Ki-67 is also useful, albeit less so although increased in AIS, it may be focally increased in endometriosis, tubal metaplasia, and microglandular hyperplasia and markedly elevated in reactive columnar epithelium. Moreover, strong (or complete absence of) nuclear p53 immunostaining will be seen in tumors from the endometrium or upper genital tract, while HPV-positive cervical neoplasms should show weak and heterogeneous staining. In situ hybridization for HPV, if positive, will be helpful in accurately identifying the endocervical neoplasm. However, diffuse strong p16 expression is also found in high-grade endometrial (including serous) adenocarcinomas involving the cervix and metastatic high-grade tubal or ovarian adenocarcinomas, requiring additional evaluation (outlined below), particularly in small biopsy specimens. 13 Therefore, strong diffuse p16 staining is the most important distinguishing feature. Caveats include early or superficial AIS in which Ki-67 staining may be less intense, and reactive epithelial changes in which Ki-67 staining may be strong. 12 A prototype of endocervical AIS is a columnar lesion demonstrating increased Ki-67 proliferative index with strong and diffuse p16 nuclear and cytoplasmic reactivity, and frequently lacking the expression of estrogen receptor (ER) and vimentin. Similar to the squamous lesions, Ki-67 and p16 markers are commonly used to differentiate endocervical adenocarcinoma in situ (AIS) from endocervical glandular metaplasia, tubal metaplasia, microglandular hyperplasia, and endometriosis. One solution is to render a diagnosis of вЂњSIL of uncertain grade (cervical intraepithelial neoplasia IвЂ“cervical intraepithelial neoplasia II)вЂќ when faced with this conundrum, emphasizing the option of a 6-month follow-up period during which at least half of such lesions will resolve. This is particularly critical in young women for whom unnecessary loop electrosurgical excision procedure excision can increase the risk of premature rupture of membranes during pregnancy. 8 Thus, it is imperative that the pathologist be aware of the pitfall of using p16 alone as a вЂњself-fulfilling prophetвЂќ for HSIL without considering the degree of atypia. Nevertheless, many atypia that do not fulfill the criteria for HSIL occur at the squamocolumnar junction, are strongly p16 positive, and will regress on follow-up. Such lesions may be empirically at greater risk by their location in the squamocolumnar junction and associated high-risk HPV type. On the other, we have found that this staining pattern in the cervix is strongly associated with any lesion arising at the squamocolumnar junction. On one hand, diffuse and full-thickness (block) staining has been associated with HSIL. 7 A second caveat is the distinction of LSIL from HSIL by p16 staining alone. 6 Human papilloma virus in situ (IS HPV) hybridization may be helpful in distinguishing lesions from nonneoplastic epithelium but its value in routine practice is questionable given the availability of p16. 5 In either case, the p16 staining is the most decisive in distinguishing reactive changes from SIL. Pro-Ex-C may be more useful in this setting owing to its improved specificity and lower background staining. 4 One caveat is that expression of Ki-67 can be seen well into the upper layers of immature inflamed squamous epithelium. 2, 3 A high index of Ki-67 nuclear staining and diffuse p16 nuclear and cytoplasmic expression involving most of the mucosal thickness are commonly associated with squamous intraepithelial lesions (SILs) arising from the squamocolumnar junction. 1 The expression of p16 is attributed to high-risk HPV infection. The marker of proliferation (Ki-67), the expression of topoisomerase II-О± and minichromosome maintenance protein-2 (Pro-Ex-C), and the HPV-associated cyclin-dependent kinase inhibitor 2A (p16) have been used to differentiate HSIL from several conditions with morphologic overlap, including reactive/reparative epithelial changes, immature squamous metaplasia, menopausal- and hormone-induced mucosal atrophy with atypia, and cytologic alterations induced by cautery artifact. 1 In general, when managing a patient who is human papilloma virus (HPV) positive and has either atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion (LSIL) on cervical cytology, the pathologist does not have to distinguish minor reactive epithelial atypia from LSIL in the biopsy specimen in as much as either interpretation confers a similar outcome risk of high-grade squamous intraepithelial lesion (HSIL) (5%вЂ“10%) during the next 2 years of follow-up. Immunohistochemistry in the cervix is helpful primarily in the differentiation of benign reactive epithelial changes from either squamous or columnar neoplasia.

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