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Abstract：
BACKGROUND: Vulva squamous cell carcinoma (VSCC) develops through two separate molecular pathways-one involving high-risk human papilloma virus infection (HPV-associated), and the other without HPV infection (HPV-independent) often involving TP53 mutation. HPV-associated VSCC generally has a better progression-free survival than HPV-independent VSCC. The aim of this study was to determine TP53 mutation status using immunohistochemistry, compare different methods of HPV detection and correlate both with survival in a retrospective cohort of 123 patients with VSCC.
METHODS: Immunohistochemistry for p53, Ki67 and p16INK4A (a surrogate marker for HPV infection) was performed on formalin-fixed paraffin-embedded tissues from a cohort of surgically treated VSCC patients to identify molecular subtypes of VSCC. Presence of HPV infection was detected by HPV DNA PCR and HPV mRNA in situ hybridization (ISH). The Pearson chi-square test and multivariable Cox regression model were used to investigate the association of different parameters with progression-free survival and disease-specific survival (DSS), and Kaplan-Meier curves were used to show the association of different parameters with survival.
RESULTS: The results of p53 and p16INK4A immunohistochemistry confirmed three VSCC subtypes associated with different prognosis. The TP53 mutation status was identified as an independent prognostic factor of worse progression-free survival (p = 0.024) after adjustment for FIGO stage. p16INK4A immunohistochemistry, mRNA ISH, and DNA PCR had excellent concordance in terms of HPV detection. According to the multivariable Cox regression model, the presence of hrHPV mRNA correlated significantly with increased progression-free survival (p = 0.040) and DSS (p = 0.045), after adjustment for other confounders.
CONCLUSIONS: p53 and p16INK4A immunohistochemistry stratify VSCC cohort into three subtypes with TP53mutated patients having the worst prognosis. The detection of hrHPV mRNA by ISH was an independent predictor of increased survival. Thus, the combined detection of p53 and HPV mRNA might improve risk stratification in VSCC.
METHODS: Immunohistochemistry for p53, Ki67 and p16INK4A (a surrogate marker for HPV infection) was performed on formalin-fixed paraffin-embedded tissues from a cohort of surgically treated VSCC patients to identify molecular subtypes of VSCC. Presence of HPV infection was detected by HPV DNA PCR and HPV mRNA in situ hybridization (ISH). The Pearson chi-square test and multivariable Cox regression model were used to investigate the association of different parameters with progression-free survival and disease-specific survival (DSS), and Kaplan-Meier curves were used to show the association of different parameters with survival.
RESULTS: The results of p53 and p16INK4A immunohistochemistry confirmed three VSCC subtypes associated with different prognosis. The TP53 mutation status was identified as an independent prognostic factor of worse progression-free survival (p = 0.024) after adjustment for FIGO stage. p16INK4A immunohistochemistry, mRNA ISH, and DNA PCR had excellent concordance in terms of HPV detection. According to the multivariable Cox regression model, the presence of hrHPV mRNA correlated significantly with increased progression-free survival (p = 0.040) and DSS (p = 0.045), after adjustment for other confounders.
CONCLUSIONS: p53 and p16INK4A immunohistochemistry stratify VSCC cohort into three subtypes with TP53mutated patients having the worst prognosis. The detection of hrHPV mRNA by ISH was an independent predictor of increased survival. Thus, the combined detection of p53 and HPV mRNA might improve risk stratification in VSCC.
摘要：
背景：外阴鳞状细胞癌（VSCC）是通过两个独立的分子途径发展的，一个涉及高危型人乳头瘤病毒感染（HPV相关），另一种没有HPV感染（不依赖HPV），通常涉及TP53突变。HPV相关的VSCC通常比不依赖HPV的VSCC具有更好的无进展生存期。这项研究的目的是使用免疫组织化学确定TP53突变状态，在123例VSCC患者的回顾性队列中，比较了不同的HPV检测方法，并将两者与生存率相关联。
方法：对一组经手术治疗的VSCC患者的福尔马林固定的石蜡包埋组织进行p53，Ki67和p16INK4A（HPV感染的替代标记）的免疫组织化学，以鉴定VSCC的分子亚型。通过HPVDNAPCR和HPVmRNA原位杂交（ISH）检测HPV感染的存在。采用Pearson卡方检验和多变量Cox回归模型研究不同参数与无进展生存期和疾病特异性生存期(DSS)的关系。和Kaplan-Meier曲线用于显示不同参数与生存的关联。
结果：p53和p16INK4A免疫组织化学结果证实了三种VSCC亚型与不同的预后相关。在调整FIGO分期后，TP53突变状态被确定为无进展生存期较差的独立预后因素(p=0.024)。p16INK4A免疫组织化学，ISHmRNA,DNAPCR在HPV检测方面具有良好的一致性。根据多变量Cox回归模型，hrHPVmRNA的存在与无进展生存期（p=0.040）和DSS（p=0.045）的增加显着相关，在对其他混杂因素进行调整后。
结论：p53和p16INK4A免疫组织化学将VSCC队列分为三种亚型，TP53突变的患者预后最差。ISH检测hrHPVmRNA是增加生存率的独立预测因子。因此，p53和HPVmRNA的联合检测可能改善VSCC的危险分层.
方法：对一组经手术治疗的VSCC患者的福尔马林固定的石蜡包埋组织进行p53，Ki67和p16INK4A（HPV感染的替代标记）的免疫组织化学，以鉴定VSCC的分子亚型。通过HPVDNAPCR和HPVmRNA原位杂交（ISH）检测HPV感染的存在。采用Pearson卡方检验和多变量Cox回归模型研究不同参数与无进展生存期和疾病特异性生存期(DSS)的关系。和Kaplan-Meier曲线用于显示不同参数与生存的关联。
结果：p53和p16INK4A免疫组织化学结果证实了三种VSCC亚型与不同的预后相关。在调整FIGO分期后，TP53突变状态被确定为无进展生存期较差的独立预后因素(p=0.024)。p16INK4A免疫组织化学，ISHmRNA,DNAPCR在HPV检测方面具有良好的一致性。根据多变量Cox回归模型，hrHPVmRNA的存在与无进展生存期（p=0.040）和DSS（p=0.045）的增加显着相关，在对其他混杂因素进行调整后。
结论：p53和p16INK4A免疫组织化学将VSCC队列分为三种亚型，TP53突变的患者预后最差。ISH检测hrHPVmRNA是增加生存率的独立预测因子。因此，p53和HPVmRNA的联合检测可能改善VSCC的危险分层.
