Cervical cancer is the second most common cause of cancer death in women worldwide, with an estimated 510
000 newly diagnosed cervical cancer cases and 288
000 deaths annually (Pagliusi, 2006
). Although implementation of nationwide cervical cytological screening programs has led to a dramatic decline in the incidence of cervical squamous cell carcinoma, the rate of endocervical adenocarcinomas is on the rise, particularly in young women (Smith et al, 2000
; Bray et al, 2005
). The false negative rate in the cytological test for cervical adenocarcinomas, generally speaking, is higher than that for squamous lesions (SLs) (Makino et al, 1995
). Several factors may contribute to such a difference; ill-defined cytological criteria for separating neoplastic glandular cells from benign mimics may have an important role.
In 2001, the Bethesda System introduced the term ‘atypical glandular cells (AGCs)', replacing the term ‘AGCs of undetermined significance', thereby classifying glandular cell abnormalities exceeding those typical reactive changes, but lacking features diagnostic of adenocarcinoma, into the following three categories: AGC of unclear cell origin, atypical endocervical cells and atypical endometrial cells (Solomon et al, 2002
). However, in clinical practice, such a sub-categorization of AGC remains a diagnostic challenge with poor inter-observer agreement. The studies show that 17–80% (mean, 41%) of women with an AGC diagnosis were found to harbour significant cervical lesions (SCLs), including high-grade cervical intraepithelial neoplasia (CIN2 and CIN3), adenocarcinoma in situ
(AIS) and invasive carcinoma. The rate of invasive carcinoma has been reported to be up to 10% (Liao and Stanbridge, 2000
; Lee et al, 2002
; Cangiarella and Chhieng, 2003
From the clinical point of view, young women with AGC are often treated aggressively with cervical conization because of the relative lack of accuracy of colposcopy and endocervical curettage for excluding SCLs. It has been well documented that SCLs, including invasive carcinoma, may exist in AGC patients even when the results of colposcopic examination and endocervical sampling are normal (Andersen and Arffmann, 1989
). Therefore, from a cost-benefit standpoint, and from a desire to avoid unnecessary invasive procedures, an accurate screening method or test is needed to determine which women with a cytological diagnosis of AGC harbour a SCL. In the recent years, many biomarkers have been developed and, among those, human papillomavirus (HPV) and carbonic anhydrase IX (CA-IX) appear to be particularly promising.
Infection with oncogenic high-risk HPV (H-HPV) strain(s) is widely accepted to be an important aetiologic factor for cervical cancer (zur Hausen, 2002
; Schiffman et al, 2007
; Bosch et al, 2008
). Clinical trials have established the importance of H-HPV testing for the detection of significant SLs, including CIN2, CIN3 and squamous cell carcinoma (Solomon et al, 2001
). Furthermore, H-HPV has been detected in 80–90% of adenocarcinomas and their precursor glandular lesions (GL) (Pirog et al, 2000
; Bosch et al, 2008
). However, there are only limited data available with respect to H-HPV testing as a diagnostic tool in the detection of glandular neoplasia.
In the 1990s, the antigen MN was identified (Zavada et al, 1993
). The antigen MN is a transmembrane glycoprotein, and is a member of the carbonic anhydrase gene family, and is more specifically designated carbonic anhydrase IX (CA-IX) (Opavsky et al, 1996
). The CA-IX is a biomarker of several human tumours, including carcinomas of the cervix and kidney (Liao et al, 1994
). The expression of CA-IX in cancerous tissues, and its absence in normal counterparts, has led to the speculation that it has a function in carcinogenesis (Wykoff et al, 2000
; Ivanov et al, 2001
). Its expression is controlled by the transcription factor, hypoxia-inducible factor-1, and is upregulated in hypoxic regions of tumour tissues (Swietach et al, 2007
In a survey of benign and neoplastic cervical tissues and Pap smears (PSs), it was observed that virtually all AGC associated with AIS and adenocarcinoma expressed high levels of CA-IX antigen, but this biomarker was rarely detected in the benign cervical cells/cervical tissues. This suggested the possibility that the expression of CA-IX may serve as a useful biomarker for diagnosing AIS and adenocarcinoma (Liao et al, 1994
; Liao and Stanbridge, 1996
In 1998, the Gynecologic Oncology Group (GOG), a national multi-institutional clinical trials group, supported by the US National Cancer Institute, conducted a study of women with a cytological diagnosis of AGC. In total, 25 institutions in the United States and 11 institutions in Japan participated in the trial. Here, we report the results from the Japanese cohort. The objective of this study, included in GOG protocol #171, was to determine whether CA-IX expression in a conventional PS is a diagnostic biomarker for a SCL in Japanese women with a cytological diagnosis of AGC and to explore the diagnostic value of H-HPV testing alone or in combination with CA-IX.