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Podoplanin: A Novel Marker for Oral Cancer Risk in Patients With Oral Premalignancy

Hidetoshi Kawaguchi, Adel K. El-Naggar, Vali Papadimitrakopoulou, Hening Ren, You-Hong Fan, Lei Feng, J. Jack Lee, Edward Kim, Waun Ki Hong, Scott M. Lippman, Li Mao

From the Departments of Thoracic/Head and Neck Medical Oncology, Biostatistics and Applied Mathematics, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Corresponding author: Li Mao, MD, Department of Thoracic/Head and Neck Medical Oncology, Unit 432, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: lmao{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Purpose Oral leukoplakia (OPL) is a heterogeneous oral lesion with an increased oral cancer risk. Current clinical parameters cannot predict the potential of malignant transformation in patients with OPL. We have shown that podoplanin, a lymphatic endothelial marker, is highly expressed in oral cancer and some oral premalignancies. The purpose of this study is to determine a role of podoplanin in predicting oral cancer development in patients with OPL.

Patients and Methods Podoplanin expression was determined in 150 OPL patients with long-term follow-up using immunohistochemistry. Association between the protein expression patterns and clinicopathologic parameters including oral cancer development during the follow-up were analyzed.

Results Fifty-six (37%) of the 150 OPL patients exhibited podoplanin expression in the basal and suprabasal layers and were classified as podoplanin positive. Podoplanin positivity was more frequent in older patients (P = .016), females (P = .020), and dysplastic lesions (P = .040). Patients with OPL that was podoplanin positive had significantly higher incidence of oral cancer than did those whose OPL was podoplanin negative (P = .0002). In the multivariate analysis using histology and podoplanin as cofactors, podoplanin was the only independent factor for oral cancer development (hazard ratio = 3.087; 95% CI, 1.530 to 6.231; P = .002). Importantly, oral cancer risk can be further stratified by considering both histology and podoplanin information.

Conclusion Podoplanin is frequently expressed in OPL. Together with histology, podoplanin may serve as a powerful biomarker to predict the risk for oral cancer development in patients with OPL.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Oral leukoplakia (OPL) comprises a multitude of histologically diverse lesions with variable but overall increased risk for development of invasive oral squamous cell carcinoma.¹ In several well-conducted studies, the malignant transformation rates of OPL were reported to range from 17% to 24% of the patients with median follow-up more than 7 years.^2,3 Although lesions with dysplastic features are thought to be at a higher risk of oral cancer, the majority of the oral cancers developed from lesions that lacked dysplastic changes.^2,3 Therefore, additional objective markers to identify high-risk lesions are needed for proper management recommendations.

Oral cancer development is a multistep process with accumulation of genetic, epigenetic, and metabolic alterations resulting from exposure to carcinogens.^4,5 A number of these alterations have been identified in the last decade, and led to improvement in the understanding of the underlying biology of the disease.⁵ Deletions at critical tumor suppressor loci in OPL are associated with an increased risk of oral cancer development in patients with OPL.^6,7

Podoplanin is specifically expressed in lymphatic endothelial cells but not in blood endothelial cells,⁸ and has been utilized as a specific marker for recognizing lymphatic vessels.^9,10 Podoplanin-null mice died at birth as a result of lethal respiratory failure accompanied by immature lymphatic vessel formation,^11,12 indicating that podoplanin plays an important role in regulating peripheral lung cell proliferation and lymphatic vascular development. Podoplanin expression has been reported in carcinomas of the skin, lung, uterus, and esophagus.^13-17 We recently reported a high podoplanin expression in head and neck squamous cell carcinoma, particularly in oral cancers; the high expression was significantly associated with patients’ lymph node metastasis and poor survival.¹⁸ It was noted that podoplanin was expressed in some hyperplastic and dysplastic lesions adjacent to the primary oral cancers,¹⁸ suggesting that expression of podoplanin may occur in early oral tumorigenesis and may play a role in the malignant transformation.

The purpose of this study was to determine the role of podoplanin in early oral tumorigenesis and as a biomarker for cancer risk assessment. We examined podoplanin expression patterns in OPL lesions from 150 patients who enrolled into a chemoprevention clinical trial and were prospectively followed up for a median of 7.5 years. The expression patterns were analyzed to determine their correlation with clinicopathologic parameters including oral cancer development during the follow-up period.

	PATIENTS AND METHODS

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Patients and Specimens
All of the 163 patients who were enrolled onto a randomized chemoprevention trial at The University of Texas M.D. Anderson Cancer Center (Houston, TX) were eligible for this study. The patients were diagnosed with OPL and randomly assigned to intervention with 13-cis-retinoic acid versus β-carotene + retinyl palmitate (RP) versus RP alone from 1994 to 2001. Formalin-fixed, paraffin-embedded biopsy specimens obtained before treatment or after enrollment but before treatment were used for the study. Clinicopathologic parameters were obtained from the clinical trial database. The follow-up data were obtained from a combination of chart review and telephone interview. The study was approved by the institutional review board, and written informed consent was obtained from all patients.

Tissue Processing and Immunohistochemistry
Tissue sections (4 µm thick) from formalin-fixed, paraffin-embedded tissue blocks of OPL were mounted on positively charged glass slides. Immunohistochemistry was performed using the avidin-biotin peroxidase complex (ABC) technique, as described previously.¹⁸ Briefly, slides were deparaffinized through a series of xylene baths and rehydrated with graded concentrations of alcohol. To retrieve antigenicity, slides were steamed with 10 mmol/L citrate buffer (pH, 6.0; DAKO Cytomation, Carpinteria, CA) for 20 minutes. The slides were then immersed in methanol containing 3% hydrogen peroxide for 10 minutes, followed by incubation in 10% horse serum for 30 minutes at room temperature. The slides were then incubated with monoclonal antibody D2-40 (antipodoplanin) at 1:100 dilution (Vector Laboratories, Burlingame, CA) at 4°C overnight followed by signal development processes using the Vectastatin Elite ABC kit according to the manufacturer's protocol (Vector). The slides were counterstained with Mayer's hematoxylin (DAKO Cytomation). Expression of podoplanin in lymphatic endothelial cells in stroma served as an internal positive control.

Cell membrane immunoreactivity was considered podoplanin expressed. The expression was scored as: 0 if no expression was observed in any part of the epithelium; 1 if expression was restricted to the basal layer of the epithelium; 2 if expression was observed in the basal and suprabasal layers at one area; 3 if the suprabasal layer expression was observed at two or three areas; and 4 if the suprabasal layer expression was observed at more than three areas. The scores were based on examination of the whole section in each biopsy by three observers (H.K., L.M., and A.K.E.N.), who were blinded to the clinical information, under a multiheaded microscope.

Statistical Analysis
The associations between podoplanin expression status and clinicopathologic parameters were analyzed using the ² test or Fisher's exact test for categoric variables and the Wilcoxon rank sum test for continuous variables. For time-to-event analysis, Kaplan-Meier curves were plotted. The median time to event with 95% CI and event-free survival rates at years 3, 5, and 10 were determined. Cox proportional hazards models were utilized for univariate and multivariate analyses. The hazard ratios with 95% CI and P values were reported. All tests were two-sided, and P values less than .05 were considered statistically significant.

	RESULTS

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Characteristics of the Patients
Of the 163 patients enrolled in the chemoprevention trial, 13 (8%) were excluded because of lack of tissue blocks (n = 8) or lack of epithelial layers in the tissue sections (n = 5). In 18 (12%) of the 150 remaining patients analyzed in this study, biopsy specimens were obtained after enrollment because the paraffin blocks from baseline biopsies were unavailable. The medium follow-up period for the patient population was 7.5 years, with 35 (23%) of the 150 patients developing invasive cancer in the oral cavity: 18 tumors at the same sites of the original OPL and 17 tumors at different sites from the original OPL.

Expression of Podoplanin in OPL
Podoplanin expression was consistently detected in endothelial cells of lymphatic vessels, but was highly variable in epithelium of the OPL lesions, from no expression (Fig 1A) to high expression (Fig 1E) in the patient population. In OPL, podoplanin expression was observed on the cell membrane predominantly at the basal layer (Fig 1B). In some cases, the expression extended to suprabasal layer or above at one or multiple pockets (Fig 1C-1E).

View larger version (57K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Podoplanin expression. (A-E) Representative expression of podoplanin corresponding to scores 0 to 4. The lower part of each panel is a magnified view of the box in the upper part of the panel. The blue arrows indicate basal layers and the red arrows lymphatic vessels. The pink circles are nests with positive podoplanin expression.

Podoplanin Expression and Clinicopathologic Parameters
Distribution of the podoplanin expression status and its associations with general clinicopathologic parameters are summarized in Table 1. Significantly more podoplanin-positive lesions were found in older patients (P = .016), females (P = .02), and lesions with dysplasia (P = .04). There was no statistically significant correlation between podoplanin status and smoking history and alcohol consumption. Because we observed an association between dysplasia and podoplanin expression status, we analyzed the expression status with more detailed histologic classification of the lesions and found that the frequencies of podoplanin expression increase with increased severity of dysplasia, particularly from mild dysplasia to moderate or severe dysplasia/carcinoma in situ (Fig 2A). Whereas 32 (32%) of the 101 OPL lesions with only hyperplasia were podoplanin-positive, 15 (41%) of the 37 lesions with mild dysplasia, seven (70%) of the 10 lesions with moderate dysplasia, and both of the two lesions with severe dysplasia/carcinoma in situ exhibited positive podoplanin (P = .02). Despite such association, podoplanin expression may provide additional information beyond histologic features. Figure 2B shows an example in which the lesion exhibited mild dysplastic histology but expressed podoplanin across all the layers of the epithelium, indicating an outgrowth of the abnormal clone. The patient subsequently developed invasive oral cancer at the biopsy site 26 months after the biopsy was taken.

View larger version (60K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Frequencies of positive podoplanin by histology. Representative example of histology (B) and podoplanin expression (C) in adjacent oral leukoplakia sections. The boxes show the same area with mild dysplasia (B) and clonally expanded cells with positive podoplanin expression (C). HYP, hyperplasia; MLD, mild dysplasia; MOD, moderate dysplasia; SED, severe dysplasia/carcinoma in situ.

View larger version (23K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Oral cancer-free survivals (A) by podoplanin scores; (B) by podoplanin-positive (+) or podoplanin-negative (–); and (C) by both podoplanin and histology. (D) Event chart showing distance between biopsy and cancer diagnosis. The upper panel contains patients with negative podoplanin, and the lower shows patients with positive podoplanin. The dashed line represents 3 years after podoplanin analysis.

To examine the course to oral cancer development between the group with negative podoplanin expression and the group with positive podoplanin expression, we used the interval event chart¹⁹ to display the time to oral cancer diagnosis (Fig 3D). Among the 22 cases with positive podoplanin expression, 18 (82%) developed oral cancer within 3 years after the OPL biopsies were examined compared with only five (38%) of the 13 cases with negative podoplanin expression (P = .013).

	DISCUSSION

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A unique feature of our study is its prospective nature, the large number of patients in this type of disease setting, and the length of follow-up. Thirty-five of the 150 patients studied developed invasive oral cancer during the follow-up period, which provided considerable statistical power for correlative analyses. Because 92% of the all eligible patients in the clinical trial were included in the current study, we contend that our results represent the study population of the chemoprevention trial.

Podoplanin is abnormally expressed in the early oral tumorigenesis, with 70% of OPL showing podoplanin expression in some of the basal cells. However, podoplanin expression alone may not be sufficient to promote tumorigenesis because many of the lesions exhibit the protein expression only in the basal layer cells. Other factors are needed to promote clonal expansion of the abnormal cells. The upward clonal expansion of the podoplanin-expressing cells in the epithelial layers supports this notion. Indeed, lesions with such clonal expansion carry a significantly higher risk of oral cancer development (Fig 3A-B). The ability to detect the cells expanding beyond basal layers may allow us to visualize potential clonal expansion, possibly from stem-cell clones, during tumorigenesis (Fig 2B). More studies are needed to compare lesions with clonal expansion determined by other markers and podoplanin expression patterns to address whether podoplanin expression patterns provide additional information beyond clonal expansion.

Although the biologic roles of podoplanin are not fully understood, studies have suggested that podoplanin is biologically important in tumorigenesis and malignant progression. It has been shown that PA2.26 antigen, a homolog of human podoplanin, was upregulated during murine epidermal remodeling and carcinogenesis²⁰ and induction of PA2.26 in mouse epidermal cells and tumor cells resulted in an increased cell migration and malignant transformation.^21,22 In squamous cell carcinomas, expression of podoplanin is restricted to the invasive front of tumors.^13,14 Podoplanin is also found to promote tumor cell invasion by inducing collective cell migration via the downregulation of the activities of small Rho family GTPases.¹⁷ Furthermore, podoplanin may reduce cell-cell adhesion and expression of E-cadherin.¹² Together, these results support the role of podoplanin in tumorigenesis and malignant progression.

In oral squamous cell carcinomas, approximately 90% express podoplanin, and higher expression levels are associated with lymph node metastasis and poor clinical outcome.¹⁸ In this study, we found that 37% of OPL lesions exhibit expression patterns similar to those found in oral squamous cell carcinomas. The expression patterns correlate with dysplasia of the OPL lesions in a grade-dependent manner (Fig 2A; Table 1) and a higher rate of oral cancer development (Fig 3A-B). These results suggest a role of podoplanin in oral cancer initiation and progression.

From the biomarker standpoint, the potential utility of podoplanin expression depends on whether it can provide additional value beyond current clinical and pathologic assessments. In this study cohort, histology of the OPL lesions has a significant role in assessing oral cancer risk, but podoplanin seems a stronger predictor. In fact, the lesions showed no dysplasia in 54% of the patients who developed oral cancer (data not shown). Because both dysplasia and podoplanin were independent factors for oral cancer development, it is logical that combining the two factors may enhance cancer risk assessment and supported by our data. At 3 years after the sample assessment, less than 3% of the patients with nondysplastic and podoplanin-negative OPL developed oral cancer compared with more than 38% of those who had lesions with both dysplasia and positive podoplanin expression (Fig 3C). Because histologic assessment is the standard clinical practice for these lesions and the interpretation of podoplanin expression is relatively simple, it is reasonable to recommend that podoplanin expression be added to the routine histologic evaluation of OPL lesions after the results are validated in independent studies.

Of further interest is that 13 (37%) of the oral cancers developed in patients with podoplanin-negative lesions. Considering that approximately 90% of the oral cancers express some level of podoplanin,¹⁸ it is possible that the OPL lesions showing negative podoplanin were biopsied before the abnormality developed. Indeed, cancers from the podoplanin-negative group took significantly longer to develop (Fig 3D). If additional biopsies had been performed closer to the cancer development, some of the lesions might have shown podoplanin-positive patterns. Another possibility is that the biopsies taken were from a different clonal site than the one from which the cancer eventually developed. OPLs from the group that developed cancer at the same sites had a higher rate of podoplanin expression than those from the group that developed cancer at different sites (although not statistically significant), supporting this notion. At the molecular level, we and others have shown that the multifocal oral lesions may have a single clonal origin or derive independently.^23,24 Therefore, cancers developed at distinct sites are likely to represent a mixture of lesions derived from clones of the original OPL lesions and those developed independently. In fact, the patients with podoplanin-negative OPL lesions rarely developed oral cancer at the same biopsy sites (data not shown), consistent with the notion that some of the oral cancers developed from the podoplanin-negative individuals were derived from lesions not clinically visible at the time of biopsy and therefore unexamined.

One potential confounding factor that may influence the results of the present study is the effect of chemopreventive agents. The impact of the agents in podoplanin expression may be determined by a comparative analysis of samples obtained before and after treatment and by in vitro biologic experiments in the future. Nevertheless, the early occurrence of podoplanin expression in oral tumorigenesis, the strong association between high podoplanin expression and cancer development, and the role of podoplanin in promoting cell invasion revealed in the in vitro experiments, suggest that podoplanin may be used as a biomarker for oral cancer risk assessment and a potential chemoprevention target.

	Authors’ Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Conception and design: Li Mao

Financial support: Waun Ki Hong, Li Mao

Administrative support: Waun Ki Hong, Scott M. Lippman, Li Mao

Provision of study materials or patients: Adel K. El-Naggar, Vali Papadimitrakopoulou, Edward Kim, Waun Ki Hong, Scott M. Lippman

Collection and assembly of data: Hidetoshi Kawaguchi, You-Hong Fan, Li Mao

Data analysis and interpretation: Hidetoshi Kawaguchi, Adel K. El-Naggar, Hening Ren, Lei Feng, J. Jack Lee, Li Mao

Manuscript writing: Hidetoshi Kawaguchi, Li Mao

Final approval of manuscript: Li Mao

	NOTES

 
Supported in part by National Cancer Institute Grants No. PO1 CA52051, PO1 CA106451, P50 CA97007, and P30 CA16672, and by the Uehara Memorial Foundation (H.K.)

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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12. Schacht V, Ramirez MI, Hong YK, et al: T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J 22:3546-3556, 2003[CrossRef][Medline]

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14. Martín-Villar E, Scholl FG, Gamallo C, et al: Characterization of human PA2.26 antigen (T1alpha-2, podoplanin), a small membrane mucin induced in oral squamous cell carcinomas. Int J Cancer 113:899-910, 2005[CrossRef][Medline]

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16. Dumoff KL, Chu CS, Harris EE, et al: Low podoplanin expression in pretreatment biopsy material predicts poor prognosis in advanced-stage squamous cell carcinoma of the uterine cervix treated by primary radiation. Mod Pathol 19:708-716, 2006[CrossRef][Medline]

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21. Scholl FG, Gamallo C, Vilaró S, et al: Identification of PA2.26 antigen as a novel cell-surface mucin-type glycoprotein that induces plasma membrane extensions and increased motility in keratinocytes. J Cell Sci 112:4601-4613, 1999[Abstract]

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Submitted July 6, 2007; accepted August 21, 2007.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kawaguchi, H. Articles by Mao, L. Search for Related Content PubMed PubMed Citation Articles by Kawaguchi, H. Articles by Mao, L. Related Articles Related Editorial Social Bookmarking                            What's this?