Department of Pathology, Kawasaki Medical University, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
Department of Otolaryngology, Head and Neck Surgery, Kawasaki Medical University, Kurashiki, Okayama, Japan.
Head Neck Pathol. 2023 Sep;17(3):658-672. doi: 10.1007/s12105-023-01567-5. Epub 2023 Jul 24.
Human papillomavirus (HPV)-associated oropharyngeal cancer occasionally has a poor prognosis, making prognostic risk stratification crucial. Protease-activated receptor-1 (PAR1) is involved in carcinogenesis, and its expression is regulated by alpha-arrestin domain-containing protein 3 (ARRDC3). It is also involved in the tumor microenvironment. We sought to evaluate the predictive ability of PAR1, ARRDC3, and tumor-infiltrating lymphocyte (TIL) scores in patients with oropharyngeal, hypopharyngeal, and uterine cervical cancers, serving as comparators for HPV-associated oropharyngeal cancer.
Immunohistochemical analysis of p16, ARRDC3, and PAR1 expression was performed on 79 oropharyngeal, 44 hypopharyngeal, and 42 uterine cervical cancer samples. The TIL scores were assessed and classified into the following groups based on invasion: low: 0-10%, medium: 20-40%, and high: > 50%. For prognostic analysis, the three groups were evaluated by dividing them into low, medium, and high categories, or alternatively into two groups using the median value as the cutoff.
p16 was expressed in 44 (56%) oropharyngeal, 8 (18%) hypopharyngeal, and all uterine cervical cancer samples. ARRDC3 was detected in 39 (49%) oropharyngeal, 25 (57%) hypopharyngeal, and 23 (55%) uterine cervical cancer samples. PAR1 was expressed in 45 (57%) oropharyngeal, 22 (50%) hypopharyngeal, and 22 (50%) uterine cervical cancer samples. Patients diagnosed with p16-positive oropharyngeal cancer had a substantially improved prognosis compared to those diagnosed with p16-negative cancer. The PAR1-negative cases had a considerably improved prognosis compared to the positive cases (disease-specific survival [DSS] and -negative cases (disease-free survival [DFS]). Multivariate analysis revealed that ARRDC3-positive cases had an appreciably better DSS prognosis than patients with p16-negative oropharyngeal cancers. PAR1-positive patients among patients with p16-positive oropharyngeal cancer had a poor prognosis. With respect to DFS, patients with PAR1-positive and p16-negative oropharyngeal cancer had a 35-fold higher recurrence rate than those with PAR1-negative and p16-negative oropharyngeal cancer.
Our results suggest that PAR1 expression affects the prognosis and recurrence rate of HPV-associated oropharyngeal cancer.
人乳头瘤病毒（HPV）相关的口咽癌偶尔预后较差，因此预后风险分层至关重要。蛋白酶激活受体 1（PAR1）参与了癌症的发生，其表达受含有α-抑制蛋白结构域的蛋白 3（ARRDC3）调节。PAR1 还参与肿瘤微环境。我们试图评估 PAR1、ARRDC3 和肿瘤浸润淋巴细胞（TIL）评分在口咽癌、下咽癌和宫颈癌患者中的预测能力，这些患者作为 HPV 相关口咽癌的对照。
对 79 例口咽癌、44 例下咽癌和 42 例宫颈癌样本进行 p16、ARRDC3 和 PAR1 表达的免疫组织化学分析。评估 TIL 评分并根据浸润程度分为低：0-10%、中：20-40%和高：>50%。为了进行预后分析，将三组病例通过低、中、高分类进行评估，或者用中位数作为截点将三组病例分为两组进行评估。
p16 在 44 例（56%）口咽癌、8 例（18%）下咽癌和所有宫颈癌样本中表达。ARRDC3 在 39 例（49%）口咽癌、25 例（57%）下咽癌和 23 例（55%）宫颈癌样本中检出。PAR1 在 45 例（57%）口咽癌、22 例（50%）下咽癌和 22 例（50%）宫颈癌样本中表达。与 p16 阴性癌症患者相比，诊断为 p16 阳性口咽癌的患者预后显著改善。PAR1 阴性病例的预后明显优于阳性病例（疾病特异性生存率[DSS]和阴性病例（无病生存率[DFS]）。多变量分析显示，与 p16 阴性口咽癌患者相比，ARRDC3 阳性病例的 DSS 预后明显更好。在 p16 阳性口咽癌患者中，PAR1 阳性患者的预后较差。就 DFS 而言，PAR1 阳性和 p16 阴性口咽癌患者的复发率比 PAR1 阴性和 p16 阴性口咽癌患者高 35 倍。
我们的结果表明，PAR1 表达影响 HPV 相关口咽癌的预后和复发率。
