Document Type : Original Research

Authors

Department of Pathology, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India

Abstract

Background & Objective: Head and Neck Squamous cell carcinoma (HNSCC) is one of the leading cancers worldwide. Cervical lymph node metastasis is the most adverse prognostic factor for patients with HNSCC. As there are no reliable factors in predicting lymph node metastasis, recent researchers focus on identifying various metastasis markers that will aid treatment selection. Podoplanin is a recent marker strongly associated with lymph node metastasis, aggressive tumor behavior, and poor prognosis. The expression of podoplanin in human squamous cell cancers and its association with cancer cell motility suggest a possibility that it could be used as a biomarker to predict lymph node metastasis. To study the expression of podoplanin in head and neck squamous cell carcinoma, determine its association with clinicopathological variables, and predict its use as a biomarker in predicting lymph node metastasis.
Methods: The present study was conducted in a tertiary care hospital. Podoplanin expression was studied in 45 cases of HNSCC and its association with clinicopathological variables. The predictive power of podoplanin was further analyzed using univariate and multivariate logistic regression analysis. The positive and negative predictive values of podoplanin were determined concerning the presence or absence of lymph node metastasis.
Results: Podoplanin expression is significantly associated with histological grade (P=0.03) and lymph node metastasis (P=0.01). In logistic regression analysis, podoplanin expression (Odds Ratio: 5.66, Confidence Interval: 1.23 -25.87, P=0.02) was a significant independent predictor of lymph node metastasis.
Conclusion: Our study demonstrates that podoplanin provides prognostic information and predicts lymph node metastasis which was consistent with our studies in the literature. Thus, podoplanin may help better stratify patients selected for elective neck node dissection in early tumor stages and clinically negative regional disease.

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    1. Prasad B, Kashyap B, Babu GS, Kumar GR, Manyam R. Expression of podoplanin in different grades of oral squamous cell carcinoma. Ann med health sci res. 2015;5(4):299-304. [PMID] [PMCID] [DOI:10.4103/2141-9248.160181]
    2. Kreppel M, Scheer M, Drebber U, Ritter L, Zöller JE. Impact of podoplanin expression in oral squamous cell carcinoma: clinical and histopathologic correlations. Virchows Arch. 2010;456(5):473-82. [DOI:10.1007/s00428-010-0915-7] [PMID]
    3. Logeswari J, Malathi N, Thamizhchelvan H, Sangeetha N, Nirmala SV. Expression of podoplanin in oral premalignant and malignant lesions and its potential as a biomarker. Indian J Dent Res. 2014;25(3):305. [DOI:10.4103/0970-9290.138321] [PMID]
    4. Wei WI. Commentary: Head and neck carcinomas in the developing. BMJ-BRIT MED J. 2002;325(7368):827. [PMID] [PMCID] [DOI:10.1136/bmj.325.7368.822]
    5. Zhang Z, Helman JI, Li LJ. Lymphangiogenesis, lymphatic endothelial cells and lymphatic metastasis in head and neck cancer-a review of mechanisms. Int J Oral Sci. 2010;2(1):5-14. [DOI:10.4248/IJOS10006] [PMID] [PMCID]
    6. Raica M, Cimpean AM, Ribatti D. The role of podoplanin in tumor progression and metastasis. Anticancer Res. 2008;28(5B):2997-3006.
    7. Wicki A, Christofori G. The potential role of podoplanin in tumour invasion. Br. J. Cancer. 2007;96(1):1-5. [DOI:10.1038/sj.bjc.6603518] [PMID] [PMCID]
    8. Kim HY, Rha KS, Shim G, Kim JH, Kim JM, Huang SM, Koo BS. Podoplanin is involved in the prognosis of head and neck squamous cell carcinoma through interaction with VEGF-C. Oncol. Rep. 2015;34(2):833-42. [DOI:10.3892/or.2015.4070] [PMID]
    9. Cirligeriu L, Cimpean AM, Raica M, Doroş CI. Dual role of podoplanin in oral cancer development. in vivo. 2014;28(3):341-7.
    10. Cueni LN, Hegyi I, Shin JW, Albinger-Hegyi A, Gruber S, Kunstfeld R, Moch H, Detmar M. Tumor lymphangiogenesis and metastasis to lymph nodes induced by cancer cell expression of podoplanin. Am J Pathol. 2010;177(2):1004-16. [DOI:10.2353/ajpath.2010.090703] [PMID] [PMCID]
    11. Wicki A, Lehembre F, Wick N, Hantusch B, Kerjaschki D, Christofori G. Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer cell. 2006;9(4):261-72. [DOI:10.1016/j.ccr.2006.03.010] [PMID]
    12. Logeswari J, Malathi N, Thamizhchelvan H, Sangeetha N, Nirmala SV. Expression of podoplanin in oral premalignant and malignant lesions and its potential as a biomarker. Indian J Dent Res. 2014;25(3):305. [DOI:10.4103/0970-9290.138321] [PMID]
    13. de Vicente JC, Santamarta TR, Rodrigo JP, García-Pedrero JM, Allonca E, Blanco-Lorenzo V. Expression of podoplanin in the invasion front of oral squamous cell carcinoma is not prognostic for survival. Virchows Arch. 2015;466(5):549-58. [DOI:10.1007/s00428-015-1746-3] [PMID]
    14. Sgaramella N, Lindell Jonsson E, Boldrup L, Califano L, Coates PJ, Tartaro G, Lo Muzio L, Fåhraeus R, Colella G, Dell'AversanaOrabona G, Loljung L. High expression of podoplanin in squamous cell carcinoma of the tongue occurs predominantly in patients≤ 40 years but does not correlate with tumour spread. J PatholClin Res. 2016;2(1):3-8. [DOI:10.1002/cjp2.28] [PMID] [PMCID]
    15. Hamada M, Ebihara Y, Nagata K, Yano M, Kogashiwa Y, Nakahira M, Sugasawa M, Nagatsuka H, Yasuda M. Podoplanin is an efficient predictor of neck lymph node metastasis in tongue squamous cell carcinoma with low tumor budding grade. Oncol. Lett. 2020;19(4):2602-8. [DOI:10.3892/ol.2020.11358]
    16. Dhull AK, Atri R, Dhankhar R, Chauhan AK, Kaushal V. Major risk factors in head and neck cancer: a retrospective analysis of 12-year experiences. World J Oncol. 2018;9(3):80. [DOI:10.14740/wjon1104w] [PMID] [PMCID]
    17. Hashibe M, Brennan P, Benhamou S, Castellsague X, Chen C, Curado MP, Maso LD, Daudt AW, Fabianova E, Wünsch-Filho V, Franceschi S. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst. 2007;99(10):777-89. [DOI:10.1093/jnci/djk179] [PMID]
    18. Kawaguchi H, El-Naggar AK, Papadimitrakopoulou V, Ren H, Fan YH, Feng L, Lee JJ, Kim E, Hong WK, Lippman SM, Mao L. Podoplanin: a novel marker for oral cancer risk in patients with oral premalignancy. J ClinOncol. 2008;26(3):354-60. [DOI:10.1200/JCO.2007.13.4072] [PMID]
    19. Kanliada D, Coskunpinar E, Orhan KS, Oltulu YM, Celik M, Eren A, Yaylim I, Deger K. Investigation of biomarker in laryngeal carcinomas. J Clin Lab Anal. 2014;28(3):186-90. [DOI:10.1002/jcla.21664] [PMID] [PMCID]
    20. Znaor A, Brennan P, Gajalakshmi V, Mathew A, Shanta V, Varghese C, Boffetta P. Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. Int J Cancer. 2003;105(5):681-6. [DOI:10.1002/ijc.11114] [PMID]
    21. Inoue H, Miyazaki Y, Kikuchi K, Yoshida N, Ide F, Ohmori Y, Tomomura A, Sakashita H, Kusama K. Podoplanin expression during dysplasia-carcinoma sequence in the oral cavity. Tumor Biol. 2012;33(1):183-94. [DOI:10.1007/s13277-011-0261-7] [PMID]
    22. Huber GF, Fritzsche FR, Züllig L, Storz M, Graf N, Haerle SK, Jochum W, Stoeckli SJ, Moch H. Podoplanin expression correlates with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx. Int J Cancer. 2011;129(6):1404-9. [DOI:10.1002/ijc.25795] [PMID]
    23. Yuan P, Temam S, El‐Naggar A, Zhou X, Liu DD, Lee JJ, Mao L. Overexpression of podoplanin in oral cancer and its association with poor clinical outcome. Cancer. 2006;107(3):563-9. [DOI:10.1002/cncr.22061] [PMID]
    24. Almeida AD, Oliveira DT, Pereira MC, Faustino SE, Nonogaki S, Carvalho AL, Kowalski LP. Podoplanin and VEGF-C immunoexpression in oral squamous cell carcinomas: prognostic significance. Anticancer Res. 2013;33(9):3969-76.
    25. Osazuwa-Peters N, Boakye EA, Chen BY, Tobo BB, Varvares MA. Association between head and neck squamous cell carcinoma survival, smoking at diagnosis, and marital status. JAMA Otolaryngol Head Neck Surg. 2018;144(1):43-50. [DOI:10.1001/jamaoto.2017.1880] [PMID] [PMCID]
    26. Cueni LN, Hegyi I, Shin JW, Albinger-Hegyi A, Gruber S, Kunstfeld R, Moch H, Detmar M. Tumor lymphangiogenesis and metastasis to lymph nodes induced by cancer cell expression of podoplanin. Am J Pathol. 2010;177(2):1004-16. [DOI:10.2353/ajpath.2010.090703] [PMID] [PMCID]
    27. Mermod M, Bongiovanni M, Petrova TV, Dubikovskaya EA, Simon C, Tolstonog G, Monnier Y. Correlation between podoplanin expression and extracapsular spread in squamous cell carcinoma of the oral cavity using subjective immunoreactivity scores and semiquantitative image analysis. Head Neck. 2017;39(1):98-108. [DOI:10.1002/hed.24537] [PMID]
    28. Kane SV, Gupta M, Kakade AC, D'Cruz A. Depth of invasion is the most significant histological predictor of subclinical cervical lymph node metastasis in early squamous carcinomas of the oral cavity. Eur J SurgOncol (EJSO). 2006;32 (7):795-803. [DOI:10.1016/j.ejso.2006.05.004] [PMID]
    29. Faisal M, Abu Bakar M, Sarwar A, Adeel M, Batool F, Malik KI, Jamshed A, Hussain R. Depth of invasion (DOI) as a predictor of cervical nodal metastasis and local recurrence in early stage squamous cell carcinoma of oral tongue (ESSCOT). PLoS One. 2018;13(8):e0202632. [DOI:10.1371/journal.pone.0202632] [PMID] [PMCID]
    30. Jardim JF, Francisco AL, Gondak R, Damascena A, Kowalski LP. Prognostic impact of perineural invasion and lymphovascular invasion in advanced stage oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2015;44(1):23-8. [DOI:10.1016/j.ijom.2014.10.006] [PMID]
    31. Cañueto J, Cardeñoso‐Álvarez E, Cosano‐Quero A, Santos‐Briz Á, Fernández‐López E, Pérez‐Losada J et al. The expression of podoplanin is associated with poor outcome in cutaneous squamous cell carcinoma. J CutanPathol. 2017; 44(2):144-51. [DOI:10.1111/cup.12859] [PMID]
    32. Kunita A, Baeriswyl V, Meda C, Cabuy E, Takeshita K, Giraudo E, Wicki A, Fukayama M, Christofori G. Inflammatory cytokines induce podoplanin expression at the tumor invasive front. Am J Pathol. 2018;188(5):1276-88. [DOI:10.1016/j.ajpath.2018.01.016] [PMID]
    33. Jethwa AR, Khariwala SS. Tobacco-related carcinogenesis in head and neck cancer. Cancer Metastasis Rev. 2017; 36(3):411-23. [PMCID] [DOI:10.1007/s10555-017-9689-6] [PMID]
    34. Huber GF, Fritzsche FR, Züllig L, Storz M, Graf N, Haerle SK, Jochum W, Stoeckli SJ, Moch H. Podoplanin expression correlates with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx. Int J Cancer. 2011;129(6):1404-9. [DOI:10.1002/ijc.25795] [PMID]
    35. Kozłowski M, Naumnik W, Nikliński J, Milewski R, Łapuć G, Laudański J. Lymphatic vessel invasion detected by the endothelial lymphatic marker D2-40 (podoplanin) is predictive of regional lymph node status and an independent prognostic factor in patients with resected esophageal cancer. Folia HistochemCytobiol. 2011;49(1):90-7. [DOI:10.5603/FHC.2011.0013] [PMID]
    36. Dumoff KL, Chu CS, Harris EE, Holtz D, Xu X, Zhang PJ, Acs G. 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. 2006;19(5):708-16. [DOI:10.1038/modpathol.3800580] [PMID]