The Predictive and Prognostic Significance of c-erb-B2, EGFR, PTEN, mTOR, PI3K, p27, and ERCC1 Expression in Hepatocellular Carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC) is the fifth most common fatal cancer and an important healthcare problem worldwide. There are many studies describing the prognostic and predictive effects of epidermal growth factor receptor 2 (c-erb-B2) and epidermal growth factor receptor 1 (EGFR), transmembrane tyrosine kinases that influence cell growth and proliferation in many tumors.

Objectives: The current study aimed to investigate the expression levels of c-erb-B2, EGFR, PTEN, mTOR, PI3K, p27, and ERCC1 in hepatocellular carcinoma (HCC) and their correlation with other clinicopathologic features.

Patients and methods: Fifty HCC cases were stained immunohistochemically with these markers. Correlations between the markers and clinicopathologic characteristics and survival rates were analyzed.

Results: No membranous c-erb-B2 staining was seen, whereas cytoplasmic positivity was present in 92% of HCC samples, membranous EGFR was observed in 40%, PI3K was found in all samples, and mTOR was seen in 30%, whereas reduced or absent PTEN expression was observed in 56% of samples and loss of p27 was seen in 92% of the cases. c-erb-B2 and mTOR overexpression, as well as reduced expression of p27, all correlated with multiple tumors (P = 0.041, P < 0.001, and P < 0.001, respectively). P27 loss, and mTOR and EGFR positivity were significantly correlated with AFP (P = 0.047, P = 0.004, and P = 0.008, respectively). Angiolymphatic invasion was more commonly seen in EGFR- and ERCC1-positive cases (P = 0.003 and P = 0.005). EGFR was also correlated with histological grade (P = 0.039). No significant correlations were found among PTEN , PI3K, and the clinicopathological parameters. Disease-free or overall survival rates showed significant differences among therapy modalities, AFP levels, angiolymphatic or lymph node invasions, and ERCC1 and p27 expression levels (P < 0.05).

Conclusions: c-erb-B2, EGFR, mTOR, ERCC1 overexpression levels, and loss of p27 may play roles in hepatocarcinogenesis and may be significant predictors of aggressive tumor behavior. These markers were found to be correlated with certain clinicopathologic features, therapy modalities, and survival rates in the current study. These findings may help in planning new, targeted treatment strategies .

Keywords: Carcinoma; Hepatocellular; Immunohistochemistry.

Figures

Figure 1. Macroscopic and Microscopic Views of Hepatocellular Carcinoma

A) Multifocal HCC. B) Grade I. C) Grade II. D) Grade III Hepatocellular Carcinoma (HE; × 100, × 100, × 200)

Figure 2. Cytoplasmic 3+ Staining of c-erb-B2 in HCC and 1+ Staining in Adjacent Liver Parenchyma (× 100)

Figure 3. Membranous EGFR Staining (× 400)

Figure 4. PTEN Showing Nuclear Positivity in HCC, While Noncancerous Tissue is Negative

The positive Signal in the Paranchyma is Attributable to Lymphocytes (× 100)

Figure 5. Moderate to Strong Cytoplasmic PI3K Staining (× 200)

Figure 6. Moderate Cytoplasmic mTOR Staining (× 200)

Figure 7. P27 Expression in HCC (× 200)

Figure 8. ERCC Nuclear Expression in HCC (× 400)