Histopathological Outcomes of Women with Abnormal Cervical Cytology : a Review of Literature in Thailand

Cervical cancer remains the major health problem in Thailand and many other developing countries. This is mainly because of failure to initiate or sustain effective screening strategy. In recent population-based cancer registries, the highest incidence of cervical cancer in Thailand was noted in Chiang Mai with an average agestandardized incidence rate (ASR) of 28.9 per 100000, followed by Lampang (ASR, 22.4) and Bangkok (ASR, 20.9) (Moore et al., 2010). Although high-risk Human Papillomavirus (HR-HPV) test and HPV genotyping have certain role in cervical cancer screening nowadays, these tests are not widely available in developing countries. Cervical cytology is still the principal screening method. Subsequent management of abnormal cervical cytology to detect underlying cervical lesions is also important. Generally, management of abnormal cervical cytology depends on the risk of encountering high-grade cervical disease. However, the risks of high-grade cervical disease encountered in abnormal cervical cytology may vary among different regions of the world and across the country. Therefore, information regarding the incidence of significant cervical disease from different areas or populations is crucial for designing and implementing area-specific management approach. This review was conducted to evaluate the incidence of high-grade cervical diseases among Thai


Introduction
Cervical cancer remains the major health problem in Thailand and many other developing countries.This is mainly because of failure to initiate or sustain effective screening strategy.In recent population-based cancer registries, the highest incidence of cervical cancer in Thailand was noted in Chiang Mai with an average agestandardized incidence rate (ASR) of 28.9 per 100000, followed by Lampang (ASR,22.4) and Bangkok (ASR, 20.9) (Moore et al., 2010).
Although high-risk Human Papillomavirus (HR-HPV) test and HPV genotyping have certain role in cervical cancer screening nowadays, these tests are not widely available in developing countries.Cervical cytology is still the principal screening method.Subsequent management of abnormal cervical cytology to detect underlying cervical lesions is also important.Generally, management of abnormal cervical cytology depends on the risk of encountering high-grade cervical disease.However, the risks of high-grade cervical disease encountered in abnormal cervical cytology may vary among different regions of the world and across the country.Therefore, information regarding the incidence of significant cervical disease from different areas or populations is crucial for designing and implementing area-specific management approach.This review was conducted to evaluate the incidence of high-grade cervical diseases among Thai

Methodological Approach
An electronic literature search was performed through PubMed, Scopus, Web of Science, and Thai database of health science journals (thailand.digitaljournals.org).A systematic search strategy was developed based on a preliminary scope of studies involving cervical histopathological outcomes among Thai women with abnormal cervical smears regardless of smear technique.However, only studies that applied the 2001 Bethesda System for reporting cervical cytology were included.Search terms were formulated based on an interpretation of the population/problem of interest, intervention and context (or PICO) framework (Cooke et al., 2012).Reference lists of eligible publications were reviewed to ascertain additional relevant papers.The authors may be contacted for more information if necessary.The last update searching was performed in April, 2014.The review results were reported according to type of smear abnormality.

Atypical squamous cells
One of the fundamental revisions of the 2001 Bethesda System for reporting cervical cytology was the elimination Chumnan Kietpeerakool et al of atypical squamous cell of undetermined significance (ASCUS), favor reactive and ASCUS, not otherwise specified.All interpretations of ASC are qualified as "of undetermined significance" (ASC-US) or "cannot exclude high-grade squamous intraepithelial lesion" (ASC-H) (Solomon and Nayar, 2004).

Atypical squamous cells of undetermined significance
Criteria for interpretation of ASC-US include: 1) nuclei size of approximately two and one half to three times the area of the nucleus of a normal intermediate squamous cell; 2) slightly increased ratio of nuclear to cytoplasmic area; 3) minimal nuclear hyperchromasia and irregularity in chromatin distribution or nuclear shape: and 4) nuclear abnormality associated with dense orangeophilic cytoplasm, or the so-called "atypical parakeratosis" (Solomon and Nayar, 2004).

Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion
Atypical squamous cells, cannot exclude highgrade squamous intraepithelial lesion (ASC-H) denotes cytological features with some, but not all, of the cytomorphologic criteria for high-grade squamous intraepithelial lesion (HSIL) (Solomon and Nayar, 2004).Immediate colposcopy is recommended for women with ASC-H cytology.Two studies on the histopathological outcomes of women with ASC-H conducted in Thailand were available for review (Table 1).In our previous report, the rate of significantly cervical lesion in women with smears revealing ASC-H was 75.0%, in which 9.3% were invasive cancer (Kietpeerakool et al., 2009).In the recent study by Kingnate et al (2014), incidence of CIN 2-3/AIS and invasive lesion was 10.5% and 2.6%, respectively.In the literature, almost all studies evaluating histopathologic results of ASC-H smears were reported from North America where the incidence of cervical cancer appears to be relatively low (Alli and Ali, 2003;Louro et al., 2003;Selvaggi, 2003;Liman et al., 2005;Barreth et al., 2006;Saad et al., 2006;Srodon et al., 2006;McHale et al., 2007).The rate of underlying high-grade cervical lesion varied widely from 10% to 80%, in which less than 3.5% were invasive lesion (Alli and Ali, 2003;Louro et al., 2003;Selvaggi, 2003;Liman et al., 2005;Barreth et al., 2006;Saad et al., 2006;Srodon et al., 2006;McHale et al., 2007).
Because of a lax criterion for interpreting ASC-H smear, poor interobserver agreement is anticipated which might be partly attributable for the wide variation of the rate of significant cervical lesion as have been noted in either Thai or North American settings (Quddus et al., 2001;Sherman et al., 2001).However, the notably high incidence of invasive lesion demonstrated (2.6%-9.3%)might indicate the necessity for aggressive management in Thai women with ASC-H cytology to make certain that occult invasive lesions could be detected and treated in a timely fashion.

Low-grade squamous intraepithelial lesion
In low-grade squamous intraepithelial lesion (LSIL) cytology, the cells are of the superficial or intermediate cell types which have enlarged nuclei that are 4-6 times the size of a normal intermediate cell nucleus.The nuclei are usually hyperchromatic, and multinucleation is common However, in LSIL with marked HPV cytopathic changes, the nucleus are often only 2-3 times the size of a normal intermediate cell nucleus (Solomon and Nayar, 2004).In a region with a low incidence of cervical cancer, positive smear results for LSIL were associated with CIN2-3/AIS in approximately 12%-18% of women on initial colposcopy and with less than 1% of underlying invasive cancer (Massad et al., 2001;ALTS Group, 2003;Fairman et al., 2004;Chute et al., 2006).In Thailand, reported incidence of significant cervical pathology ranges from 11.2% to 32.2% (Table 2) (Khuakoonratt et al., 2008;Boonlikit, 2008;Kiatiyosnusorn et al., 2010;Ekalaksananan et al., 2011;Pothisuwan et al., 2011;Kingnate et al., 2014).The significant finding noted in some studies in Thailand is a relatively high incidence of underlying high-grade cervical lesion (11.2%-30.3%)and invasive lesion (1.3%-1.9%)(Khuakoonratt et al., 2008;Kiatiyosnusorn et al., 2010).Recommended management of LSIL cytology might be either colposcopy or cytological follow-up and varies between countries (Scheungraber et al., 2004).Nevertheless, immediate colposcopy might be appropriate in Thailand in which the patients' compliance is suboptimal (Rattanalappaiboon et al., 2014).

Squamous cell carcinoma cytology
Squamous cell carcinoma (SCCA) cytology is sparse.In general, SCCA cytology could be subdivided into 2 categories including keratinizing and non-keratinizing types.In nonkeratinizing type, cells display most of the cytological characteristics of HSIL.Tumor diathesis is frequently present.In contrast, the pathognomonic feature of smear suggesting keratinizing squamous cell carcinoma is a marked variation in cellular size and shape.A tumor diathesis is usually less than that observed in nonkeratinizing type (Solomon and Nayar, 2004).Data regarding cervical pathology among women with SCCA cytology are limited due to the rarity of this smear abnormality.Two studies conducted in US population demonstrated approximately 15%-24% the risk of harboring invasive lesion in women with SCCA cytology (Jones adn Davey, 2000;Massad et al., 2001).These rates were much lower than those reported in the studies from Thailand.The study conducted in Chiang Mai reported that the incidence of significant cervical lesion in SCCA cytology was 98%, in which 33.3% were invasive disease (Charoenkwan et al., 2006).Another study by Aue-aungkul et al (2011), in evaluating the clinical feasibility of the see and treat approach in managing Thai women with abnormal cervical cytology, from the same hospital reported that approximately 55.6% of women with SCCA cytology had invasive cervical lesions.An extraordinarily high incidence of underlying invasive lesion in women with SCCA cytology was concordantly found in recent reports from the other areas of Thailand by Ruengkhachorn et al ( 2012) and Kingnate et al (2014): 82.5% and 77.4% respectively.Thus, a high likelihood of harboring invasive disease in Thai women with SCCA smears should be kept in mind while taking care of women with SCCA cytology.

Atypical glandular cells
Screening for glandular disease of cervix remains among the major issues in gynecologic cytopathology.The 2001 Bethesda System has revised the reporting cervical smear interpreting glandular abnormality (Solomon and Nayar, 2004).This was in order to improve communication between laboratories and clinicians, indicate understanding of features of glandular neoplasia in cervical smear thereby result in appropriate approach for the patients.
A challenge in evaluating women with AGC bases on a wide variety of potential sites origin ranging from endocervix, endometrium, fallopian tube, ovary, and even of very rarely from extragenital sites.Per the 2001 Bethesda System, atypical glandular cells (AGC) is categorized according to the sites of origin (endocervical or endometrial) whenever feasible; otherwise, the generic "AGC" is used.Atypical endocervical cells may be further qualified as "favor neoplasia", if not so, "not otherwise specified (NOS) may be stated.Atypical endometrial cells are not recommended to be further qualified because of unreliable subcategorizing this category (Solomon and Nayar, 2004).
Four studies on the underlying lesions in women with AGC cytology conducted in Thailand were identified.Firstly, Sawangsang et al (2011) from Chiang Mai University Hospital reported that approximately 15% of women with AGC-NOS smears had significant lesions (CIN2-3, AIS, atypical endometrial hyperplasia, cancer), in which 2.2% were invasive lesions and all were cervical cancer.Of women with AGC-FN cytology, approximately 41.2% had significant lesions, in which, respectively, 17.6% and 5.9% were endometrial adenocarcinoma and cervical cancer.
Additional three studies were conducted in Bangkok.Lojindarat et al (2012) reported 32.4% significant lesions in women with smear interpreting AGC, in which 18.3% were invasive lesion.Diagnoses of underlying significant lesion after AGC-FN were significantly more likely than those with AGC-NOS smears (53.8% vs 20.0%).Chatchotikawong et al (2012) reported that the likelihood of cancer precursor and malignant histologic results in the AGC-NOS group was 31.7% and 23.7%, respectively, as compared with 65.4% and 55.1% of women in the AGC-FN group.An interested finding in this study was a relatively high incidence of extragenital malignant lesions (3.8% of AGC-NOS and 5.1% of AGC-FN smears) (Chatchotikawong et al., 2012).Recently, Kingnate et al (2014) observed that approximately 10.4% and 4.5% of women with AGC-NOS smears had CIN 2-3/AIS and invasive lesion, respectively.For women with AGC-FN, the incidence of significant lesion was 15% in which 5% were invasive lesion.

Conclusion
This review documents a relatively high rate of significant lesions particularly invasive disease among Thai women with abnormal cervical cytology screening even in those having only minimal smear abnormality.This baseline information must be taken into consideration in management of women with abnormal cytological screening to achieve the goals of comprehensive cervical cancer control in Thailand.