Elsevier

Oral Oncology

Volume 40, Issue 3, March 2004, Pages 257-263
Oral Oncology

Reduced expression of hyaluronan is a strong indicator of poor survival in oral squamous cell carcinoma

https://doi.org/10.1016/j.oraloncology.2003.08.004Get rights and content

Abstract

Several malignant tumours accumulate hyaluronan (HA), a matrix component suggested to promote cancer cell growth and migration. The expression and prognostic value of HA was analysed in a cohort of 151 oral squamous cell carcinoma (SCC) patients with adequate archival tumour material and follow-up data. The tumour samples were stained using a biotinylated HA-specific probe. Normal squamous epithelium showed a strong and homogeneously distributed staining for HA. The most superficial layers were HA-negative. In moderate (n=11) and high grade (n=16) dysplasias an irregular HA staining was observed around invasive cancer. Malignant transformation in oral squamous cell epithelium changed the staining toward irregular with focal reduction of HA. The well (n=92) or moderately differentiated (n=47) carcinomas had a strong HA staining intensity. In poorly differentiated tumours (n=12) the HA staining was weaker and mainly intracellular. The stromal tissue showed usually moderate (n=69) or strong (n=67) HA staining intensity with no statistically significant correlation with the degree of tumour differentiation. At the end of the follow-up (median 52 months) 66 (43%) patients had died because of an oral SCC. A significant difference in overall survival (OS) and disease free survival (DFS) (P=0.0002 and 0.0020, respectively) was noticed between the patients with the different epithelial staining patterns for HA. The reduction of HA staining was associated with poor survival. In Cox's multivariate analysis HA staining was a significant independent predictor of OS (P=0.011) and DFS (P=0.013). These results suggest that HA is a prognostic marker in oral squamous cell carcinoma.

Introduction

Oral cancer is the sixth most common cancer worldwide. The most common type of oral cancer is squamous cell carcinoma (SCC) accounting almost nine out of 10 oral malignancies.1 The prognostic evaluation and the decisions on treatment strategy are mainly based on the TNM-classification.2 The survival depends on several factors: the stage of the disease (size of the primary lesion, local extension, lymph node involvement, distant metastasis), the site of the primary tumour, the adequacy of the initial treatment, the Karnofsky performance status, and the histological differentiation of the malignancy.1 Despite advanced treatment strategies the survival of oral cancer patients has not changed over the last decades. In search for accurate tools by which the prognosis of an individual oral SCC could be predicted tumour suppressor genes,3, 4, 5 cell proliferation,6 angiogenesis7 and cell adhesion molecules8, 9 have been studied in oral carcinoma.

Hyaluronan (HA) is an unbranched polysaccharide consisting of repeating disaccharide units of N-acetyl-glucosamine and glucuronic acid.10 It is almost ubiquitously distributed in various human tissues. The highest concentration of HA is found within soft connective tissues, predominantly in the skin.11 HA is synthesised at the cell surface by the membrane-bound enzyme hyaluronan synthase.12 Many functions have been attributed to HA including cell migration, proliferation and differentiation during embryonic development, wound healing and inflammation.10 Notably, HA fragments are angiogenic, stimulating tumour neovascularisation and aiding in tumour metastasis.13 Studies from several epithelial neoplasms show that HA has a significant role in tumour progression and metastasis.14, 15, 16, 17, 18, 19 It has turned out that the majority of squamous cell carcinomas are characterised by a high percentage of HA-positive cancer cells20, 21 in contrast to adenocarcinomas, which seem to display a low percentage of HA-positive cancer cells. Because of the intriguing association of SCC and HA and the need to better predict the behaviour of an individual tumour, we evaluated the expression of HA and its prognostic value in a series of 151 oral SCCs with complete follow-up data.

Section snippets

Patients

A total of 151 oral SCC patients with adequate archival tumour material were studied. These patients were selected from a consecutive series of 239 patients diagnosed and treated for oral SCC at Kuopio University Hospital and Jyväskylä Central Hospital, Finland between 1979 and 1998, excluding cases with insufficient tumour material or follow-up data.

The clinical data from each case were reviewed by two clinicians: one oncologist and one otolaryngologist. The tumour staging was carried out

HA staining in normal epithelium and dysplasias

Normal epithelium showed a strong staining for HA. A homogeneous staining pattern was present in all layers of the epithelium except the most superficial layers which were negative (Fig. 1a). In dysplastic epithelium (n=27) a distinct difference from the normal staining pattern was evident. The strong HA positivity extended up to the most superficial layer (Fig. 1b). Localised areas with reduced, intracellular and irregular signal for HA were observed in moderate (n=11) and high grade

Discussion

Several studies have shown the importance of HA in the progression of various human cancers.16, 17, 18, 19, 20, 21 Although many tumours are enriched with HA, they show considerable differences in HA expression depending on the cellular origin, as well as on the histological type.24 HA expression is generally high in normal squamous cells and most carcinomas of squamous cell origin as shown also in the present study. This is in contrast to non-stratified epithelia, which show no or only slight

Acknowledgements

The study has been supported by Kuopio and Tampere University Hospital EVO funding and the Northern Savo Cancer Fund. The authors thank Mrs. A. Parkkinen for the skilful immunohistochemical assistance and Mrs. P. Halonen for assistance with statistical analysis.

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    Present Address: Department of Pathology, Tampere University Hospital and Tampere University, PO Box 2000, FIN-33521, Tampere, Finland.

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