ReviewCervical adenocarcinoma: Moving towards better prevention☆
Highlights
► HPV-16, -18 and -45 account for approximately 90% of ADC worldwide. ► ADC is difficult to detect through current cervical screening methods. ► Prophylactic HPV vaccination may have a significant impact on the prevention of ADC.
Introduction
Cervical cancer is the third most common cancer among women and the fourth leading cause of female cancer deaths. Each year, more than 500,000 new cases and around 275,000 deaths occur globally [1]. While developed countries have witnessed a steady decline in the incidence of cervical cancer since the implementation of cytologic cervical cancer surveillance in the 1950s, cervical screening does not occur in all countries and cervical cancer still occurs in countries where screening has been implemented [2]. This may be due to methodologic limitations of screening and/or screening coverage [3], [4], [5]. Furthermore, the majority of the cervical cancer decline can be attributed to a decrease in squamous cell carcinoma (SCC); in contrast, there has been a rise in the absolute and relative incidence of cervical adenocarcinoma (ADC) in many countries [5], [6], [7], [8], [9]. In many western countries, ADC currently accounts for up to 25% of all cases of cervical cancer [10]. This may again be due to the limitations of detecting ADC at screening or it may be that the incidence of ADC is truly on the rise [9]. There is some debate as to whether failure to detect pre-invasive ADC is a reason for ADC often being diagnosed at an advanced disease stage and frequently being associated with a worse prognosis. ADC differs from SCC in terms of epidemiology, etiology and prognosis.
The purpose of this manuscript is to review the current scientific knowledge on ADC with regard to histologic classification, epidemiology, clinical considerations and prognosis, and bio-molecular characteristics, as well as co-factors and behavioral factors affecting ADC prevalence. Where relevant, differences between ADC and SCC have been highlighted. The current detection techniques and their limitations, and considerations for optimizing ADC prevention are also discussed.
Methodologically, we searched PubMed, publicly available websites and congress abstracts for data and literature using the following keywords in combination with ADC: epidemiology, human papillomavirus (HPV), co-factors, behavioral factors, prognosis, prevention and vaccination.
The most common invasive cervical cancers (ICC) are SCC and ADC, which account for 75–90% and 10–25% of ICC, respectively, depending on the study [5], [9], [10], [11], [12], [13]. SCC is the predominant type and develops from the squamous cells that cover the surface of the ectocervix. SCC most often occurs at the squamocellular junction between the ecto- and endocervix and is therefore diagnosed earlier by cytologic screening [11], [14], [15]. In contrast, ADC develops from the mucus-producing gland cells of the endocervix [11]. Anatomical and other factors can affect the location of the lesion but the initial growth of ADC is often within the endocervical canal; therefore, the ectocervix appears normal and lesions are often diagnosed much later than for SCC [15]. Moreover, during the process of metaplasia, islands of endocervical glands can still be seen among the ectocervical squamous epithelium or under it [16], [17].
Colposcopically, there are no clear criteria for the appearances of endocervical gland dysplasia, ADC in situ (AIS) or microinvasive ADC compared with the more standard colposcopic findings of various squamous intraepithelial lesions [15]. Furthermore, histologically there are difficulties interpreting the morphologic abnormalities of glandular cells [18]. AIS may occur beneath the transformation zone and may be covered by normal lining. AIS may be multicentric in 13–27% of women [16], [19]. AIS may also occur in association with cervical intraepithelial neoplasia (CIN), but it is unclear whether the site of neoplastic transformation will involve glandular or squamous epithelium [20], [21]. Some authors have suggested that AIS (or a large proportion of AIS) is not a precursor of ADC or that the proportion of AIS that progresses to ADC is much lower than the proportion of carcinomas in situ that progresses to SCC [22].
It is also important to note that histologic distinction between endocervical ADC and endometrial ADC is often difficult, and misdiagnoses may occur. A three-marker panel including vimentin, an estrogen or progesterone receptor and an HPV marker may aid in determining the site of origin, but these panels do not perform well with special variant carcinomas [23], [24], [25], [26]. A pre-operative distinction is important because primary surgical management differs between the two tumors [23], [24]. Therefore, if endocervical ADC is misdiagnosed as endometrial ADC, it may be more advanced when eventually diagnosed and treated.
Adenosquamous cell carcinoma has features of both SCC and ADC. Adenosquamous cell carcinomas are often included in ADC classification because of their relatively small numbers [11], [27]. Other rare types of cervical cancer include melanoma, sarcoma, lymphoma, neuroendocrine tumors and cancers of unspecified histology [5], [11], [28].
Section snippets
Incidence and prevalence of ADC – how has it evolved over the last few decades?
Globally, ADC accounts for an average of 10–25% of all ICC [9], [10], [12], [13], [29]. However, there is a wide variation between different cancer registries, as reported by the International Agency for Research on Cancer. The incidence of ADC varies from 5.5 to 30.0% in Europe, 7.5–23.9% in the Americas, 2.8–22.6% in Asia, 1.8–14.0% in Africa and 8.3–23.2% in Oceania [2].
Regional differences may be the result of the variability of parameters between studies, such as sample size [30],
What is the evidence that ADC occurs more frequently in young adult women and how could this be explained?
Several studies have shown that the incidence of ADC appears to be increasing more rapidly in young women [31], [32]. In a Canadian study conducted between the early 70s and mid-90s, the overall incidence of SCC significantly declined, but the risk of developing ADC in the 20–34-year and 35–49-year age groups trebled and doubled, respectively; in older women, however, it remained stable [32]. Similarly, in the Netherlands, while the overall incidence rate of ADC remained stable, it increased in
Conventional cytology
Includes collection of a sample of the ectocervical (squamous epithelial) and endocervical (columnar epithelial) cells at the transformation zone by a Pap smear or the more recently developed liquid-based cytology (LBC) [3]. Prompt suspension of the cells using LBC eliminates the problem of air drying, which can limit interpretation of conventional cervical cytology [95].
Guidelines
Cervical screening guidelines in Europe and the United States differ in terms of age, frequency, and screening methodologies
Discussion
This review has highlighted several clinical aspects of ADC; a disease that is of particular concern to clinicians because it is rising in incidence, both in absolute and relative terms, when compared with SCC [7], [8], [35], [36], [37], [38], [39], [40], [41]. ADC cases are also increasing in developed countries, despite the presence of cervical screening programs that have been very effective in reducing morbidity and mortality associated with SCC. This has been explained by a lack of clear
Acknowledgments
We would like to thank Roseanne Girnary (MediTech Media) for writing assistance. Editorial assistance and manuscript coordination were provided by Denis Sohy and Dirk Saerens on behalf of GlaxoSmithKline Biologicals. This study was funded and coordinated by GlaxoSmithKline Biologicals.
Conflict of interest statement: Professor Seoud is on the GSK-sponsored EXCCEL medical advisory board, and received honoraria from both GSK and MSD-Schering to lecture and research funds. Professor Tjalma has been
References (141)
- et al.
The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States – a 24-year population-based study
Gynecol Oncol
(2000) - et al.
Chapter 2: The burden of HPV-related cancers
Vaccine
(2006) - et al.
Epidemiology and natural history of human papillomavirus infections and type-specific implications in cervical neoplasia
Vaccine
(2008) - et al.
The anatomic distribution of cervical adenocarcinoma in situ: implications for treatment
Am J Obstet Gynecol
(1987) - et al.
Microinvasive adenocarcinoma of the cervix: a clinicopathologic study of 77 women
Obstet Gynecol
(1997) - et al.
Adenocarcinoma: a unique cervical cancer
Gynecol Oncol
(2010) - et al.
Epidemiology of adenocarcinoma of the cervix
Gynecol Oncol
(1988) - et al.
Comparison of adenocarcinoma and squamous cell carcinoma of the uterine cervix: a population-based epidemiologic study
Am J Obstet Gynecol
(1992) - et al.
Primary adenocarcinoma of the cervix
Am J Obstet Gynecol
(1952) - et al.
Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case–control study
Lancet
(2002)
Cervical cancer and use of hormonal contraceptives: a systematic review
Lancet
Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study
Lancet Oncol
Classification of papillomaviruses
Virology
The carcinogenicity of human papillomavirus types reflects viral evolution
Virology
Comparison of human papillomavirus genotypes, sexual, and reproductive risk factors of cervical adenocarcinoma and squamous cell carcinoma: Northeastern United States
Am J Obstet Gynecol
Prevalence of human papillomavirus DNA in different histological subtypes of cervical adenocarcinoma
Am J Pathol
Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis
Lancet Infect Dis
Physical state and expression of HPV DNA in benign and dysplastic cervical tissue: different levels of viral integration are correlated with lesion grade
Gynecol Oncol
Influence of histologic type and age on survival rates for invasive cervical carcinoma in Taiwan
Gynecol Oncol
Cervical cancer: effect of glandular cell type on prognosis, treatment, and survival
Obstet Gynecol
Adenocarcinoma as an independent risk factor for disease recurrence in patients with stage IB cervical carcinoma
Gynecol Oncol
Prognosis and clinicopathological characteristics of Ib–IIb adenocarcinoma of the uterine cervix in patients who have had radical hysterectomy
Eur J Surg Oncol
Prognosis of the adenocarcinoma of the cervix uteri: a comparative study
Gynecol Oncol
A comparison of prognoses of pathologic stage Ib adenocarcinoma and squamous cell carcinoma of the uterine cervix
Gynecol Oncol
Carcinoma of the cervix uteri
FIGO 26th annual report on the results of treatment in gynecological cancer
Int J Gynaecol Obstet
Oncological safety of laparoscopic-assisted vaginal radical trachelectomy (LARVT or Dargent's operation): a comparative study with laparoscopic-assisted vaginal radical hysterectomy (LARVH)
Gynecol Oncol
Ovarian metastasis in carcinoma of the uterine cervix
Gynecol Oncol
Incidence of ovarian metastasis in patients with cancer of the uterine cervix
Gynecol Oncol
Prognostic factors in adenocarcinoma of the uterine cervix
Gynecol Oncol
Cervical cytology screening practices among obstetrician–gynecologists
Obstet Gynecol
Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008
Int J Cancer
European guidelines for quality assurance in cervical cancer screening
Coverage of cervical cancer screening in 57 countries: low average levels and large inequalities
PLoS Med
International trends in incidence of cervical cancer: II. Squamous-cell carcinoma
Int J Cancer
Trends in incidence and mortality rates of squamous cell carcinoma and adenocarcinoma of cervix – worldwide
Asian Pac J Cancer Prev
Prognostic value of histopathology and trends in cervical cancer: a SEER population study
BMC Cancer
International trends in the incidence of cervical cancer: I. Adenocarcinoma and adenosquamous cell carcinomas
Int J Cancer
Human papillomavirus and cervical cancer
Clin Microbiol Rev
Cytological aspects of uterine cervical adenocarcinoma, adenosquamous carcinoma and combined adenocarcinoma–squamous carcinoma: appraisal of diagnostic criteria for in situ versus invasive lesions
Cytopathology
Endocervical glandular dysplasia, adenocarcinoma in situ, and early invasive (microinvasive) adenocarcinoma of the uterine cervix
Semin Diagn Pathol
Adenocarcinoma in situ of the cervix: an underdiagnosed lesion
Cancer
Symposium part 4: should pathologists diagnose endocervical preneoplastic lesions “less than” adenocarcinoma in situ? Counterpoint
Int J Gynecol Pathol
Symposium part I: adenocarcinoma in situ, glandular dysplasia, and early invasive adenocarcinoma of the uterine cervix
Int J Gynecol Pathol
A longitudinal Swedish study on screening for squamous cell carcinoma and adenocarcinoma: evidence of effectiveness and overtreatment
Cancer Epidemiol Biomarkers Prev
Primary endometrioid adenocarcinoma of the cervix with widespread squamous metaplasia – a potential diagnostic pitfall
Diagn Pathol
A panel of immunohistochemical stains, including carcinoembryonic antigen, vimentin, and estrogen receptor, aids the distinction between primary endometrial and endocervical adenocarcinomas
Int J Gynecol Pathol
A panel of 3 markers including p16, ProExC, or HPV ISH is optimal for distinguishing between primary endometrial and endocervical adenocarcinomas
Am J Surg Pathol
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2020, Cancer LettersCitation Excerpt :For example, loss of E2, the transcriptional repressor of E6 and E7 protein, could cause dysregulated expression of these oncoproteins and further lead to aberrant proliferation and malignant progression. Invasive cervical cancer (ICC) can be divided into three groups: squamous cervical cancers (SCC) which account for 75–90% of ICCs, adenocarcinomas (ADC), and adenosquamous cell carcinomas (ASC) [57]. Studies have found that almost 100% of the SCC and 86% of the ADC are HPV positive [58,59].
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