NEWS & VIEWS CERVICAL CANCER

Squamocolumnar junction ablation —tying up loose ends? Michael Herfs and Christopher P. Crum Refers to Mirkovic, J. et al. Carcinogenic HPV infection in the squamo-columnar junction. J. Pathol. http://dx.doi.org/10.1002/ path.4533 (2015)

Despite the commercialization of HPV vaccines, cervical cancer remains a major cause of death, especially in developing countries. Recent data implicate a discrete population of cells within the cervical squamocolumnar junction in the pathogenesis of cervical precancerous lesions, indicating that ablation of these cells might reduce the rate of cervical cancer in high-risk populations. Annually, cervical cancer afflicts over 500,000 women worldwide, and results in nearly 250,000 deaths. The incidence of this disease is approximately fivefold higher in developing countries relative to the USA or western Europe.1 In industrialized c­ountries, the incidence rates have decreased since the introduction of the Papanicolaou (Pap) smear test, which can be attributed to several factors. First, initial and sub­ sequent screening increases the detection of asymptomatic cancers that would previously have gone undetected; moreover, screening enriches for earlier stage neoplasms that are associ­ated with a higher curative treatment success rate. Second, detection and prompt treatment of preneoplastic lesions inter­ rupts the precursor–­cancer continuum by removing high-grade cervical intra­epithelial neoplasms (CIN2/3). Third, in women with CIN2/3, ablation of the tissue at risk by either cryotherapy or surgical excision (using the loop electrosurgical excision pro­ cedure [LEEP] or the use of cone biopsy) is associated with a dramatic reduction in the risk of recurrent cervical cancer.2 The risk of disease recurrence would presumably be reduced further by the prior acquisition of human papillomavirus (HPV) type-specific immunity; exploiting this natural defence is now the goal of HPV-vaccine campaigns directed primarily at premenarchal women. There are several obstacles to cancer prevention programmes that rely solely on vaccination, at least in the short-term. The first is the reduced efficacy in women who are older and already sexually active, as the

vaccine does not suppress the evolution of precancerous lesions if they have devel­ oped. The second is the costs and logistics of delivering the vaccine to underserved populations. The third obstacle is the lack of broad-spectrum efficacy across serotypes, although this issue is being addressed with newer generations of vaccines. Given the unavoidable delays in the implementation of vaccine programmes, coupled with the current high rates of cancer in low-income countries, the next 30 years could witness up to 15  million new cases of cervical cancers that are potentially preventable.1 Now, a new study implicated squamoco­ lumnar (SC) junction cells as a predomi­ nant site of HPV infection,3 and therefore these cells could be a target for prevention of cervical neoplasms. An important aspect of cervical cancer tumorigenesis is the development of pre­c ancerous lesions at the entrance to the  cervix, specifically at the junction of the ectocervical squamous and endo­ cervical columnar epithelia. This SC junc­ tion has long been presumed to harbour cells suscept­ible to cervical cancer, and by extension, carcinogenic HPV infection. The potential significant role of this region in cancer prevention was illustrated by the extremely low risk of cervical cancer observed after ablation or excision of the SC junction, particularly if a concurrent HPV infection and cervical abnormality were excluded.2 Excision and/or ablation are normally performed in the treatment of preinvasive disease and this approach

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seems equally effective irrespective of whether it is used to treat a carcinogenic or n­oncarcinogenic HPV infection. Until recently, the location of the SC‑ junction cells and their histomorpho­logy were unknown; however, in 2012, follow­ing the seminal discovery of residual embry­ onic cells at the oesophagogastric junction,4 a multi-institutional collabor­ation identi­ fied a population of similar cells within the SC‑junction of the cervix that could be particularly relevant to cervical cancer prevention.5 Of note, the study showed that most CIN3 and invasive cancers shared expression of genes with the SC‑junction cells, implying that they arose directly from this cell population.5 Further corroborating these results, transcriptionally active HPV infection was detected in normal-appearing SC‑junction cells.3 By contrast, HPV infec­ tion of the squamous epithelium at sites that do not harbour these SC‑junction cells, including the ectocervix, vagina and vulva, seems to be less efficient in generating malignancy.1 Indeed, the reported frequen­ cies for vaginal and vulva cancers worldwide are up to 15-fold less than for cancers of the cervix.1 Taken together, these data infer that the risk of developing cervical cancer is strongly linked to a particularly vulnerable cell population within the cervix in which the initial carcinogenic HPV i­n fection occurs (Figure 1).

‘‘

…removing the most vulnerable cell population is a novel and affordable strategy that could be successful…

’’

The increased susceptibility of SC‑ junction cells to HPV infection could be multifactorial, and although the trigger that initiates the neoplastic transformation of SC‑junction cells remains unknown, these cells do not seem to regenerate after exci­ sion of the ecto–endocervical junction.5 Of note, follow-up data suggest that removal of these cells will influence patterns of disease. Kocken et al.2 found that following cone biopsy, which typically removes the entire SC‑junction, the risk of CIN was as high as 17%; however, if both an HPV infec­ tion and an abnormal cervical cytology VOLUME 12  |  JULY 2015

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NEWS & VIEWS were excluded initially, the 10-year risk of CIN3 dropped to 0%.2 Furthermore, recent evidence has shown that once persistent (un­excised) CINs were excluded, recurrent and/or new lesions after SC‑junction abla­ tion were at an ectocervical location, tested negative for SC‑junction markers, were typi­ cally of lower histological grade (CIN1), and were prone to spontaneous resolution.6 These studies strongly suggest that the baseline risk of CIN3 following SC‑junction excision is reduced by a greater extent than expected, given the risks of exposure to new carcinogenic HPV infections. No wellcontrolled trials have tested the hypothesis that ‘prophylactic’ SC‑junction ablation alone would reduce the risk of CIN 3 or invasive cancer. However, studies from single practices several decades ago had reported a profound reduction in cervical cancer risk with cauterization of the cervix post-partum. 7,8 In 1978, an analysis of data from a Finnish screening programme registry covering the total female popula­ tion (~430,000 women) found a sixfold decreased risk of cervical cancer in the subgroup who underwent electrocoagula­ tion of the uterine cervix compared with women who did not undergo this pro­ cedure.9 More recently, taking a different perspective, a study in South Africa exam­ ined the frequency of HPV infection follow­ ing cervical cryotherapy in HIV-negative women who were carcinogenic HPV nega­ tive at the time of treatment.10 After 3 years, HPV infection was reduced by 55% in the treated group compared with the control Ectocervix/TZ

group that comprised of women who did not undergo cryotherapy.10 Over the past 30 years, the field of cervi­ cal cancer has pursued a dual mission: the discovery of a cancer-preventive vaccine; and the development of reagents for the simplification of screening protocols and the manage­ment of cervical abnormali­ ties. With regard to the latter approach, HPV testing has been effective in lengthen­ ing screening intervals and improving the management of low-risk Pap-smear abnor­ malities. However, in the context of cancer prevention, these initiatives are costly and are thus largely directed at populations in resource-rich countries—posing greater challenges in locations where cervical cancer rates are high and screening programmes are underdeveloped. Targeting the major source of the disease by removing the most vulner­ able cell population is a novel and affordable strategy that could be successful irrespec­ tive of HPV type. This strategy could be implemented simply by taking advantage of access to the vulnerable population at a specific time (such as post-partum or in case of an asymptomatic HPV infection) and using a widely available, portable apparatus (with low morbidity) designed to target the SC junction at the cervical entrance. This approach is unlikely to completely eliminate cervical cancer in the treated population and would certainly not eliminate the risk of exposure to carcinogenic HPV; however, on the basis of historical, theoretical, and experi­ mental data, it might substantially reduce the rate of cervical cancer in underserved

SC junction

Endocervix

HPV

90% CIN3/SCC

Krt7

Nature or Reviews | Clinical Figure 1 | HPV-related cervical carcinogenesis. Following micro-trauma abrasions, basalOncology keratinocyte infection is likely to result in active infections and subsequent HPV-related (pre) neoplastic lesions developing in the ectocervix/TZ. According to immunohistochemical/ transcriptional analyses, ectocervix/TZ infection theoretically would be responsible for approximately 10% of all CIN3 and cervical cancers. By contrast, 90% of CIN3 and invasive cancers arise within or very near the SC junction and express SC‑junction biomarkers, in keeping with the epidemiological ratio (~12:1) of cervical to vaginal/vulvar squamous cell carcinoma. Abbreviations: CIN, cervical intraepithelial neoplasms; SC, squamocolumnar; TZ, transformation zone.

JULY 2015  |  VOLUME 12



populations that are currently vulnerable to this epidemic, and such an approach merits further study in a controlled trial. Finally, the impact of SC‑junction removal on HIV infection, either directly or indirectly by low­ ering the rate of HPV infection, is another variable worthy of i­nvestigation in these underserved populations. Laboratory of Experimental Pathology, GIGA‑Cancer, University of Liege, CHU-Sart Tilman B23, 13 Hippocrate Avenue, 4000 Liege, Belgium (M.H.). Department of Pathology, Division of Women’s and Perinatal Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA (C.P.C.). Correspondence to: M.H. [email protected] doi:10.1038/nrclinonc.2015.104 Published online 2 June 2015 Acknowledgements The authors thank Dr Frank McKeon, Wa Xian and their colleagues at the University of Liege and the Brigham and Women’s Hospital for their helpful discussions. The work of the authors is supported in part by a grant from the National Cancer Institute (5R21CA173190‑02 to C.P.C.), by the Belgian Fund for Medical Scientific Research (M.H.), by the Centre Anti-Cancereux près l’Université de Liège (M.H.) and by the Fonds Léon Frédéricq (M.H.). Competing interests The authors declare no competing interests. 1.

Forman, D. et al. Global burden of human papillomavirus and related diseases. Vaccine 30 (Suppl. 5), F12–F23 (2012). 2. Kocken, M. et al. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Lancet Oncol. 12, 441–450 (2011). 3. Mirkovic, J. et al. Carcinogenic HPV infection in the squamo-columnar junction. J. Pathol. http://dx.doi.org/10.1002/path.4533 (2015). 4. Wang, X. et al. Residual embryonic cells as precursors of a Barrett’s-like metaplasia. Cell 145, 1023–1035 (2011). 5. Herfs, M. et al. A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer. Proc. Natl Acad. Sci. USA 109, 10516–10521 (2012). 6. Herfs, M. et al. Unique recurrence patterns of cervical intraepithelial neoplasia following excision of the squamo-columnar junction. Int. J. Cancer 136, 1043–1052 (2015). 7. Younge, P. A. Cancer of the uterine cervix; a preventable disease. Obstet. Gynecol. 10, 469–481 (1957). 8. Peyton, F. W., Peyton, R. R., Anderson, V. L. & Pavnica, P. The importance of cauterization to maintain a healthy cervix. Long-term study from a private gynecologic practice. Am. J. Obstet. Gynecol. 131, 374–380 (1978). 9. Kauraniemi, T., Räsänen-Virtanen, U. & Hakama, M. Risk of cervical cancer among an electrocoagulated population. Am. J. Obstet. Gynecol. 131, 533–538 (1978). 10. Taylor, S. et al. Reduced acquisition and reactivation of human papillomavirus infections among older women treated with cryotherapy: results from a randomized trial in South Africa. BMC Med. 8, 40 (2010).

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Cervical cancer: squamocolumnar junction ablation--tying up loose ends?

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