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ORIGINAL RESEARCH  
Year : 2014  |  Volume : 25  |  Issue : 3  |  Page : 305-310
Expression of podoplanin in oral premalignant and malignant lesions and its potential as a biomarker


1 Departments of Oral Pathology and Microbiology, Meenakshi Ammal Dental College, Maduravoyal, Tamil Nadu, India
2 Faculty of Dental Sciences, Sri Ramachandra University, Chennai, Tamil Nadu, India

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Date of Submission25-Feb-2013
Date of Decision30-Sep-2013
Date of Acceptance20-Jul-2014
Date of Web Publication7-Aug-2014
 

   Abstract 

Aim: To analyze and compare the expression of podoplanin in normal oral tissues, leukoplakia and oral squamous cell carcinoma (OSCC) and to predict its use as a biomarker.
Materials and Methods: Ninety-two formalin fixed paraffin embedded tissue samples comprising of 32 cases of leukoplakia, 50 cases of OSCCs and ten normal gingival samples. The samples were retrieved from archives and immunohistochemically analyzed using podoplanin. Appendix tissue samples were used for control purposes. The results were tabulated and statistically analyzed using ANOVA/Kruskal-Wallis test with post-hoc tests, where demographic details are compared and analyzed using Pearson Chi-square test.
Results: The study results showed, absence of podoplanin expression in the epithelium of all the gingival samples (Group I). Positive podoplanin expression noticed in 19 out of 32 (59.4%) cases of leukoplakia (Group II) and 41 out of 50 (82%) cases of OSCCs (Group III). The expression of podoplanin among different groups was highly significant (P = 0.000).
Conclusion: The podoplanin may be considered as a predictor marker in assessing malignant transformation of premalignancies and prognosis of oral malignancy. Indeed it is believed that podoplanin might play a role in tumor progression though exact mechanism is not fully elucidated. Further research is required to understand its exact pathophysiology.

Keywords: Leukoplakia, oral squamous cell carcinoma, podoplanin

How to cite this article:
Logeswari J, Malathi N, Thamizhchelvan H, Sangeetha N, Nirmala S V. Expression of podoplanin in oral premalignant and malignant lesions and its potential as a biomarker. Indian J Dent Res 2014;25:305-10

How to cite this URL:
Logeswari J, Malathi N, Thamizhchelvan H, Sangeetha N, Nirmala S V. Expression of podoplanin in oral premalignant and malignant lesions and its potential as a biomarker. Indian J Dent Res [serial online] 2014 [cited 2019 Dec 7];25:305-10. Available from: http://www.ijdr.in/text.asp?2014/25/3/305/138321
Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the head and neck region. Two-third of the head and neck squamous cell carcinomas (HNSCC) occurs with incidence of 500,000 new cases every year worldwide. [1],[2],[3] In India, OSCCs accounts the leading cause of mortality in men, reaching up to 22.9% of cancer-related deaths. [4] Indefinitive proliferation of tumor cells results from accumulation of multiple genetic alterations, influenced by a patient's genetic predisposition as well as by environmental influences, including tobacco, alcohol, chronic inflammation, and viral infection. [3],[5]

Podoplanin (also known as Aggrus, M2A, E11, GP38) is a 40 kDa O-linked sialoglycoprotein, a molecule expressed in lymphatic endothelial cells (LECs), which can be recognized by a specific monoclonal antibody named D2-40. [2],[5],[6] It is identified as the endogenous ligand of C type lectin like receptor 2 on platelets that induces platelet aggregation on activation. [1],[2] Podoplanin expression is completely restricted to LECs in vascular system, that allows to distinguish lymphatic vessels from blood vessels immunohistochemically. [7],[8] Recent immunohistochemical analysis has revealed podoplanin reactivity in various normal cells such as podocytes and alveolar Type-I cells and also in number of neoplastic tissues such as squamous cell carcinoma, mesothelioma, and germ cell tumors. Thus, its expression might be related to tumor cell migration and invasion. [7],[8],[9],[10]

For the past 50 years, despite of latest advances in treatment modality, the survival rate of patients with OSCC has not improved significantly. [11] The recent works are therefore focused on identification of a novel molecular factor that may be effective as both diagnostic and prognostic marker even at a premalignant stage. Expression of podoplanin in human cancers and its relationship with tumor invasion raises the possibility that it could be used as a marker for cancer diagnosis and prognosis. Hence, the present study is an attempt to analyze the expression pattern of podoplanin in leukoplakia and OSCCs and to predict its use as a biomarker in diagnosis and prognosis.


   Materials and methods Top


The study material consists of 92 formalin fixed paraffin embedded tissue specimens, which were divided into three groups. Ten normal gingival samples (Group I) obtained during extraction of premolars for orthodontic purpose after obtaining a patient consent. Remaining 82 samples were retrieved from the archival materials, comprised of previously diagnosed 32 cases of oral leukoplakia (Group II) and 50 cases of OSCC (Group III) from Department of Oral and Maxillofacial Pathology and Microbiology, Faculty of Dental Sciences, Sri Ramachandra University, Chennai. All 92 tissue specimens along with appendix tissue sections (positive control) were considered for immunohistochemical staining of podoplanin. Primary antibody prediluted ready to use primary antipodoplanin monoclonal antibody, clone-D2-40 (Dako, Carpenteria, CA, USA) and secondary antibody - supersensitive polymer/horse radish peroxide (HRP)/diamino benzidine (DAB) IHC detection kit (Biogenex, San Ramon, CA, USA), were used.

Immunohistochemistry

In brief, immunohistochemical analysis were performed on the 4 μm thick sections made onto poly-L Lysine coated slides and were deparaffinized by fresh xylene, followed by dehydration in graded alcohol. The sections were treated with peroxide block for 15 min in room temperature for blocking endogenous peroxidase, followed by pressure cooker antigen retrieval for 15 min. The tissue sections were incubated with power block for 15 min. Further tissue sections were incubated in prediluted ready to use primary antipodoplanin monoclonal antibody, clone-D2-40 (Dako, Carpenteria, CA, USA) for 40 min. All the sections were incubated with super enhancer and with HRP at room temperature for 30 min each. The sections were incubated with DAB chromogen for 5-10 min. Finally, slides were washed and counterstained with hematoxylin. The negative control slides were similarly stained, except an omission of primary antibody. The slides were then evaluated in semi quantitative manner by two observers under light microscope.

Immunohistochemical analysis

The podoplanin expression was observed in cell membrane and cytoplasm of the tissue sections. In leukoplakia, immunostaining was assessed as stated by Kawaguchi et al. [5] with modifications and scored as follows, Score (0) - no expression was observed in any part of the epithelium, Score (1) - expression restricted to the basal layer of epithelium and Score (2) - expression in basal and supra basal layer. In OSCC immunostaining scores followed were, Score (0) - no expression was observed in any part of the tumor island, Score (1) - expression in 0-25% of the tumor island, Score (2) - expression in 25-50% of the tumor island, Score (3) - expression in 50-75% of the tumor island and Score (4) - expression in 75-100% of the tumor island.

Statistical analysis

All the parameters were tabulated and the expression of podoplanin was analyzed statistically among different groups using ANOVA/Kruskal-Wallis test with post-hoc tests. The demographic details such as age, sex, site, and habits were also elicited and compared with podoplanin expression using Pearson Chi-square test. The significance was set at P < 0.05 level. Kappa statistics was not performed considering the size of the sample.


   Results Top


The podoplanin expression with other parameters such as age, sex, sites and habits in the study groups were statistically insignificant. Human appendix tissues used as a positive control and showed strong membranous staining [Figure 1]. As expected, podoplanin expression was consistently detected with high immunoreactivity in LECs in the connective tissue of all cases, according to its established role as a lymphatic marker. The immunoreactivity for podoplanin among different groups [Table 1] and [Figure 2] was as follows:
Figure 1: Section showing positive staining of podoplanin in appendix tissue (immunohistochemistry, ×20)

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Figure 2: Expression of podoplanin among three groups

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Table 1: Expression of podoplanin in the study sample


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  • In all the samples of control group (Group I), the epithelium stained negative (Score 0) with Podoplanin
  • Out of 32 leukoplakia cases (Group II), 19 (59.4%) cases showed podoplanin expression in the epithelium. Among this, 15 cases (42.87%) had Score 1 and 4 cases (12.5%) had Score 2
  • Among 50 squamous cell carcinoma cases (Group III), 41 cases (82%) showed positive expression to podoplanin Of which, 16 cases had Score 1, 7 cases had Score 2, 15 cases had Score 3 and 3 cases had Score 4
  • The expression of podoplanin among three groups showed statistical significance with mean value P = 0.00 (highly significant).



   Discussion Top


Head and neck squamous cell carcinoma is the 6 th most common neoplasm in head and neck region. [1],[2] Under developed and developing countries have more occurrence of this type of neoplasm due to extensive use of tobacco in various forms. Despite all the efforts in early diagnosis and adjuvant therapy, morbidity, and specific mortality continues to increase worldwide, which can be attributed by late diagnosis. [1],[2],[3],[4],[5],[6],[7],[8],[9],[10] Hence, recent researches are focused on identifying various markers for early cancer detection and prognostication. Podoplanin is one such recent marker whose relationship with various tumor invasions raises the possibility to employ podoplanin as a biomarker for diagnosis and prognosis.

In this study, we analyzed the podoplanin expression in patients with leukoplakia and OSCCs, podoplanin expressions was also compared with other clinical parameters such as gender of the patients, site of the lesions, age and habits-related to the disease and there was no statistical significance, except Group II (leukoplakia patients) with age (P < 0.04). This may be because of the long-term exposure to the habits in oral cavity.

The Group I samples (normal gingiva) showed negative podoplanin expression in the epithelium [Figure 3], whereas the LECs of the connective tissue stained positive with podoplanin.
Figure 3: Section showing negative podoplanin expression in normal gingival tissue (immunohistochemistry, ×10)

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Podoplanin expression in Group II (leukoplakia) showed highly variable expression. Out of 32 cases of leukoplakia, the epithelium of only 19 (59.4%) cases showed positive podoplanin expression [Figure 4]. Among the positive cases, 15 cases (42.87%) showed podoplanin expression restricted to the basal layer of the epithelium (Score 1)
Figure 4: Section showing podoplanin expression in the Basal cell layer of hyperorthokeratosis (leukoplakia) with Score 1 (leukoplakia) (immunohistochemistry, ×20)

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[Figure 5]a] and 4 cases (12.5%) showed podoplanin expression extending up to the parabasal layer (Score 2) [Figure 5]b]. The later cases can be correlated with risk of malignant potential, as stated by Kawaguchi et al. [5] in oral leukoplakia samples. 13 (40.6%) cases showed negative expression [Table 1]. This could be either because of lesion biopsied before abnormality developed or could be because of biopsy taken at the different clonal site than from which lesion had eventually developed. The upward clonal expression of podoplanin beyond the basal layer of the epithelium in leukoplakia cases, carry a significantly higher risk of cancer development than in patients with negative expression. It is also recommended to assess podoplanin expression along with histological evaluation of oral leukoplakia cases. [5] Similar podoplanin expression is also noted laryngeal premalignancies [11] and other oral premalignancies like oral lichen planus. [12] Indeed these finding define podoplanin as a marker for risk assessment in malignant transformation of oral leukoplakia.
Figure 5: (a) Section showing podoplanin expression restricted to basal cell layer of hyperorthokeratosis with Score 1 (immunohistochemistry, ×20). (b) Section showing podoplanin expression extending in the parabasal cell layer of hyperorthokeratosis with Score 2 (immunohistochemistry, ×40)

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Out of 50 cases of squamous cell carcinoma, 41 (82%) cases expressed podoplanin and 9 (18%) cases showed negative expression [Table 1]. Nevertheless, podoplanin expression alone may not be sufficient to promote tumourigenesis, other factors are also needed to promote clonal expansion of the abnormal cells, which could attribute to negative expression of podoplanin in some of the lesions. The exact role played by podoplanin in tumorigenesis is not fully elucidated, indeed the podoplanin might favor tumor invasion through cytoskeleton reorganization of tumor cells [13],[14] not only by collective cell migration, but also by single cell migration following the loss of E-cadherin [15] and thus play a role in tumor development. Similar observations were made in other studies of OSCC. [1],[2],[5],[15]

Podoplanin expression in different grades of OSCC was generally heterogeneous and displayed two patterns, namely diffuse and focal [Figure 6]. In focal pattern, only the peripheral cells of the tumor island, showed positive expression [Figure 7]. However in diffuse pattern, most of the tumor cells in the island stained with podoplanin [Figure 8]. A similar staining pattern was observed in OSCC [1],[2] and also in other carcinomas such as uterine cervical carcinoma [16] and laryngeal squamous cell carcinoma. [10]
Figure 6: Section showing staining of podoplanin in both the diffuse and focal pattern in the tumor islands of well-differentiated Squamous cell carcinoma (immunohistochemistry, ×40)

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Figure 7: Section showing podoplanin expression in focal pattern (only in periphery of tumor islands) in Squamous cell carcinoma (immunohistochemistry, ×10)

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Figure 8: Section showing podoplanin expression in diffuse pattern (in entire tumor islands) in Squamous cell carcinoma (immunohistochemistry, ×40)

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In the present study, 15 (71.42%) cases of WSCCs showed focal pattern. The probable presence of podoplanin expression only in tumor periphery is because of the terminal differentiation of tumor cells that results from maturation and/or degenerative changes. [14] It has also been proposed that the focal expression of podoplanin in the periphery of the tumor nest may indicate lower biological aggressiveness than the diffuse pattern. [9] The stromal derived growth factors like epidermal growth factor, fibroblast growth factor 2, and transforming growth factor-beta might also up regulate the expression of podoplanin and may induce specific location of podoplanin expression. [15] The above mentioned notion supports us to postulate that podoplanin expression may be modulated by the tumor stroma.

The staining pattern in different grades of OSCC was highly variable. The well-differentiated squamous cell carcinoma and moderately differentiated squamous cell carcinoma showed moderate to intense membrane staining. Whereas poorly differentiated squamous cell carcinomas, frequently showed cytoplasmic and membrane staining. One recurrent case of well differentiated squamous cell carcinomas with lymph node metastasis showed high expression of podoplanin with Score 4. The positive expression of podoplanin was also observed in both tumor and peritumoral area lymph vessels but was not assessed and correlated in the present study. As it has been a proposed factor that podoplanin enhance tumor cell invasion and lymph node metastasis by increasing the lymphagiogenesis and tumor cell mobility. Thus high levels of podoplanin expression in lymph node metastatis, indicates shortest disease specific survival. [1],[2],[5],[14],[15],[16],[17],[18],[19],[20],[21],[22]

Surprisingly few nonlymphatic endothelial tissues components such as muscle showed positive podoplanin expression in 15 cases of SCC [Figure 9] and four cases of SCC, also showed strong podoplanin expression in the myoepithelial cells of the acinar cells and intercalated ducts of salivary gland tissue. It is hypothesized that podoplanin might play an important role in mediating cellular contractile properties, cytoskeletal reorganization and also in maintaining shape of myoepithelial cell foot processes to protect acinar cells from the outside. [7],[23]
Figure 9: Section showing podoplanin expression in muscle tissue (immunohistochemistry, ×40)

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Thus in this study, expression of podoplanin in various study groups reveal that the normal gingival tissues did not express podoplanin with increase in expression of podoplanin in leukoplakia and OSCC with statistical significance [Table 1] and [Figure 3]. This also allows us to recommend the evaluation of podoplanin along with histopathological evaluation since it can also provide additional information like malignant transformation which cannot be detected merely by clinical and histopathological analysis.


   Conclusion Top


According to the study results and literature evidences, it can be concluded that the podoplanin has a valuable role as a predictable marker for assessing malignant transformation of premalignancy and prognosis of oral malignancy. Further advanced studies are required for better understanding of the pathophysiological functions of podoplanin mediated tumor initiation and prognosis of cancer.

 
   References Top

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2.Bartuli FN, Luciani F, Caddeo F, Compagni S, Piva P, Ottria L, et al. Podoplanin in the development and progression of oral cavity cancer: A preliminary study. Oral Implantol (Rome) 2012;5:33-41.  Back to cited text no. 2
    
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8.Noda Y, Amano I, Hata M, Kojima H, Sawa Y. Immunohistochemical examination on the distribution of cells expressed lymphatic endothelial marker podoplanin and LYVE-1 in the mouse tongue tissue. Acta Histochem Cytochem 2010;43:61-8.  Back to cited text no. 8
    
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10.Suzuki H, Onimaru M, Yonemitsu Y, Maehara Y, Nakamura S, Sueishi K. Podoplanin in cancer cells is experimentally able to attenuate prolymphangiogenic and lymphogenous metastatic potentials of lung squamoid cancer cells. Mol Cancer 2010;9:287.  Back to cited text no. 10
    
11.Rodrigo JP, García-Carracedo D, González MV, Mancebo G, Fresno MF, García-Pedrero J. Podoplanin expression in the development and progression of laryngeal squamous cell carcinomas. Mol Cancer 2010;9:48.  Back to cited text no. 11
    
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13.Schacht V, Dadras SS, Johnson LA, Jackson DG, Hong YK, Detmar M. Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. Am J Pathol 2005;166:913-21.  Back to cited text no. 13
    
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18. Raica M, Cimpean AM, Ribatti D. The role of podoplanin in tumor progression and metastasis. Anticancer Res 2008;28:2997-3006.  Back to cited text no. 18
    
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21.Mashhadiabbas F, Mahjour F, Mahjour SB, Fereidooni F, Hosseini FS. The immunohistochemical characterization of MMP-2, MMP-10, TIMP-1, TIMP-2, and podoplanin in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:240-50.  Back to cited text no. 21
    
22. Martín-Villar E, Fernández-Muñoz B, Parsons M, Yurrita MM, Megías D, Pérez-Gómez E, et al. Podoplanin associates with CD44 to promote directional cell migration. Mol Biol Cell 2010;21:4387-99.  Back to cited text no. 22
    
23.Carvalho FM, Zaganelli FL, Almeida BG, Goes JC, Baracat EC, Carvalho JP. Prognostic value of podoplanin expression in intratumoral stroma and neoplastic cells of uterine cervical carcinomas. Clinics (Sao Paulo) 2010;65:1279-83.  Back to cited text no. 23
    

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Correspondence Address:
J Logeswari
Departments of Oral Pathology and Microbiology, Meenakshi Ammal Dental College, Maduravoyal, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-9290.138321

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
 
 
    Tables

  [Table 1]

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