Oncogenic Human Papillomavirus–infected Immature Metaplastic Cells and Cervical Neoplasia

Abstract

Persistent cervical high-risk human papillomavirus (HR-HPV) infection results in high-grade cervical intraepithelial neoplasia (CIN2/3) and cervical carcinoma. The susceptibility of the cervix to HPV carcinogenesis and the importance of HPV18 in cervical carcinoma despite relative infrequency in CIN2/3 could be linked to HR-HPV infection of immature metaplasia (IM) at the squamocolumnar junction. Atypical IM (AIM) is an equivocal category used to describe changes in IM suggestive of high-grade neoplasia, which causes diagnostic and management problems. We used laser capture microscopy combined with polymerase chain reaction in 24 women with HPV18, HPV16, or other HPV infections on cytologic analysis and a cervical loop electrosurgical excision procedure to locate HR-HPV in cervical tissue. HPV18-positive AIM and CIN2/3 were present in 7/12 cases with HPV18 on cytologic analysis. In 2 cases with HPV18 and other HPV types, HPV18 was only present in AIM and not in CIN2/3. HPV16-positive AIM was present in 3/7 and HPV16-positive CIN2/3 in 5/7 cases with HPV16. No cases had HPV16 AIM without CIN2/3. Other HR-HPV-positive AIM and CIN2/3 cases were present, respectively, in 1/6 and 5/6 cases positive for HR-HPV types other than HPV16/18. In a subset, 94% HPV18 AIM regions showed CK17 and p16 positivity, and 41% were CK7 positive. CIN2/3 and AIM with other HR-HPVs showed similar patterns. AIM was a particular feature of HPV18 infection in women with CIN2/3. HR-HPV infection of CK7/17-positive AIM expressing p16 was particularly seen for HPV18 with and without classical CIN2/3 and should be regarded as a high-grade precancer.

Two major pathways of recurrent high‐grade squamous intraepithelial lesions of the cervix

“…In our experience, nearly all glands underneath the metaplastic and dysplastic squamous epithelium of the TZ and the adjacent columnar epithelium consistently stain positive for CK7, while the original squamous epithelium of the cervix is negative for CK7 (Dako CK7 Clone OV‐TL 12/30). Similar results were described by van der Marel et al . We therefore challenge the statement that CK7 is a SCJ marker and that only HR‐HPV infected CK7 positive SCJ cells give rise to primary HSIL/invasive cervical cancer or recurrent HSIL/invasive cervical cancer after LEEP treatment.…”

The variable clinicopathological categories and role of human papillomavirus in cervical adenocarcinoma: A hospital based nation‐wide multi‐center retrospective study across China

“…The high prevalence of HPV-18 in CADC and its importance in ADC-CX may be related to the finding that HPV-18 is often located in the zone of immature metaplasia in the cervix, where cells have the potential for differentiation into both glandular and squamous epithelium. 33 The importance of HPV-16 and 218 has been supported by Dahlstrom's study, which found that both were detectable up to 14 years before a diagnosis of cervical adenocarcinoma. 34 HPV-52 and 245 were found in much lower proportions (5.61%, 3.92%), and HPV-59/31/58 were relatively rare (1.87-2.24%).…”

p16 staining has limited value in predicting the outcome of histological low-grade squamous intraepithelial lesions of the cervix

“…[11][12][13][14] The value of p16 in the diagnostic process is important, because it is detected in almost all HSIL/CIN2-3, whereas reactive mimickers, such as immature metaplasia or atrophy, are negative or show focal staining. 5,13,15 Thus, p16 staining has achieved a major role in indisputably classifying a lesion as HSIL/CIN2-3 or as reactive. 5,13,15 In contrast with the almost constantly positive results of HSIL/CIN2-3 the results of p16 staining in LSIL/CIN1 vary greatly, with some lesions being completely negative or showing focal staining, whereas others show a diffuse, basal, positive reaction.…”

“…5,13,15 Thus, p16 staining has achieved a major role in indisputably classifying a lesion as HSIL/CIN2-3 or as reactive. 5,13,15 In contrast with the almost constantly positive results of HSIL/CIN2-3 the results of p16 staining in LSIL/CIN1 vary greatly, with some lesions being completely negative or showing focal staining, whereas others show a diffuse, basal, positive reaction. 5,11 This variability in staining has raised the question as to whether p16 overexpression in patients with LSIL/CIN1 could be correlated with the potential of 'progression'.…”