Department of Gynecologic Oncology and Section of Translational Research, Hyogo Cancer Center, 13-70 Kita-Oji, Akashi, Japan.
Int J Gynecol Cancer. 2013 Jul;23(6):1084-91. doi: 10.1097/IGC.0b013e3182981bdc.
Cervical cancer is the second most common cancer in females worldwide, and the majority of squamous cell carcinomas and adenocarcinomas are associated with high-risk human papillomavirus (HPV) infection. However, the relationship between clear cell carcinoma of the cervix (CCCC) and HPV is unclear. In this study, we sought to determine if HPV infection is associated with CCCC and to elucidate the signaling pathways involved.
We collected samples from 13 CCCC patients and collated the relevant clinicopathologic data. We then evaluated the presence of HPV types 16, 18, 31, 33, 35, 52, and 58 by broad-spectrum amplification by polymerase chain reaction and HPV types 39, 45, 51, 56, 59, and 68 by nested polymerase chain reaction assay that combines degenerate E6/E7 consensus primers and type-specific primers from extracted genomic DNA. Immunohistochemistry was used to analyze the expression of EGFR (epidermal growth factor receptor), HER2, PTEN (phosphatase and tensin homolog), phospho-AKT, phospho-mTOR (mammalian target of rapamycin), p16, and p53. EGFR and HER2 gene amplification was determined by fluorescence in situ hybridization.
Patients with stage IB CCCC had a better 3-year overall survival rate compared with those with advanced-stage cancer (100% vs 44%; P = 0.014). High-risk HPVs were not detected in any of the cases examined. EGFR immunostaining was observed in 9 (75%) of 12 patients, HER2 in 3 (25%) of 12, PTEN in 6 (50%) of 12, and phospho-AKT in 7 (58%) of 12, and phospho-mTOR in 6 (50%) of 12. EGFR amplification could not be detected, but HER2 amplification was identified in 1 of (12.5%) 8 cases.
Patients with stage I CCCC demonstrated good overall survival and rare recurrence. Clear cell carcinoma of the cervix is unrelated to high-risk HPV infection; hence, current vaccines will not prevent the incidence of CCCC. However, increased EGFR or HER2 expression or activation of AKT or mTOR was observed in all cases, indicating that inhibitors of tyrosine kinases or the AKT-mTOR pathway may be suitable treatment regimens for CCCC.
宫颈癌是全球女性中第二常见的癌症，大多数鳞状细胞癌和腺癌都与高危型人乳头瘤病毒（HPV）感染有关。然而，宫颈透明细胞癌（CCCC）与 HPV 的关系尚不清楚。在本研究中，我们旨在确定 HPV 感染是否与 CCCC 相关，并阐明涉及的信号通路。
我们收集了 13 例 CCCC 患者的样本，并整理了相关的临床病理数据。然后，我们通过聚合酶链反应的广谱扩增评估了 HPV 16、18、31、33、35、52 和 58 型的存在情况，并通过巢式聚合酶链反应检测 HPV 39、45、51、56、59 和 68 型，该方法结合了从提取的基因组 DNA 中提取的退化 E6/E7 共有引物和型特异性引物。免疫组织化学用于分析表皮生长因子受体（EGFR）、HER2、PTEN（磷酸酶和张力蛋白同源物）、磷酸化 AKT、磷酸化 mTOR（雷帕霉素的哺乳动物靶标）、p16 和 p53 的表达。通过荧光原位杂交确定 EGFR 和 HER2 基因扩增。
IB 期 CCCC 患者的 3 年总生存率优于晚期癌症患者（100% vs 44%；P=0.014）。在所有检查的病例中均未检测到高危型 HPV。12 例患者中有 9 例（75%）存在 EGFR 免疫染色，12 例中有 3 例（25%）存在 HER2 免疫染色，12 例中有 6 例（50%）存在 PTEN 免疫染色，12 例中有 7 例（58%）存在磷酸化 AKT 免疫染色，12 例中有 6 例（50%）存在磷酸化 mTOR 免疫染色。未检测到 EGFR 扩增，但在 8 例中的 1 例（12.5%）中检测到 HER2 扩增。
IB 期 CCCC 患者总体生存良好且复发率低。宫颈透明细胞癌与高危型 HPV 感染无关；因此，目前的疫苗不会预防 CCCC 的发生。然而，所有病例均观察到 EGFR 或 HER2 表达增加或 AKT 或 mTOR 激活，表明酪氨酸激酶抑制剂或 AKT-mTOR 通路抑制剂可能是 CCCC 的合适治疗方案。
