Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki and HUS Helsinki University Hospital, P.O.Box 263, 00029 HUS, Helsinki, Finland.
Department of Pathology, University of Helsinki and HUS Helsinki University Hospital, P.O.Box 21, 00014 HUS, Helsinki, Finland.
Cancer Immunol Immunother. 2019 Aug;68(8):1263-1272. doi: 10.1007/s00262-019-02362-4. Epub 2019 Jun 25.
An emerging subset of oropharyngeal squamous cell carcinomas (OPSCC) is caused by HPV. HPV-positive OPSCC has a better prognosis than HPV-negative OPSCC, but other prognostic markers for these two different diseases are scarce. Our aim was to evaluate serum levels and tumor expression of matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and to assess their prognostic role in HPV-positive and HPV-negative OPSCC.
A total of 90 consecutive OPSCC patients diagnosed and treated with curative intent at the Helsinki University Hospital between 2012 and 2016 were included. Serum samples were prospectively collected. An immunofluorometric assay and an enzyme-linked immunosorbent assay were used to determine MMP-8 and TIMP-1 serum concentrations, respectively. HPV status of the tumors was determined using a combination of HPV-DNA genotyping and p16-INK4a immunohistochemistry. The endpoints were overall survival (OS) and disease-free survival (DFS).
High TIMP-1 serum levels were strongly and independently associated with poorer OS (adjusted HR 14.7, 95% CI 1.8-117.4, p = 0.011) and DFS (adjusted HR 8.7, 95% CI 1.3-57.1, p = 0.024) among HPV-negative patients; this association was not observed in HPV-positive OPSCC. Although TIMP-1 was immunoexpressed in the majority of the tumor tissue samples, the level of immunoexpression was not associated with prognosis, nor did MMP-8 serum levels.
Our results indicate that serum TIMP-1 levels may serve as an independent prognostic marker for HPV-negative OPSCC patients.
口咽鳞状细胞癌（OPSCC）的一个新兴亚组是由 HPV 引起的。HPV 阳性 OPSCC 的预后优于 HPV 阴性 OPSCC，但这两种不同疾病的其他预后标志物却很少。我们的目的是评估基质金属蛋白酶-8（MMP-8）和金属蛋白酶组织抑制剂-1（TIMP-1）的血清水平和肿瘤表达，并评估它们在 HPV 阳性和 HPV 阴性 OPSCC 中的预后作用。
共纳入 2012 年至 2016 年期间在赫尔辛基大学医院接受根治性治疗的 90 例连续 OPSCC 患者。前瞻性收集血清样本。使用免疫荧光测定法和酶联免疫吸附试验分别测定 MMP-8 和 TIMP-1 的血清浓度。采用 HPV-DNA 基因分型和 p16-INK4a 免疫组织化学相结合的方法确定肿瘤的 HPV 状态。终点是总生存（OS）和无病生存（DFS）。
高 TIMP-1 血清水平与 HPV 阴性患者的 OS（调整 HR 14.7，95%CI 1.8-117.4，p=0.011）和 DFS（调整 HR 8.7，95%CI 1.3-57.1，p=0.024）显著相关，且独立相关；而在 HPV 阳性 OPSCC 中则无此相关性。尽管 TIMP-1 在大多数肿瘤组织样本中均有免疫表达，但免疫表达水平与预后无关，MMP-8 血清水平也与预后无关。
我们的研究结果表明，血清 TIMP-1 水平可能是 HPV 阴性 OPSCC 患者的独立预后标志物。
