Prognostic and predictive factors

Even though the prevalence of OSCC is higher in men than women [8], the prognosis is similar between the sexes. The importance of age at the time of diagnosis however is controversial. Some reports say that age influences the outcome, where older patients display worse prognosis [25], while others find an even distribution of prognosis across the age groups [6]. When it comes to alcohol and smoking there are conflicting reports on

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prognosis. Some claim it has no effect and others claims it does [25]. Poor prognosis is often associated with lower socioeconomic status and lower education, and early detection of (pre)malignant lesions is of importance for improving prognosis [25,26].

TNM-staging. TNM-staging classifies tumours according to tumour size (T; T0-T4), lymph node metastasis (N; N0-N3) and distant metastasis (M; M0-M1) (see table 1) [4,10]. The tumours TNM-stage is strongly correlated to the prognosis of the patient, and is the main contributor to establishing the proper treatment strategy [8]. The individual T, N and M values classifies the tumour to either of four stages (stage I-IV) (see table 1), where a higher stage is strongly associated with worse prognosis [8,25]. Patients baring cervical lymph node metastasis (N+) are classified as stage III. Metastases to lymph nodes is widely accepted as a major prognostic factor, where (N+) patients display worse prognosis and are far more susceptible to recurrence [25]. If distant metastasis (M+) is found, the disease is classified as stage IV, reducing the 5-year survival rate from approximately 45% to 20% [8]. A common problem is that patients with tumours of the same stage often respond differently to the same treatment [10]. This might in part be explained by the molecular heterogeneity of these tumours [1,27], hence better prognostic markers are needed, especially biomarkers predicting invasive and metastatic tumour behaviour.

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Table 1: TNM staging of OSCC.

Tumour < 2 cm in greatest dimension.

Tumour more than 2 cm - 4 cm in greatest dimension.

Tumour > 4 cm in greatest dimension.

Tumour invades adjacent structures.

Metastasis in a single ipsilateral lymph node. < 3 cm in greatest dimension.

Metastasis in a single ipsilateral lymph node. 3 – 6 cm in greatest dimension.

Metastasis in multiple ipsilateral lymph nodes. < 6 cm in greatest dimension.

Metastasis to bilateral lymph nodes. < 6 cm in greatest dimension.

Metastasis in a lymph node > 6 cm in greatest dimension.

Distant metastasis (M-status)

Histopathological grading. Histopathological grading (pG1-pG3) of OSCC was in the 70’s suggested as an indicator of prognosis [28,29]. However, tumour grade alone is now

recognised as a poor tool for predicting outcome and treatment strategy in OSCC [10,30,31].

To improve the prognostic value of tumour grading, it has now been recommended to combine it with tumour growth pattern (type I-IV), as described in the “clinical features and histology” section [14-16,32,33]. A tumour-induced “reactive” stroma (also termed

desmoplasia) is necessary for tumourigenesis and metastasis. Desmoplasia is characterized by the presence of fibroblasts and myofibroblasts surrounding the invasive tumour island.

However little is known about how the tumour stroma affects prognosis and henceforth treatment stratification of OSCC [15].

Molecular heterogeneity and prognostic biomarkers. OSCC has proven to be a molecular heterogeneous type of tumour. All head and neck tumours may be subdivided into two main classes: those infected with high-risk HPV, especially HPV 16 and 18, comprising approx. 20%

of all the tumours, and those that are not, approx. 80% (figure 4) [1,34,35]. Interestingly, patients infected with high-risk HPV show improved disease specific survival, with these tumours preferentially locating to the oropharynx [36]. HPV-infected tumours will most

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often harbour a wild-type TP53 gene, which encodes the apoptosis regulating protein p53.

During an HPV infection, the viral oncogenes E6 and E7 will encode proteins that result in the loss of apoptotic control through degradation of p53 and the binding of retinoblastoma (Rb) proteins, respectively [10]. This leads to a loss of regulation during the cell cycle, leading to an accumulation of DNA damage and cancer progression. In tumour cells not infected with HPV, it is estimated that approx. 60-80% of the tumours will have mutations in the p53 or Rb-pathways [1,37,38]. Mutations in the tumour suppressor gene TP53 are frequently observed in tumours from patients that are smokers and drinkers [10]. The p53 protein has therefore been suggested as a prognostic marker, predicting recurrence [25]. However, a review of published literature on popular OSCC biomarkers, p53 was found correlated with poor survival in only six of the 11 studies [39].

For HNSCC in general, other genes have been shown to be important in development and progression: CDKN2A encoding p16^INK4A, CCND1 encoding cyclin D1, RB1/RBL1 encoding p170 and RBL1 encoding p130 [1].

Figure 4: Molecular heterogeneity of HNSCC. HNSCC may be subdivided in those tumour cells infected with high-risk HPV (approx. 20%) and those that are not infected with HPV (approx. 80%). The majority of HPV-negative tumours will harbour a p53 mutation, driving the tumourigenesis. Image from [1], with permission.

Several studies also report that the epidermal growth factor receptor (EGFR) is

overexpressed in HNSCC [40-43]. Overexpression of EGFR in OSCC has been correlated with increased tumour size, advanced pathological stage, increased incidence and severity of recurrence, decreased disease-free survival, and hence functions as a promising prognostic

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marker. Furthermore, EGFR has been a hot target in the development of new treatment strategies [44]. In a study using expression profiling of 60 tumours, 56 were found positive for EGFR expression. Out of the 56 EGFR-positive tumours, 34 also showed positive

immunostaining for phosphorylated EGFR (pEGFR) [45]. In a study including 82 NHSCC patients, where only 14 displayed phosphorylation of EGFR, a significant correlation was found between pEGFR and prognosis [41]. Both tyrosine kinase inhibitors and EGFR-targeted antibodies have been tested in clinical trials, resulting in merely 5-15% response rates when used as a sole treatment in recurrent and metastatic disease [46]. A phase III clinical trial, where the use of radiotherapy and an anti-EGFR antibody (cetuximab) was combined, resulted in prolonged progression-free survival in patients with HNSCC [47]. However, contradictive results are published on the prognostic value of EGFR. As described by Søland and Brusevold only two of the seven studies reviewed showed a correlation between EGFR expression and survival [39].

The Ki67 marker is located in the nucleus of cells undergoing proliferation, and it is thought to indicate how fast the tumour is growing [48]. Some studies find that Ki67 correlates with poor prognosis, although contradictive findings do exist [27,39,49,50].

Expression of certain matrix metalloproteinases (MMPs) in the primary tumour have been correlated with tumour stage [48] and poor prognosis in a subgroup of patients lacking lymph node metastasis [51]. Also proteins of the plasminogen activation (PA) system have been suggested as prognostic markers and therapeutic targets in OSCC [52-56], which will be discussed in more detail later.