Literature Review:
Factors and predictors of persistent lesion (positive hr-HPV DNA test or abnormal cytology) after treatment of high grade cervical intraepithelial Neoplasia with large loop excision of transformation zone (LLETZ)
{Author Name}
{Institution Affiliation}
Introduction
The Human Papillomavirus (HPV) infection is the primary factor that increases the risk of the cervical cancer development and cervical intraepithelial neoplasia (CIN) in the uterine cervix (Soderlund-Strand et al., 2014). Approximately 150 diverse types of HPV have been discovered, and most of them are carcinogenic. Persistent infections of high-risk HPV must lead to the development of high-grade cervical intraepithelial neoplasia (CIN 2 and 3), and if it is not treated appropriately, it contains a potential risk of invasive carcinoma (Soderlund-Strand et al., 2014; Innamaa et al., 2015; Garutti et al., 2016).
Conservative treatment approaches such as large loop excision of transformation zone (LLETZ) is the conventional method for treating the high-grade CIN. Evidence has shown that LLETZ has been successful in providing an absolute cure, but the recurrence of disease has been consistently observed in 10% of the cases post-treatment. Most of the failure cases are observed within the first two years of the treatment. Thus, it is highly recommended that the females with advanced CIN 2+ treated with LLETZ should be kept under strict gynecological surveillance with frequent HPV screening tests. Three standard tests are recommended in such cases namely, Pap smear based cytology, HPV-DNA genotyping and Colposcopy (Heymans et al., 2011; Garutti et al., 2016). Various studies have discovered the significant predictive determinants that help in identifying the individuals who are at high risk of developing cervical cancer. These risk factors are age, the extent of the lesion, status of dysplasia, imperfect exclusion of the lesion and immunosuppressive therapy provided to the patient.
This literature review focuses on the factors and predictors of persistent lesions (hr-SIL) even after treating the hr-CIN with LLETZ procedure. It also aims to discover the role of the test of cure that includes hr-HPV DNA test and Pap smear in the case of high-grade CIN (CIN 2 and CIN 3).
Women treated for cervical cancer are comparatively more susceptible to the recurrence of the disease and therefore post-treatment management is a challenging task for such population. Approaches to post-treatment surveillance are essential to assure the achievement of treatment objectives which is termed as “test of cure” or ToC (Cuschieri et al., 2016; Smart et al., 2010). A range of multiple methods has been evaluated and integrated for an active screening of the women after treatment. These protocols differ in technology as well as frequency of follow-ups. The most acceptable screening programs include cytology and HPV testing. These two may also be employed in the combination of each other. The molecular HPV testing possesses high sensitivity against pathogens that makes it more appealing in the perspective of post-treatment surveillance (Cuschieri et al., 2016).
Moreover, the comparative evaluation of the specificity and sensitivity of HPV testing with cytology has been conducted by multiple researchers. A study showed that the collective specificity and sensitivity of former method had been 81% and 93% while the values of the later protocol for the similar traits had been 84% and 72%, respectively (Cuschieri et al., 2016). Therefore, it has been verified that HPV testing is comparatively more sensitive and suitable as a post treatment standalone test. The combined tests of HPV testing and cytology showed a slightly better sensitivity but less specificity. A meta-analysis showed that the sensitivity of HPV testing for advanced CIN was 94% while along with cytology it was 95%. Sensitivity is the main aspect of the ToC. Thus the individuals with HPV-negative test require less intense monitoring (Cuschieri et al., 2016). Cuschieri and co-researchers stated that the management of HPV-positive patients is highly challenging. They also cited a Scottish data of women after the six months of treatment which exhibited that 22% of females were HPV positive while cytology-based test could detect only half of them. It confirms the high sensitivity of HPV test in the comparison of cytology (Cuschieri et al., 2016).
Furthermore, the evaluation of HPV genotyping among ToC target populace revealed several remarkable facts. It was observed that women with type-specific persistent infection were highly susceptible to CIN2+ while HPV-16 positive women were found more vulnerable to residual disease in comparison of hr-HPV types (Cuschieri et al., 2016).
A retrospective cohort study conducted by Palmer and co-workers investigated the significance of LLETZ in remaining margins and CIN among the females requiring hr-HPV ToC. The study emphasized the importance of subsequent follow-up in primary care during ToC and concluded that no safety issues are associated with ToC trail (Palmer et al. 2015).
Mo et al. (2015) conducted a study to assess the HC-2 platform of HPV screening in combination with cytology for identifying the residual disease post LEEP (loop electrosurgical excision procedure) procedure in high-grade CIN (2-3). This retrospective review concluded three main points. First, the persistence hr-HPV DNA is the main cause of the recurrent or residual disease post-treatment among women with high-grade CIN. In this case, the pre-treatment margin and viral load can be considered as significant predictors. Second, the follow-up should begin at sixth-month post-LLTEZ and should be lasted for at least 24 months with combined HPV and cytology test. The third point is that the patients with high pre-treatment viral load should be considered highly susceptible and should be given more ToC attention (Mo et al., 2015).
Factors and Predictors of recurrence in HG-SIL
In the high-grade CIN2+ patient post-LLTEZ, the reversion of residual disease is a major concern of gynecologists. Multiple studies have inspected and presented possible predictive factors for identifying the highly vulnerable women to residual or recurrent disease. Persistent cervical infection with the presence of hr-HPV has been considered the major factor of developing cervical cancer as well as the progression of its precursor lesions or high-grade squamous intraepithelial lesion (HG-SIL). Therefore, the excision of the infected tissues has been suggested most effective treatment of CIN2+. According to Heymans (2011), the other important predictive factors include the age of the women, lesion size, grade of CIN pre-LLTEZ treatment, the condition of the removed lesion and its margin as well as the immunosuppressive therapy (Heymans et al., 2011; Ribaldone et al., 2010).
The presence of HPV post-treatment can promote the return of cervical disease (Soderlund-Strand et al. 2015; Innamaa et al., 2015). Furthermore, Mo et al. (2015) emphasized that the pre-treatment viral load and margin range are also significant predictors of invasive cervical dysplasia. In the case of positive endocervical margins the recurrence in high-grade CIN is very high, and at this stage, the retreatment can also be failed, thus a very strict and closer surveillance is compulsory. Leguevaque et al. (2010) also highlighted the severity of high-grade lesions and positive excision margins as a risk factor for recurrence of the disease. Sarian et al. (2004) added that along with HPV persistence post-LLETZ, smoking and the interaction between age and conization margins also predict the recurrence risk in HGSIL.
Discussion
This review describes the role of Cytology and HPV DNA test in ToC as well as presents the predictive factors responsible for recurring HGSIL and CIN. This review helped in understanding the significance of HPV test in conjunction with cytology. It has been concluded that HPV test alone can demonstrate sensitivity up to 94% while it is a little higher (95%) when employed with cytology. Thus, due to high sensitivity HPV test is suitable and efficient as the post-treatment standalone screening test (Cuschieri et al., 2016; Smart et al., 2010).
According to the experts, the post-treatment positive HPV, and positive endocervical margins are the major cause of disease reversion and such patients need closer surveillance. Apart from these factors, the age of the patient, pre-treatment viral load, and SIL margin range also predict the recurrence of cervical cancer (Innamaa et al., 2015; Soderlund-Strand et al., 2015).
Conclusion
This literature review provided valuable insights into the role of HPV screening tests in ToC post-treatment CIN2+ patients. It has highlighted that a persistent hr-HPV infection is the main predictor of cervical cancer as well as HGSIL recurrence. Other predictive factors are also discussed that may lead to the reversion of cervical carcinoma post treatment. On the basis of this review, it can be concluded that a combination of HPV genotyping and cytology is the best method for identifying the women at risk. This review has offered significant informative facts regarding the CIN2+ as well as HGSIL that may lead to the development of novel strategies for treating and diagnosing the susceptible women. It will help in offering them a better quality of life and can protect them from the residual/recurrent phase of the disease.
References
Cuschieri, K., Bhatia, R., Cruickshank, M., Hillemanns, P., & Arbyn, M. (2016). HPV testing in
the context of post-treatment follow up (test of cure). Journal of Clinical Virology, 76,
S56-S61.
Garutti, P., Borghi, C., Bedoni, C., Bonaccorsi, G., Greco, P., Tognon, M., & Martini, F. (2016).
HPV-based strategy in follow-up of patients treated for high-grade cervical intra-
epithelial neoplasia: 5-year results in a public health surveillance setting. European
Heymans, J., Benoy, I. H., Poppe, W., & Depuydt, C. E. (2011). Type‐specific HPV geno‐typing
improves detection of recurrent high‐grade cervical neoplasia after
conisation. International journal of cancer, 129(4), 903-909.
Innamaa, A., Dudding, N., Ellis, K., Crossley, J., Smith, J. H., Tidy, J. A., & Palmer, J. E.
(2015). High‐risk HPV platforms and test of cure: should specific HPV platforms more
suited to screening in a ‘test of cure’scenario be recommended?. Cytopathology, 26(6),
381-387.
Leguevaque, P., Motton, S., Decharme, A., Soulé-Tholy, M., Escourrou, G., & Hoff, J. (2010).
Predictors of recurrence in high-grade cervical lesions and a plan of
management. European Journal of Surgical Oncology (EJSO), 36(11), 1073-1079.
Mo, L. Z., Song, H. L., Wang, J. L., He, Q., Qiu, Z. C., & Li, F. (2015). Pap smear combined
with hpv testing: A reasonable tool for women with high-grade cervical intraepithelial
neoplasia treated by LEEP. Asian Pac J Cancer Prev, 16(10), 4297-4302.
Palmer, J. E., Ravenscroft, S., Ellis, K., Crossley, J., Dudding, N., Smith, J. H., & Tidy, J. A.
(2015). Does LLETZ excision margin status predict residual disease in women who have
undergone post‐treatment cervical cytology and high‐risk human papillomavirus
testing?. Cytopathology.
Ribaldone, R., Boldorini, R., Capuano, A., Arrigoni, S., Di Oto, A., & Surico, N. (2010). Role of
HPV testing in the follow-up of women treated for cervical dysplasia. Archives of
gynecology and obstetrics, 282(2), 193-197.
Sarian, L. O. Z., Derchain, S. F. M., da Rocha Pitta, D., Morais, S. S., & Rabelo-Santos, S. H. (2004). Factors associated with HPV persistence after treatment for high-grade cervical
intra-epithelial neoplasia with large loop excision of the transformation zone
(LLETZ). Journal of clinical virology, 31(4), 270-274.
Smart, O. C., Sykes, P., Macnab, H., & Jennings, L. (2010). Testing for high risk human
papilloma virus in the initial follow‐up of women treated for high‐grade squamous
intraepithelial lesions. Australian and New Zealand Journal of Obstetrics and
Gynaecology, 50(2), 164-167.
Söderlund‐Strand, A., Kjellberg, L., & Dillner, J. (2014). Human papillomavirus type‐specific
persistence and recurrence after treatment for cervical dysplasia. Journal of medical
virology, 86(4), 634-641.
