Cyclin D1 immunoreactivity in normal endocervix and diagnostic value in reactive and neoplastic endocervical lesions

Abstract

It may be difficult to distinguish reactive glandular lesions from adenocarcinoma in situ of the uterine cervix, and although several immunohistochemical markers have established value in this diagnostic setting, none is completely reliable. We have noted that neoplastic endocervical lesions often show loss of nuclear cyclin D1 expression in contrast to benign glandular cells. Therefore, we investigated cyclin D1 staining in a series of 64 cervical biopsy specimens including examples of normal and reactive endocervical epithelium, adenocarcinoma in situ, stratified mucin-producing intraepithelial lesions, and invasive adenocarcinoma. Thirteen specimens also included a component of high-grade cervical squamous intraepithelial neoplasia. Normal endocervical epithelium usually expressed cyclin D1, although staining was typically focal, and there was increased immunoreactivity in reactive and metaplastic glandular cells including tubo-endometrioid metaplasia. In contrast, most cases of adenocarcinoma in situ were completely negative and, therefore, cyclin D1 staining distinguished benign from neoplastic epithelial cells. Although focal cyclin D1 expression was observed in 5/19 cases of adenocarcinoma in situ, the staining was associated with more marked cytological atypia precluding confusion with a reactive process. The invasive adenocarcinomas were mainly negative for cyclin D1. However, focal staining was observed in 10/19 cases and was mainly restricted to cells at the deep tumor margin, or to small infiltrative glands and detached cell clusters within the stroma. In conclusion, cyclin D1 can be included within an immunohistochemical panel to aid in the distinction between reactive cervical glandular lesions and adenocarcinoma in situ. The localized distribution of staining within invasive lesions suggests that cyclin D1 up-regulation has a specific role during the progression of some endocervical adenocarcinomas.

Immunohistochemical Expression of Cyclin D1, p16Ink4a, p21WAF1, and Ki-67 Correlates With the Severity of Cervical Neoplasia

“…In several studies, the prognostic value of p53 immunostaining has not been confirmed in cervical cancer (12,21,(24)(25)(26). Our results showed weaker and sparser cyclin D1 immunoreactivity in HSIL and cancer cases as compared with normal areas and LSIL group (Po0.001), which is in agreement with those previously reported (29)(30)(31)(32). D-type cyclins may not be required for G1 progression in HPV-transformed cervical epithelium, as E7 oncoprotein binds to and interferes with the pRb function, bypassing the normal requirement for cyclin D1-CDK in the initiation of cell-cycle entry.…”

“…We have observed high p53 positivity in all groups, which corroborates its possible role in cervical carcinogenesis; however, p53 did not prove to be a good biomarker for distinguishing low-from high-grade lesions, as previously reported (24,25). As a result, there is a loss of the positive feedback loop and, therefore, a downregulation of cyclin D1 despite the concurrent increase in cellular proliferation (9,28,29). Nevertheless, some authors have reported an association between high epithelial expression of p53 and/or pRb and spontaneous regression of high-grade lesions (15,27), which suggests downregulation of both E6 and E7 due to the host immune responses (15).…”

“…Nevertheless, some authors have reported an association between high epithelial expression of p53 and/or pRb and spontaneous regression of high-grade lesions (15,27), which suggests downregulation of both E6 and E7 due to the host immune responses (15). A recent study revealed absence or focal positivity for cyclin D1 in neoplastic endocervical lesions (29). As a result, there is a loss of the positive feedback loop and, therefore, a downregulation of cyclin D1 despite the concurrent increase in cellular proliferation (9,28,29).…”

Fascin and cyclin D1 immunoreactivity in non-neoplastic vulvar squamous epithelium, vulvar intraepithelial neoplasia and invasive squamous carcinoma: correlation with Ki67 and p16 protein expression

“…In contrast, uVIN showed consistently reduced cyclin D1 reactivity despite the increase in Ki67 labelling thus indicating discordant expression of these proliferation-associated proteins. Similar findings have been reported in cervical squamous and glandular intraepithelial lesions and in HPV-associated neoplasms of the head and neck,13 14 27–29 and this most likely reflects HPV-related disruption of intracellular feedback loops involving the retinoblastoma protein. Our findings suggest that the reduced expression of cyclin D1 could also be used diagnostically in conjunction with ‘positive’ staining markers such as p16 protein and Ki67 to support a diagnosis of uVIN, and to distinguish the basaloid and differentiated subtypes of VIN.…”

Endometrial metaplasias and reactive changes: a spectrum of altered differentiation

“…In the endometrium, ciliated and tubal metaplasia (CTM) is the most common type of metaplasia and also occurs frequently in the cervix, where its location at the squamocolumnar junction, mild atypicality, lack of intracytoplasmic mucin and frequent positivity for p16 INK4A can lead to its misdiagnosis as an in situ endocervical adenocarcinoma 24 25. In the uterine isthmic region, ciliated glands are so common as to be considered normal.…”