The Significance Of P16 Expression And Human Papillomavirus Detection In Distinction Of Endocervical And Endometrial Adenocarcinomas

Background:It is well known that the differential diagnosis of endocerical adenocarcinomas (ECAs) and endometrial adenocarcinoma(EMAs) can be difficult because the morphologic spectrum of them overlaps and Anatomic site is close to each other, especially in biopsy and curettage specimens. Preoperative determination of the primary site in these cases is useful because surgical management and treatment protocol of them usually differ. p16 is an inhibitor of cyclin-dependent kinases(CDK), and overexpression of p16 has been observed in cervical intraepithelial lesions(CIN) and invasive carcinomas associated with human papillomavirus(HPV) infection including squamous cell carcinoma(SCC) and adenocarcinoma(ADC).Methods:We investigated the utility of p16 immunohistochemistry (IHC) in the distinction of ECAs and EMAs. p16 expression was assessed in 41 unequivocal ECAs and 72 unequivocal EMAs in hysterectomy specimens, p16 expression was interpreted using the semiquantitative scoring system in considering staining area extent and intensity. We also evaluated the relationship between p16 staining circumstances and clinicopathological features, such as pathological subtype, degree of differentiation, depth of invasion, lymph node metastasis and FIGO stage. Hybrid capture 2(HC2) for HPV DNA was also performed in 41 ECAs and 46 EMAs which are formalin-fixed and paraffin-embedded materials.Results:The positive rate of p16 in ECAs was 98%(40/41), as compared with 81%(58/72) in EMAs. The tumor cells in ECA showed diffuse and strong expression of p16. On the contrary, EMAs exhibited focal staining pattern. However, the staining intensity of them was similar. Furthermore, the p16 expression was associated with lymph node metastasis in ECAs. For EMAs, the expression was relevant to pathologic subtype, degree of differentiation and FIGO stage. The positive rate of HPV DNA in ECAs was 22%(9/41), but all of EMAs showed negative results. It was interesting that all serous ADCs in ECAs and EMAs demonstrated diffuse and strong p16 staining and negative HPV DNA.Conclusion:p16 immunohistochemistry and HPV testing can be used to assist in the classification of uterine ADCs of equivocal origin, especially in biopsy and curettage specimens prior to hysterectomy. The reasonable application of these two methods will be instructive for clinical doctors to choose the correct surgical approach and proper treatment program. It is a pity that these two methods might be useless in distinguishing serous ADCs in ECAs and EMAs. HC2 method is feasible in formalin-fixed and paraffin-embedded specimens but should not be recommended on account of its limitations compared with PCR amplification using SPF10 primer and gene-typing with linear probe array (LiPA) system, in particular for uterine ADCs.