Voidăzan Septimiu Toader, Dianzani Caterina, Husariu Mădălina Aurelia, Geréd Bíborka, Turdean Sabin Gligore, Uzun Cosmina Cristina, Kovacs Zsolt, Rozsnyai Florin Francisc, Neagu Nicoleta
Department of Epidemiology, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureş, 540139 Târgu Mureş, Romania.
Plastic and Reconstructive Surgery Unit, Campus Biomedico University of Rome, 00128 Rome, Italy.
Biology (Basel). 2022 Jun 23;11(7):956. doi: 10.3390/biology11070956.
Human papillomaviruses (HPVs) are common sexually transmitted infectious agents responsible for several anogenital and head and neck cancers. Cervical cancer (CC) is the fourth leading cause of death in women with cancer. The progression of a persistent HPV infection to cancer takes 15-20 years and can be preventable through screening. Cervical cytology (Pap smear) is the standard screening test for CC and precancerous lesions. For ASC-US and ASC-H lesions, a combination of Pap smear and HR-HPV analysis is recommended as a triage step before colposcopy. However, these tests cannot predict progression to CC. For this purpose, we summarized current scientific data on the role of p16/Ki-67 immunohistostaining, telomerase and fibronectin in predicting progression to CC. p16 and p16/Ki-67 dual staining (DS) were more specific than HR-HPV DNA testing for the detection of CIN2+/CIN3+ in women with ASC-US and LSIL. Similarly, hTERC FISH analysis significantly improved the specificity and positive predictive value of HPV DNA testing in differentiating CIN2+ from CIN2 cytological samples. In conclusion, p16 IHC, p16/Ki-67 DS and hTERC FISH amplification are all valid adjunctive biomarkers which significantly increase the sensitivity and specificity of cervical dysplasia diagnosis, especially when combined with HPV DNA testing. However, considering the global socioeconomic background, we can postulate that p16 and p16/ Ki-67 IHC can be used as a next step after positive cytology for ASC-US or LSIL specimens in low-income countries, instead of HPV DNA testing. Alternatively, if HPV DNA testing is covered by insurance, p16 or p16/Ki-67 DS and HPV DNA co-testing can be performed. In middle- and high-income countries, hTERC amplification can be performed as an adjunctive test to HPV DNA testing in women with ASC-US and LSIL.
人乳头瘤病毒（HPV）是常见的性传播感染病原体，可引发多种肛门生殖器癌和头颈癌。宫颈癌（CC）是女性癌症死亡的第四大主要原因。持续性HPV感染发展为癌症需要15至20年，且可通过筛查预防。宫颈细胞学检查（巴氏涂片）是宫颈癌和癌前病变的标准筛查方法。对于非典型鳞状细胞意义不明确（ASC-US）和非典型鳞状细胞不排除高度病变（ASC-H）的病变，在进行阴道镜检查前，推荐将巴氏涂片和高危型HPV分析结合作为分流步骤。然而，这些检查无法预测是否会发展为宫颈癌。为此，我们总结了目前关于p16/Ki-67免疫组化、端粒酶和纤连蛋白在预测宫颈癌发展中作用的科学数据。对于ASC-US和低度鳞状上皮内病变（LSIL）女性，p16和p16/Ki-67双重染色（DS）在检测高级别鳞状上皮内病变（CIN2+）/原位癌（CIN3+）方面比高危型HPV DNA检测更具特异性。同样，人端粒酶RNA组分（hTERC）荧光原位杂交（FISH）分析显著提高了HPV DNA检测在区分CIN2+与CIN2细胞学样本中的特异性和阳性预测值。总之，p16免疫组化（IHC）、p16/Ki-67 DS和hTERC FISH扩增都是有效的辅助生物标志物，可显著提高宫颈发育异常诊断的敏感性和特异性，尤其是与HPV DNA检测联合使用时。然而，考虑到全球社会经济背景，我们可以推测，在低收入国家，对于ASC-US或LSIL标本细胞学检查阳性后，p16和p16/Ki-67 IHC可作为下一步检查，而非HPV DNA检测。或者，如果HPV DNA检测有保险覆盖，则可同时进行p16或p16/Ki-67 DS与HPV DNA联合检测。在中高收入国家，对于ASC-US和LSIL女性，hTERC扩增可作为HPV DNA检测的辅助检查。
