Skip to main content

Advertisement

SpringerLink
Log in

CD44 Variant 6 Expression and Tumor Budding in the Medullary Invasion Front of Mandibular Gingival Squamous Cell Carcinoma Are Predictive Factors for Cervical Lymph Node Metastasis

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

Oral squamous cell carcinoma (OSCC) with invasion into the mandibular medullary space has been reported to be a predictive factor for cervical lymph node metastasis (CLNM). As CLNM has been associated with the stemness of cancer cells, we aimed to evaluate the relationship between clinical characteristics and immunohistochemical findings on the invasion front of the medullary invasive OSCC and CLNM. The medical records of 25 patients with the mandibular medullary invasive OSCC who were performed mandibulectomy and neck dissection in our department from 2010 to 2016 were examined. Serial sections were stained with antibodies against CD44 variant 6 (CD44v6) to examine cancer stemness and to evaluate the number of tumor buds in the medullary invasion front of the mandibular invasive OSCC. Categorical data were analyzed by Fisher’s exact test. The expression of CD44v6 and the number of tumor buds between the groups with and without pathological CLNM (CLNM+ and CLNM-, respectively) were analyzed using the Mann-Whitney U test. Of the 25 patients, 11 patients were CLNM+. Of the several measured variables, histologic differentiation of the mandibular invasive OSCC was a significant factor for CLNM+. CD44v6 expression and tumor bud formation in the medullary invasion front of the mandibular invasive OSCC were significantly higher in the CLNM+ group, suggests that both CD44v6 and tumor budding in the medullary invasion front are predictive factors for CLNM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

CLNM:

cervical lymph node metastasis

DSS:

disease-specific survival

EMT:

epithelial-mesenchymal transition

MGSCC:

mandibular gingival squamous cell carcinoma

OS:

overall survival

References

  1. Rautava J, Luukkaa M, Heikinheimo K, Alin J, Grenman R, Happonen RP (2007) Squamous cell carcinomas arising from different types of oral epithelia differ in their tumor and patient characteristics and survival. Oral Oncol 43:911–919

    Article  CAS  PubMed  Google Scholar 

  2. Shingaki S, Nomura T, Takada M, Kobayashi T, Suzuki I, Nakajima T (2002) Squamous cell carcinomas of the mandibular alveolus: analysis of prognostic factors. Oncology 62:17–24

    Article  PubMed  Google Scholar 

  3. Fitzpatrick SG, Neuman AN, Cohen DM, Bhattacharyya I (2012) The clinical and histologic presentation of gingival squamous cell carcinoma: a study of 519 cases. Oral Surg Oral Med Oral Pathol Oral Radiol 114:509–515

    Article  PubMed  Google Scholar 

  4. Soo KC, Spiro RH, King W, Harvey W, Strong EW (1988) Squamous carcinoma of the gums. Am J Surg 156:281–285

    Article  CAS  PubMed  Google Scholar 

  5. Overholt SM, Eicher SA, Wolf P, Weber RS (1996) Prognostic factors affecting outcome in lower gingival carcinoma. Laryngoscope 106:1335–1339

    Article  CAS  PubMed  Google Scholar 

  6. Seoane J, Varela-Centelles PI, Walsh TF, Lopez-Cedrun JL, Vazquez I (2006) Gingival squamous cell carcinoma: diagnostic delay or rapid invasion? J Periodontol 77:1229–1233

    Article  PubMed  Google Scholar 

  7. Gomez D, Faucher A, Picot V, Siberchicot F, Renaud-Salis JL, Bussières E, Pinsolle J (2000) Outcome of squamous cell carcinoma of the gingiva: a follow-up study of 83 cases. J Craniomaxillofac Surg 28:331–335

    Article  CAS  PubMed  Google Scholar 

  8. Ebrahimi A, Murali R, Gao K, Elliott MS, Clark JR (2011) The prognostic and staging implications of bone invasion in oral squamous cell carcinoma. Cancer 117:4460–4467

    Article  PubMed  Google Scholar 

  9. Lubek J, El-Hakim M, Salama AR et al (2011) Gingival carcinoma: retrospective analysis of 72 patients and indications for elective neck dissection. Br J Oral Maxillofac Surg 49:182–185

    Article  PubMed  Google Scholar 

  10. Niu LX, Feng ZE, Wang DC, Zhang JY, Sun ZP, Guo CB (2017) Prognostic factors in mandibular gingival squamous cell carcinoma: a 10-year retrospective study. Int J Oral Maxillofac Surg 46:137–143

    Article  CAS  PubMed  Google Scholar 

  11. Ogura I, Kurabayashi T, Amagasa T, Okada N, Sasaki T (2002) Mandibular bone invasion by gingival carcinoma on dental CT images as an indicator of cervical lymph node metastasis. Dentomaxillofac Radiol 31:339–343

    Article  CAS  PubMed  Google Scholar 

  12. Platz H, Fries R, Hudec M et al (1983) The prognostic relevance of various factors at the time of the first admission of the patient. retrospective DOSAC study on carcinoma of the oral cavity J Maxillofac Surg 11:3–12

    CAS  Google Scholar 

  13. Okura M, Yanamoto S, Umeda M, Otsuru M, Ota Y, Kurita H, Kamata T, Kirita T, Yamakawa N, Yamashita T, Ueda M, Komori T, Hasegawa T, Aikawa T, Japan Oral Oncology Group (2016) Prognostic and staging implications of mandibular canal invasion in lower gingival squamous cell carcinoma. Cancer Med 5:3378–3385

    Article  PubMed  PubMed Central  Google Scholar 

  14. Matsushita Y, Yanamoto S, Yamada S, Mori H, Adachi M, Takahashi H, Naruse T, Ikeda H, Shiraishi T, Minamikawa T, Shibuya Y, Komori T, Asahina I, Umeda M (2015) Correlation between degree of mandibular bone invasion and prognosis in carcinoma of the mandibular gingiva: soft tissue classification based on UICC classification. J Oral Maxillofac Surg Med Pathol 27:631–636

    Article  Google Scholar 

  15. National Comprehensive Cancer Network NCCN Guidelines for Treatment of Cancer by Site. https://www.nccn.org/professionals/physician_gls/default.aspx#site [Accessibility verified April 15, 2018]

  16. Orian-Rousseau V (2010) CD44, a therapeutic target for metastasizing tumours. Eur J Cancer 46:1271–1277

    Article  CAS  PubMed  Google Scholar 

  17. Monteiro LS, Delgado ML, Ricardo S, do Amaral B, Salazar F, Pacheco JJ, Lopes CA, Bousbaa H, Warnakulasuryia S (2016) Prognostic significance of CD44v6, p63, podoplanin and MMP-9 in oral squamous cell carcinomas. Oral Dis 22:303–312

    Article  CAS  PubMed  Google Scholar 

  18. Yanamoto S, Yamada S, Takahashi H et al (2014) Expression of the cancer stem cell markers CD44v6 and ABCG2 in tongue cancer: effect of neoadjuvant chemotherapy on local recurrence. Int J Oncol 44:1153–1162

    Article  CAS  PubMed  Google Scholar 

  19. Wang C, Huang H, Wang A et al (2011) Tumor budding correlates with poor prognosis and epithelial-mesenchymal transition in tongue squamous cell carcinoma. J Oral Pathol Med 40:545–551

    Article  PubMed  PubMed Central  Google Scholar 

  20. Shimizu S, Miyazaki A, Sonoda T, Koike K, Ogi K, Kobayashi JI, Kaneko T, Igarashi T, Ueda M, Dehari H, Miyakawa A, Hasegawa T, Hiratsuka H (2018) Tumor budding is an independent prognostic marker in early stage oral squamous cell carcinoma: with special reference to the mode of invasion and worst pattern of invasion. PLoS One 13:e0195451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hong KO Oh KY1, shin WJ et al. tumor budding is associated with poor prognosis of oral squamous cell carcinoma and histologically represents an epithelial-mesenchymal transition process. Hum Pathol in Press

  22. Mitrovic B, Schaeffer DF, Riddell RH, Kirsch R (2012) Tumor budding in colorectal carcinoma: time to take notice. Modern Pathol 25:1315–1325

    Article  CAS  Google Scholar 

  23. Pinborg JJ, Reichart PA, Smith CJ et al (1997) World Health Organization histological typing of cancer and precancer of the oral mucosa, 2nd edn, Springer

  24. Sloan P, Gale N, Hunter K et al (2017) Malignant surface epithelial tumours: squamous cell carcinoma. In: el-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ (eds) WHO classification of tumours of the head and neck, 4th edn. IARC Press, Lyon

    Google Scholar 

  25. Okuyama K, Michi Y, Mizutani M, Yamashiro M, Kaida A, Harada K (2016) Clinical study on mandibular fracture after marginal resection of the mandible. Oral Surg Oral Med Oral Pathol Oral Radiol 121:461–467

    Article  PubMed  Google Scholar 

  26. Fonseca I, Pereira T, Rosa-Santos J, Soares J (2001) Expression of CD44 isoforms in squamous cell carcinoma of the border of the tongue: a correlation with histological grade, pattern of stromal invasion, and cell differentiation. J Surg Oncol 76:115–120

    Article  CAS  PubMed  Google Scholar 

  27. Masaki T, Goto A, Sugiyama M, Matsuoka H, Abe N, Sakamoto A, Atomi Y (2001) Possible contribution of CD44 variant 6 and nuclear beta-catenin expression to the formation of budding tumor cells in patients with T1 colorectal carcinoma. Cancer 92:2539–2546

    Article  CAS  PubMed  Google Scholar 

  28. Seki M, Sano T, Yokoo S, Oyama T (2016) Histologic assessment of tumor budding in preoperative biopsies to predict nodal metastasis in squamous cell carcinoma of the tongue and floor of the mouth. Head Neck 38(Suppl 1):E1582–E1590

    Article  PubMed  Google Scholar 

  29. Nomura T, Shibahara T, Cui NH, Noma H (2005) Patterns of mandibular invasion by gingival squamous cell carcinoma. J Oral Maxillofac Surg 63:1489–1493

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Editage (http://www.editage.jp/) for English-language editing.

Author information

Authors and Affiliations

  1. Department of Clinical Oral Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1, Sakamoto, Nagasaki-shi, Nagasaki, 852-8588, Japan

    Kohei Okuyama, Tomofumi Naruse, Souichi Yanamoto, Hiroki Tsuchihashi & Masahiro Umeda

  2. Nagasaki University School of Dentistry, Nagasaki, Japan

    Hiromasa Fukushima

Authors
  1. Kohei Okuyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiromasa Fukushima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomofumi Naruse
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Souichi Yanamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroki Tsuchihashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masahiro Umeda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kohei Okuyama.

Ethics declarations

Conflict of Interest

The authors do not have any conflicts of interest to declare.

Ethics Statement/Confirmation of Patients’ Permission

This retrospective study followed the Declaration of Helsinki and ethics and the regional Ethical Review Board of Nagasaki University approved the study (Registration number; 17,091,115).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Okuyama, K., Fukushima, H., Naruse, T. et al. CD44 Variant 6 Expression and Tumor Budding in the Medullary Invasion Front of Mandibular Gingival Squamous Cell Carcinoma Are Predictive Factors for Cervical Lymph Node Metastasis. Pathol. Oncol. Res. 25, 603–609 (2019). https://doi.org/10.1007/s12253-018-0529-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-018-0529-y

Keywords

Search

Navigation