Significance of myofibroblast appearance in squamous cell carcinoma of the oral cavity on the occurrence of occult regional metastases, distant metastases, and survival


      The aim of the present study was to assess the frequency of appearance of stromal myofibroblasts in patients with oral squamous cell carcinoma (OSCC) and to further clarify whether myofibroblasts influence tumour suppression or progression. Surgical resection specimens from 152 patients with cT1–T3N0 OSCC were analysed. The frequency of myofibroblasts within the tumour stroma was assessed immunohistochemically and compared with other clinical and histopathological factors. The immunohistochemical reaction for alpha-smooth muscle actin showed positive cells in the stroma of 84.2% of OSCC (n = 128). An increased presence of myofibroblasts in the tumour stroma was significantly correlated with T stage (P = 0.019), the presence of occult neck metastasis (P < 0.001), regional recurrence (P = 0.037), and distant metastasis (P = 0.008). There was also an association between the presence of myofibroblasts and patient survival (P = 0.009). The presence of myofibroblasts was not associated with local recurrence, tumour cell differentiation, mode of invasion, or bone invasion. The results of this study suggest that myofibroblast proliferation facilitates tumour invasion, the occurrence of occult neck disease, and distant metastasis. The survival rate was poorer in patients with abundant myofibroblasts. Further investigations on tumour-associated stroma at the invasive front are needed in order to establish new diagnostic markers and therapeutic strategies.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to International Journal of Oral and Maxillofacial Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Pisani P.
        • Bray F.
        • Parkin D.M.
        Estimates of the world-wide prevalence of cancer for 25 sites in the adult population.
        Int J Cancer. 2002; 97: 72-81
        • Lippman S.M.
        • Sudbø J.
        • Hong W.K.
        Oral cancer prevention and the evolution of molecular-targeted drug development.
        J Clin Oncol. 2005; 23: 346-356
        • Galiè M.
        • Sorrentino C.
        • Montani M.
        • Micossi L.
        • Di Carlo E.
        • D’Antuono T.
        • et al.
        Mammary carcinoma provides highly tumourigenic and invasive reactive stromal cells.
        Carcinogenesis. 2005; 26: 1868-1878
        • Liotta L.A.
        • Kohn E.C.
        The microenvironment of the tumour–host interface.
        Nature. 2001; 411: 375-379
        • Lewis M.P.
        • Lygoe K.A.
        • Nystrom M.L.
        • Anderson W.P.
        • Speight P.M.
        • Marshall J.F.
        • et al.
        Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells.
        Br J Cancer. 2004; 90: 822-832
        • Barth P.J.
        • Schenck zu Schweinsberg T.
        • Ramaswamy A.
        • Moll R.
        CD34+ fibrocytes, alpha-smooth muscle antigen-positive myofibroblasts, and CD117 expression in the stroma of invasive squamous cell carcinomas of the oral cavity, pharynx, and larynx.
        Virchows Arch. 2004; 444: 231-234
        • Vered M.
        • Shohat I.
        • Buchner A.
        • Dayan D.
        Myofibroblasts in stroma of odontogenic cysts and tumors can contribute to variations in the biological behavior of lesions.
        Oral Oncol. 2005; 41: 1028-1033
        • Yamamoto E.
        • Kohama G.
        • Sunakawa H.
        • Iwai M.
        • Hiratsuka H.
        Mode of invasion, bleomycin sensitivity, and clinical course in squamous cell carcinoma of the oral cavity.
        Cancer. 1983; 51: 2175-2180
        • Sasaki T.
        • Moles D.R.
        • Imai Y.
        • Speight P.M.
        Clinico-pathological features of squamous cell carcinoma of the oral cavity in patients <40 years of age.
        J Oral Pathol Med. 2005; 34: 129-133
        • Miyamoto R.
        • Uzawa N.
        • Nagaoka S.
        • Nakakuki K.
        • Hirata Y.
        • Amagasa T.
        Potential marker of oral squamous cell carcinoma aggressiveness detected by fluorescence in situ hybridization in fine-needle aspiration biopsies.
        Cancer. 2002; 95: 2152-2159
        • Sobin L.H.
        • Gospodarowicz M.K.
        • Wittekind C.H.
        • International Union Against Cancer
        TNM Classification of malignant tumors.
        7th ed. Wiley-Blackwell, Hoboken, NJ2009
        • Bryne M.
        • Koppang H.S.
        • Lilleng R.
        • Kjaerheim A.
        Malignancy grading of the deep invasive margins of oral squamous cell carcinomas has high prognostic value.
        J Pathol. 1992; 166: 375-381
        • Leemans C.R.
        • Tiwari R.
        • Nauta J.J.
        • van der Waal I.
        • Snow G.B.
        Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma.
        Cancer. 1993; 71: 452-456
        • Shah J.P.
        • Lydiatt W.
        Treatment of cancer of the head and neck.
        CA Cancer J Clin. 1995; 45: 352-368
        • Surowiak P.
        • Murawa D.
        • Materna V.
        • Maciejczyk A.
        • Pudelko M.
        • Ciesla S.
        • et al.
        Occurrence of stromal myofibroblasts in the invasive ductal breast cancer tissue is an unfavourable prognostic factor.
        Anticancer Res. 2007; 27: 2917-2924
        • Tsujino T.
        • Seshimo I.
        • Yamamoto H.
        • Ngan C.Y.
        • Ezumi K.
        • Takemasa I.
        • et al.
        Stromal myofibroblasts predict disease recurrence for colorectal cancer.
        Clin Cancer Res. 2007; 13: 2082-2090
        • Kellermann M.G.
        • Sobral L.M.
        • da Silva S.D.
        • Zecchin K.G.
        • Graner E.
        • Lopes M.A.
        • et al.
        Mutual paracrine effects of oral squamous cell carcinoma cells and normal oral fibroblasts: induction of fibroblast to myofibroblast transdifferentiation and modulation of tumor cell proliferation.
        Oral Oncol. 2008; 44: 509-517
        • Sobral L.M.
        • Bufalino A.
        • Lopes M.A.
        • Graner E.
        • Salo T.
        • Coletta R.D.
        Myofibroblasts in the stroma of oral cancer promote tumorigenesis via secretion of activin A.
        Oral Oncol. 2011; 47: 840-846
        • Vered M.
        • Allon I.
        • Buchner A.
        • Dayan D.
        Stromal myofibroblasts and malignant transformation in a 4NQO rat tongue carcinogenesis model.
        Oral Oncol. 2007; 43: 999-1006
        • Kellermann M.G.
        • Sobral L.M.
        • da Silva S.D.
        • Zecchin K.G.
        • Graner E.
        • Lopes M.A.
        • et al.
        Myofibroblasts in the stroma of oral squamous cell carcinoma are associated with poor prognosis.
        Histopathology. 2007; 51: 849-853
        • Sappino A.P.
        • Skalli O.
        • Jackson B.
        • Schürch W.
        • Gabbiani G.
        Smooth-muscle differentiation in stromal cells of malignant and non-malignant breast tissues.
        Int J Cancer. 1988; 41: 707-712
        • Cintorino M.
        • Bellizzi de Marco E.
        • Leoncini P.
        • Tripodi S.A.
        • Xu L.J.
        • Sappino A.P.
        • et al.
        Expression of alpha-smooth-muscle actin in stromal cells of the uterine cervix during epithelial neoplastic changes.
        Int J Cancer. 1991; 47: 843-846
        • Martin M.
        • Pujuguet P.
        • Martin F.
        Role of stromal myofibroblasts infiltrating colon cancer in tumor invasion.
        Pathol Res Pract. 1996; 192: 712-717
        • Vered M.
        • Dobriyan A.
        • Dayan D.
        • Yahalom R.
        • Talmi Y.P.
        • Bedrin L.
        • et al.
        Tumor–host histopathologic variables, stromal myofibroblasts and risk score, are significantly associated with recurrent disease in tongue cancer.
        Cancer Sci. 2010; 101: 274-280
        • Bello I.O.
        • Vered M.
        • Dayan D.
        • Dobriyan A.
        • Yahalom R.
        • Alanen K.
        • et al.
        Cancer-associated fibroblasts, a parameter of the tumor microenvironment, overcomes carcinoma-associated parameters in the prognosis of patients with mobile tongue cancer.
        Oral Oncol. 2011; 47: 33-38
        • Kawashiri S.
        • Tanaka A.
        • Noguchi N.
        • Hase T.
        • Nakaya H.
        • Ohara T.
        • et al.
        Significance of stromal desmoplasia and myofibroblast appearance at the invasive front in squamous cell carcinoma of the oral cavity.
        Head Neck. 2009; 31: 1346-1353
        • de-Assis E.M.
        • Pimenta L.G.
        • Costa-e-Silva E.
        • Souza P.E.
        • Horta M.C.
        Stromal myofibroblasts in oral leukoplakia and oral squamous cell carcinoma.
        Med Oral Patol Oral Cir Bucal. 2012; 17: 733-738
        • Guarino M.
        Epithelial–mesenchymal transition and tumour invasion.
        Int J Biochem Cell Biol. 2007; 39: 2153-2160
        • Hugo H.
        • Ackland M.L.
        • Blick T.
        • Lawrence M.G.
        • Clements J.A.
        • Williams E.D.
        • et al.
        Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression.
        J Cell Physiol. 2007; 213: 374-383
        • Berndt A.
        • Büttner R.
        • Gühne S.
        • Gleinig A.
        • Richter P.
        • Chen Y.
        • et al.
        Effects of activated fibroblasts on phenotype modulation, EGFR signalling and cell cycle regulation in OSCC cells.
        Exp Cell Res. 2014; 322: 402-414