laboratory testing, lesion evaluation with bi-dimensional measurement, photographic documentation of the lesion and incisional biopsy. The bi-dimensional measurements were taken with a perioprobe calibration device and the greatest length and width bi-dimensional measurements were recorded by the senior authors. The perioprobe is a standard dental calibration device for the quantitation of gingival crevicular pocket depth for the quantitation of periodontal disease. It is calibrated in at 1 mm intervals.
Extreme care was taken not to stretch or distort the mucosa and potentially alter the lesion size. The lesions were measured twice. Photography was performed with a Fuji e510 5 megapixel digital camera. Within each photograph, a perioprobe was also used as a standardized measure. The patients were then treated for 12 weeks with a PPAR-gamma agonist. At the conclusion of the 12 week course of treatment, repeat laboratory testing, lesion evaluation via clinical examination and biopsy, and photographic documentation were performed (see Fig. 1 ).
Using Adobe Photoshop 7.0, the photographs were analyzed by measuring the lesion within the photo. This was performed by measuring the longest length and width of the lesion and also of the perioprobe specific to each photograph. The actual length of the perioprobe is standard, and thus a conversion factor was determined that was used to convert the size of the lesion in the photograph to actual size. Additionally, the boundary of each lesion was outlined within the Photoshop program tracing function, and the number of pixels that constituted the lesion was recorded. If a patient had more than one lesion, each lesion was treated individually and the value for each lesion was summed to determine the total size.
The data recorded for each patient included bi-dimensional measures of the oral leukoplakia lesion pre- and post-treatment, the dimensions and area of the lesion within the photograph, and the total pixel count of the lesion (see Table 1 ). The bi-dimensional measurements taken at the time of clinical examination were compared to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, scalar digital measurements with a standardized measuring device in the photograph, and the number of pixels.
| Measured Lesion Area | Measurement obtained at the time of physical examination using the perioprobe by multiplying longest length and width |
| Longest Measured Side | Longest measured side of the lesion obtained at the time of physical examination using the perioprobe |
| Area of Lesion in Photograph | Measurement obtained from a photograph by measuring the length of the perioprobe in the photo and also measuring the length and width of the lesion in the photo. The perioprobe’s actual length was known and was used to convert a measurement in the photo to an “actual” measurement. Area was determined by multiplying the calculated length and width |
| Pixel Count | The number of pixels within the outlined borders of the lesion. |
Statistics: Correlational coefficients were determined using the Graph Pad Prism scientific statistics program after fitting the data to a first order linear regression function (Graph Pad Software, Palo Alto, CA). P values less than .05 were considered significant.
2
Methods
This study was approved by the University of Minnesota Institutional Review Board and is also in compliance with HIPAA (Health Insurance Portability and Accountability Act) guidelines. Thirteen patients with oral dysplastic leukoplakia were evaluated. Patients were enrolled into the study if they had at least one lesion of histologically dysplastic leukoplakia as determined by biopsy. At the time of enrollment, patients underwent history, physical examination, laboratory testing, lesion evaluation with bi-dimensional measurement, photographic documentation of the lesion and incisional biopsy. The bi-dimensional measurements were taken with a perioprobe calibration device and the greatest length and width bi-dimensional measurements were recorded by the senior authors. The perioprobe is a standard dental calibration device for the quantitation of gingival crevicular pocket depth for the quantitation of periodontal disease. It is calibrated in at 1 mm intervals.
Extreme care was taken not to stretch or distort the mucosa and potentially alter the lesion size. The lesions were measured twice. Photography was performed with a Fuji e510 5 megapixel digital camera. Within each photograph, a perioprobe was also used as a standardized measure. The patients were then treated for 12 weeks with a PPAR-gamma agonist. At the conclusion of the 12 week course of treatment, repeat laboratory testing, lesion evaluation via clinical examination and biopsy, and photographic documentation were performed (see Fig. 1 ).
