Metabolo-volumetric parameters of 18 F-FDG-PET can predict expression of EGFR and HIF 1alpha in uterine cervical cancer

1. Introduction

Uterine cervical cancer (CC) is the second most common malignancy in women worldwide [1]. Furthermore, CC accounts 9% of the total new cancer cases and 8% of the total cancer deaths among females [1].

Positron emission tomography (PET) using [ 18 F]-Fluorodeoxyglucose ( 18 F-FDG) has been shown to be a useful tool for diagnosing and staging of cervical cancer [2, 3, 4, 5, 6]. Moreover, different PET parameters, namely maximal standardized uptake value (SUV max ), Metabolic Tumor Volume (MTV), and Total Lesion Glycolysis (TLG) can also predict tumor behavior of CC [2, 3, 4, 5, 6, 7]. For instance, Micco et al. showed that MTV and TLG correlated with N-stage in CC [7]. It has also been shown that different 18 F-FDG-PET parameters can be used as prognosis biomarkers in CC. So Pan et al. reported that high pretreatment SUV max ( ⩾ 11.2) of primary tumor indicated worse prognosis [8]. Furthermore, Chung et al. mentioned that SUV, MTV and TLG can predict tumor recurrence in CC [9]. In addition, MTV has been reported as an independent prognostic factor for disease free survival in patients with CC treated by radical surgery [4]. Similarly, pretreatment TLG proved to be an independent prognostic factor for disease free survival in patients with locally advanced CC treated by definitive chemoradiotherapy [3]. Finally, MTV can also predict overall survival in CC [7].

The reported data suggest that 18 F-FDG-PET parameters may be associated with several histopathological features in CC. Therefore, the aim of the present study was to investigate possible relationships between 18 F-FDG-PET parameters and clinically relevant histopathological findings in patients with CC.

This prospective study was approved by the local research ethics committee.

3. Results

An overview about the analyzed 18 F-FDG-PET and histopathological parameters is given in Table 2.

Correlation analysis identified statistically significant correlations between several parameters. TLG and MTV correlated well with expression of EGFR ( p = 0.601, P = 0.008 and p = 0.586, P = 0.011, respectively) (Table 3). Furthermore, SUV median correlated inversely with expression of HIF-1 α ( p = - 0.509, P = 0.031). Additionally, SUV mean tended to correlate with expression of EGFR and HIF-1 α (Table 3).

SUV max also tended to correlate with EGFR.

None of the 18 F-FDG-PET parameters showed significant correlations with expression of Histone 3, p53 and VEGF.

4. Discussion

The present study identified significant associations between 18 F-FDG-PET parameters and histopathological findings in uterine CC.

Previously, only few reports analyzed associations between 18 F-FDG-PET and histopathology in CC. Predominantly, biomarkers having a direct role in FDG uptake like glucose transporter type-1 (GLUT 1) and hexokinases were analyzed [12]. So Park et al. observed statistically significant slightly correlations between SUV max and expression of GLUT 1 ( r = 0.342, p = 0.008), carbonic anhydrase IX ( r = 0.281, p = 0.03) and hexokinase type II ( r = 0.571, 0.001) [12]. The identified correlations are of interest, however, they could not explain the associations between 18 F-FDG-PET and tumor behavior in CC mentioned above.

According to the literature, several histopathological features can play an important role in CC. Especially epidermal growth factor receptor (EGFR), tumor suppressor protein p53, vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1 α and histone 3 influence significantly tumor behavior [13, 14, 15, 16]. For example, EGFR, a glycoprotein receptor activates a tyrosine kinase domain to regulate multiple functions like cell growth, differentiation, gene expression and development [13, 14, 15, 16, 17]. It has been shown that overexpression of EGFR has been associated with poor prognosis in CC [15, 16, 17]. VEGF is another important factor in CC. It has been shown that VEGF is an independent prognostic factor of unfavorable clinical outcome [13, 17]. VEGF predicts disease-free survival and overall survival in CC [13, 18]. Furthermore, VEGF expression is also associated with metastasis-free survival in CC [17, 18]. Tumor suppressor protein p53 also predicts tumor prognosis in CC. According to the literature, patients with p53-positive tumors showed a shorter disease-free survival in comparison to patients with p53-negative lesions [13, 19]. Another factor, namely HIF-1 α , mediates cellular response to hypoxia and activates numerous hypoxia-response genes [13, 20]. Thereby, it prevents hypoxia-induced cell death [13, 20, 21]. High HIF-1 α expression is associated with poor survival in CC [13, 20, 21]. Finally, histone 3 plays also an important role in CC. Oversimplified; this factor is incorporated into the cell cycle and reflects proliferation potential [22]. Histone H3 acetyl K9 is an independent marker of overall survival in CC. Furthermore, histone H3 tri methyl K4 is associated with poor prognosis [22]. In addition, histone H3 tri methyl K4 is an independent marker of relapse-free survival [22].

To the best of our knowledge, previously, only two studies investigated correlations between clinically relevant histopathological features and 18 F-FDG-PET parameters in CC [12, 23]. It has been shown that KI 67 correlated moderately with SUV max ( r = 0.59, p = 0.005) and SUV mean ( r = 0.45, p = 0.04) [23]. In another study, weakly correlations were observed between cytoplasmic HIF-1 α and SUV max ( r = 0.309, p = 0.016) [12]. Furthermore, SUV max tended to correlate with expression of VEGF ( r = 0.251, p = 0.053) [12].

In the present study, several interesting aspects were observed. Firstly, widely used routine 18 F-FDG-PET parameters, namely SUV max and SUV mean did not correlate statistically significant with the analyzed histopathological features. However, metabolo-volumetric parameters MTV and TLG correlated well with expression of EGFR. This finding suggests that metabolo-volumetric parameters are more sensitive than SUV max or SUV mean in reflection of associations between metabolic activity and histopathology in CC. The identified relationships seem logical. In fact, EGFR signaling is very important in cellular homeostasis, proliferation, and growth [13]. Therefore, metabolo-volumetric 18 F-FDG-PET parameters can predict proliferation activity in CC. Furthermore, this finding is in accordance with the reported data, which identified significant correlations between 18 F-FDG-PET parameters and expression of proliferation marker KI 67 in CC [23].

Furthermore, as shown, SUV median can predict hypoxic tissue areas. HIF-1 α induces the expression of different target genes; those regulating angiogenesis and glucose metabolism are some of the most important with respect to cancer growth [13, 20].

Secondly, none of the 18 F-FDG-PET parameters showed significant correlations with expression of p53, VEGF and histone 3. Therefore, it may be postulated that 18 F-FDG-PET cannot predict tumor suppression, angiogenesis and some tumor proliferation pathways in CC. This finding is difficult to explain. As mentioned above, p53, VEGF and histone 3 influence tumor aggressiveness and invasiveness in CC. Similarly, also 18 F-FDG-PET parameters predict tumor behavior in CC. Presumably, 18 F-FDG-PET may be associated with these histopathological features. Previous investigations analyzed only associations between several standardized uptake values (SUV max and/or SUV mean ) and histopathology in CC [12, 23]. In the present study, also SUV median and volume-based parameters TLG and MTV were estimated. According to the literature, volume-based FDG PET/CT parameters were significant prognostic factors in patients with uterine cervical cancer [2, 24]. Furthermore, TLG and MTV could independently predict survival in patients with locally advanced uterine cervical cancer [2]. Therefore, it may be postulated that PET investigation of uterine cervical carcer should include estimation of volume-based parameters.

Our study is limited to the relatively small number of patients. Clearly, further investigations with more patients are needed to confirm the identified associations between 18 F-FDG-PET and histopathological parameters.

In conclusion, TLG and MTV can reflect expression of EGFR and SUV median correlated significantly with expression of HIF-1 α . None of the PET parameters can predict expression of Histone 3, p53 and VEGF.