Cervical Intraepithelial Neoplasia, Cervical Erosion, and Ectropion: Clinical Guidelines

List of Abbreviations

Terms and Definitions

Cervical erosion and cervical ectropion are classified by the International Federation for Cervical Pathology and Colposcopy (Rio de Janeiro, 2011) as non-specific cervical changes.

Cervical ectropion is the eversion of the cervical canal mucosa onto the ectocervix. Ectropion is subdivided into congenital (a variant of normal cervical structure, synonym - ectopia) and post-traumatic [1], [2], [3].

Cervical erosion (true) is a disruption of the integrity (defect) of the epithelial lining of the vaginal portion of the cervix [1], [2], [3].

Cervical leukoplakia (CL) without cellular atypia is classified as keratosis or hyperkeratosis, and with signs of atypia, as cervical dysplasia. According to the International Federation for Cervical Pathology and Colposcopy (Rio de Janeiro, 2011), CL is classified among non-specific abnormal colposcopic findings (ACF) [4]. Leukoplakia without cellular atypia is a benign cervical lesion and, in the absence of HPV, does not undergo malignant transformation [1], [3].

Cervical Intraepithelial Neoplasia (CIN) is a group of disorders characterized by impaired maturation, differentiation, and stratification of the stratified squamous epithelium of the cervix. CIN is initiated by a persistent infection caused predominantly by high-risk human papillomavirus (HR HPV) types, which maintains the progression of lesions to invasion. CIN I is characterized by a high probability of regression, is not always associated with HR HPV, and is not classified as cervical precancer. The ability of CIN I to progress to CIN II–III is questionable; CIN II–III may develop without the prior formation of CIN I, and coexistence of CIN I and CIN III lesions in the same cervix is possible [5]. CIN II–III precede cervical cancer (CC) over several years or even decades. Over such a prolonged period, CIN can be detected and cured before the development of invasive cancer via simple organ-sparing excisions [1], [2], [3].

The primary pathology of the cervix that poses a threat to a woman's life is cervical cancer (CC). All diagnostic methods and cervical examination techniques were developed for the early and differential diagnosis of precisely this disease and its obligate precancer.

CC is a common malignant neoplasm originating from the cervical epithelium that ideally meets the criteria for diseases eligible for highly effective and cost-effective screening: high prevalence and social significance, visual form, a prolonged precancerous period enabling early diagnosis and highly effective treatment with fertility preservation, and the availability of sufficiently sensitive and specific tests [1], [2], [3].

Loop excision of the cervix (LEEP, loop electrosurgical excision procedure) is a method of excising abnormal tissue using thin wire loops of various sizes and shapes, capturing a portion of the cervical canal. It includes large loop excision of the transformation zone (LLETZ, large loop excision of the transformation zone - a procedure involving electrosurgical excision of the entire transformation zone using a semi-circular loop with a small overlying portion of the cervical canal) and high-frequency electroradiosurgical conization of the cervix (HFEW conization - removal of the abnormal transformation zone with deeper (1.5 cm and more) excision of endocervical crypts using a sail-shaped wire electrode) (Appendix G5) [1], [2], [3].

Endocervical specimen (ECS) is material obtained from the cervical canal for morphological examination (cytological examination of a tissue micropreparation of the uterus or pathomorphological examination of biopsy/surgical material of the uterus) using an endocervical brush or curette [6], [7].

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Cervical ectropion is the eversion of the cervical canal mucosa onto the ectocervix.

Cervical erosion (true) is a disruption of the integrity (defect) of the mucous membrane lining the vaginal part of the cervix.

Cervical leukoplakia is defined as keratosis or hyperkeratosis (keratinization of non-keratinizing epithelium), in some cases with signs of cervical dysplasia in the underlying layers.

Cervical intraepithelial neoplasias (CIN) are a group of disorders characterized by impaired maturation, differentiation, and stratification of the stratified squamous epithelium.

LSIL — low-grade squamous intraepithelial lesions. LSIL includes koilocytosis, CIN I, and cervical condylomata [8], [9].

HSIL — high-grade squamous intraepithelial lesions. HSIL includes CIN II (moderate dysplasia), CIN III (severe dysplasia, and carcinoma in situ - CIS) [8], [9]. See Appendix A3.6 Table 4. HSIL is classified as an obligate precancerous condition of the cervix.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The main etiological factor in the development of cervical cancer is high-risk human papillomavirus (HR HPV) types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 [10].

Cervical HPV infection is primarily sexually transmitted and represents a significant risk for cervical intraepithelial neoplasia. Despite this, only a small fraction of women infected with the virus develop severe cervical intraepithelial neoplasia or invasive cervical cancer. The progression of these conditions depends on various factors, the most important of which is the HPV type. There are about 100 HPV subtypes, which are divided into oncogenic and non-oncogenic.

The most carcinogenic HPV strain, type 16, is detected in 55–60% of cervical cancer cases. The carcinogenic HPV strain 18 accounts for 10 to 15% of cervical cancer cases.

Long-term persistence of HPV (more than 2 years) is the main factor in the onset and progression of neoplasias. According to the clinico-morphological concept of cervical neoplasia development, HR HPV affects multipotent stem and amplifying cells in the transformation zone—the squamocolumnar junction (SCJ) between the stratified squamous epithelium (SSE) and columnar epithelium (CE), beneath the columnar epithelium of ectopia, in the developing transformation zone with its upper border at the transition zone, as well as in the higher canal and endocervical crypts. Under the influence of early viral genes (E6, E7), the physiological process of metaplasia becomes abnormal due to excessive proliferation of immature cells and the formation of a neovascular network to provide trophic support for the growing mass of neoplastic cells. Abnormal cells, depending on the severity of their genetic damage and the degree of neoplasia, occupy from one-third to the entire thickness of the epithelial layer, densely packed in inter-papillary spaces surrounded by a vascular network. This vascular network, identified as "punctuated" capillary loops at the tips of papillae or as horizontally arranged vessels surrounding masses of immature cells, serves as the morphological substrate for abnormal colposcopic findings, such as acetabwhite epithelium (ACE) of varying thickness, fine or coarse mosaic and punctuation, papillae, ridges, and sheets [11], [12]. Coexistence of different grades of CIN in a single patient is possible [1], which may lead to morphological underdiagnosis of the degree of neoplasia due to underestimation in limited biopsy specimens [5].

Congenital cervical ectropion is the displacement of the boundaries of the endocervical columnar epithelium beyond the external os onto the vaginal part of the cervix in young women (who have never been pregnant or given birth). Acquired (post-traumatic) ectropion develops as a result of cervical injuries that were not repaired or were improperly repaired after childbirth. Sometimes cervical injuries during late artificial pregnancy termination lead to the development of ectropion. Rupture and subsequent scarring of the cervix are accompanied by impaired microcirculation, innervation, and trophism of the tissue structures of the cervical canal, leading to its deformation—disruption of the spindle shape of the cervical canal, "gaping" of the external os, and eversion of the endocervical mucosa [1], [13].

True erosion occurs due to the traumatic impact of mechanical, thermal, and chemical factors on the cervical epithelium (abortions, diagnostic curettage, rough sexual intercourse, foreign bodies in the vagina, use of tampons, certain suppositories and vaginal tablets). STIs, chronic long-term inflammation, hormonal disorders, epithelial atrophy, and decreased immunity can also contribute to the development of true cervical erosion [13]. Cervical erosion and ectropion are not precancerous conditions and do not undergo malignant transformation in the absence of HPV.

[1] Letter of the Ministry of Health of the Russian Federation dated November 2, 2017, No. 15-4/10/2-7676 "On sending clinical guidelines (treatment protocol) 'Benign and precancerous cervical diseases from the perspective of cancer prevention'."

1.3 Epidemiology of the Disease or Condition

The prevalence of cervical cancer in the Russian Federation in 2022 was 127.6 cases per 100,000 female population, with 34.9% of cases actively detected during preventive examinations [14]. At the same time, cervical carcinoma in situ in 2022 was diagnosed in only 5,869 cases, which accounts for 37.6 per 100 newly diagnosed cases of cervical cancer. This is an extremely unfavorable ratio—pre-invasive cancer should be diagnosed manifold more often than invasive cancer. Detection of the disease at advanced stages does not significantly decrease and accounted for 34.2% in 2022 [14].

The prevalence of cervical intraepithelial lesions varies across populations, ranging from 1.5 to 7.7% for LSIL and from 0.4 to 1.5% for HSIL [15], [16], [17].

1.4 Features of Coding the Disease or Condition

According to ICD-10:

N86 Erosion and ectropion of cervix uteri, includes decubitus (trophic) ulcer, inversion of cervix, excludes inflammation of cervix uteri including cervicitis, endocervicitis and exocervicitis (N72)

N87 Dysplasia of cervix uteri (cervical intraepithelial neoplasia), excludes carcinoma in situ of cervix (D06)

N87.0 Mild cervical dysplasia, cervical intraepithelial neoplasia, grade I (CIN I). Low-grade squamous intraepithelial lesion (LSIL).

N87.1 Moderate cervical dysplasia, includes cervical intraepithelial neoplasia, grade II (CIN II)

N87.2 Severe cervical dysplasia, not elsewhere classified, excludes cervical intraepithelial neoplasia, grade III (CIN III, with or without mention of severe dysplasia or carcinoma in situ of cervix – coded as D06)

N87.9 Cervical dysplasia, unspecified

N88.0 Leukoplakia of cervix uteri

N88.1 Old laceration of cervix uteri

N88.2 Stricture and stenosis of cervix uteri

N88.4 Hypertrophic elongation of cervix uteri

N88.8 Other specified noninflammatory disorders of cervix uteri

1.5 Classification of the disease or condition

According to the World Health Organization (WHO) Classification of Tumours, Female Genital Tumours, 5th edition, 2020 [18], pre-invasive squamous lesions (squamous intraepithelial lesions — SIL) are classified into:

• low-grade squamous intraepithelial lesion (LSIL);

• high-grade squamous intraepithelial lesion (HSIL).

Currently, the generally accepted cytological classification of cervical diseases is the Bethesda System (TBS) [9], [19] (Appendix A3).

The histological grading of the severity of a lesion depends on the number and location of immature undifferentiated cells within the epithelial layer—its stratification [20].

1. CIN I — undifferentiated cells occupy the lower third of the epithelial layer.

2. CIN II — immature cells occupy the lower two-thirds of the epithelial thickness.

3. CIN III (includes severe dysplasia and pre-invasive cancer) — immature abnormal cells occupy more than two-thirds of the epithelial thickness or the entire thickness, but without invasion into the underlying stroma.

The correlation between classifications of cervical precancerous lesions is presented in the table (Appendix A3).

1.6 Clinical presentation of the disease or condition

The vast majority of patients with CIN I–III have no clinical manifestations (asymptomatic course). "Contact" vaginal bleeding occurs extremely rarely [1], [3].

With true cervical erosion, bleeding from traumatized vessels and leukorrhea of various characteristics may be observed as symptoms of cervical inflammation [1], [3].

As in the case of ectropion and ectopia, which are variants of normal cervical structure, as well as leukoplakia and condylomas, clinical symptoms are most often absent or combined with concomitant inflammation (chronic cervicitis) and are not pathognomonic [1], [3].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnostic criteria are: speculum examination of the cervix, visual assessment of the cervix after application of acetic acid (VIA), cytological examination of a cervical smear, HPV testing (molecular biological study of the cervical canal discharge for human papillomavirus (Papilloma virus)), colposcopy, and cervical biopsy [21]. Histopathological examination of the uterine biopsy material is used to verify the diagnosis.

2.1 Complaints and Anamnesis

Comments: Risk factors for the development of CIN include early onset of sexual activity, a high number and frequent change of sexual partners, smoking, concomitant sexually transmitted infections, a high number of pregnancies and deliveries, cervical trauma, presence of immunocompromising diseases (hepatitis B, C, HIV), immunosuppressive therapy, and long-term use of combined oral contraceptives (COCs – according to the Anatomical Therapeutic Chemical (ATC) classification: progestogens and estrogens, fixed combinations). It is necessary to clarify the age of sexual debut and the number of sexual partners. In case of "contact" spotting from the genital tract, their duration should be clarified, a history of surgical interventions on the cervix and HPV infection should be ascertained, and the results of previous cervical screening should be evaluated. CIN I/II/III, including pre-invasive cervical cancer (CIS), have no pathognomonic clinical manifestations and are diagnosed only by morphological methods [21], [22], [23].

2.2 Physical Examination

Comments: The visual method does not allow for the detection of cervical intraepithelial lesions. To establish a definitive diagnosis, cytological examination of a cervical smear (smears from the ecto- and endocervix), HPV testing (molecular biological study of the cervical canal discharge for human papillomavirus (Papilloma virus)), colposcopy, and cervical biopsy with histopathological examination of the uterine biopsy material are required [21].

Ectropion appears as the presence of columnar epithelium on the ectocervix, sometimes combined with deformation of the external os.

True cervical erosion is characterized by the presence of a bright red defect on the unchanged ectocervix with distinct, irregular edges formed by "ragged" stratified squamous epithelium, often with edema, vascular dilation, fibrinous exudate, and contact bleeding.

2.3 Laboratory Diagnostics

Comments: Cytological examination may be performed if a patient is under 21 years old and has been sexually active for more than 3 years.

The material must be obtained from the ectocervix and endocervix (in the absence of cervical canal atresia).

Cytological examination of smears from the ecto- and endocervix (conventional and liquid-based cytology) is one of the main methods for diagnosing the condition of the cervix. For the detection of CIN II+, the sensitivity and specificity of conventional cytology are 62.5% and 96.6%, respectively, while the sensitivity and specificity of liquid-based cytology are 72.9% and 90.3%, respectively [26]. The low reproducibility of results from repeat smears taken within 1.5–2 months after the initial ones should be taken into account; therefore, re-evaluation of initial abnormal smears is advisable when necessary. About 10% of conventional cytological smears are inadequate, which is associated with incorrect sampling technique and specimen preparation [27], [28], [29], [30]. See Appendix A 3.1.

Liquid-based cytology is more effective for detecting LSIL and HSIL due to a manifold reduction in the number of inadequate smears [31], [32].

Comments: HR-HPV testing can be performed using self-sampling devices [35], [36], [37], [38], [39].

It is advisable to perform HPV testing as a screening method for all women starting from the age of 30 in combination with cytological examination of a cervical smear – a cervical sample (co-testing) [40], [41], [42].

Comments: It is advisable to perform HPV testing with genotyping (partial or complete) to assess the degree of risk, select management tactics, and evaluate the effectiveness of CIN treatment [43].

Abnormal cytology results – ASCUS, LSIL in the presence of HR-HPV, as well as ASC-H, HSIL, AGC, AGC-NOS, and AGC-FN – regardless of HPV test results, are an indication for colposcopy, the results of which determine the necessity and method of performing a cervical biopsy [44]. Colposcopy is also indicated for all patients infected with HPV types 16 and/or 18, regardless of cytology results.

[1] Order No. 404n dated April 27, 2021, "On Approval of the Procedure for Conducting Preventive Medical Examination and Dispensary Examination of Certain Groups of the Adult Population"

[2] Letter of the Russian Ministry of Health No. 15-4/10/2-7676 dated November 2, 2017, on the dissemination of clinical guidelines (treatment protocol) "Benign and precancerous diseases of the cervix from the perspective of cancer prevention".

2.4 Instrumental Diagnostics

Comments: The diagnostic value of colposcopy decreases when complete visualization of the entire transformation zone (TZ) and the squamocolumnar junction (type 3 TZ) is not possible.

Comment: The term "ECS" is used to denote all methods of cervical canal sampling – curettage or endocervical brush sampling [7], [21], [45], [46].

Comments: The diagnosis and severity grade of CIN are established solely on the basis of histopathological examination. Cytology results do not always coincide with the histological diagnosis [41], [48].

Since a single patient may have CIN of varying severity, making a diagnosis based on limited biopsy specimens may be difficult, and underestimation of the grade of neoplasia is possible [12], [46], [48].

Comments: In young patients, targeted biopsy is acceptable provided that the TZ is fully visualized and there are no colposcopic signs suspected for invasion [21], [30], [45], [49]. In women with HSIL over 50 years of age or with type 3 TZ, cone excision of the TZ (conization) of the cervix with endocervical curettage is indicated.

Comments: Immunocytochemical study of biological material is an additional morphological method. Positive expression of p16 and Ki67 in ASC-US, ASC-H, and LSIL suggests a high probability of HSIL [50], [51], [52].

2.5 Other Procedures

Comments: Optical-electronic technology provides sensitivity comparable to liquid-based cervical cytology and can be used both as a primary screening method and for triage of HPV-positive patients [53], [54], [55].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Diet therapy is not used.

Comments: Congenital ectropion (ectopy) in HPV-negative women is a safe condition regarding the development of precancer and cervical cancer [1], [3], [57].

Comments: Unjustified destruction of ectopy and normal TZ in the event of neoplasia does not prevent disease progression in the hidden part of the canal, but contributes to diagnostic difficulties [1], [3], [12].

Comments: Treatment with immunomodulators (ATC code: L03 Immunostimulants) targeting the productive component of HPV infection, which initiates and supports CIN progression, is possible only as an adjunct to the main management strategy.

Studies with a low level of evidence have shown a number of positive results regarding drugs based on diindolylmethane, inosine pranobex, histidyl-glycyl-valyl-seryl-glycyl-histidyl-glycyl-glutaminyl-histidyl-glycyl-valyl-histidyl-glycine, and certain other drugs [3], [12], [58], [59], [60], [61], [62].

Comments: In young patients with a morphologically confirmed diagnosis of LSIL (signs of HPV infection, koilocytosis, CIN I) and no high-grade lesions, an expectant management strategy with active surveillance of the cervix for 18–24 months, consisting of cytology control every 6 months and HPV testing every 12 months, is preferred. Surgical treatment is indicated in the absence of regression after 18–24 months [1], [3], [12], [49], [64].

Comments: Destruction is possible only in young patients with LSIL with type I TZ, absence of abnormalities in endocervical smears, and no discrepancies between cytological, colposcopic, and histopathological findings. In other cases, even under the age of 25, excisional biopsy of the altered epithelium is indicated [12], [34], [65].

Comments: If microinvasion is detected in the removed cone, the patient should be referred to an oncologist with ready histological slides and paraffin blocks. During excision, the entire TZ with the transition zone and a portion of the overlying endocervical crypts must be removed. For type 1 TZ located entirely on the ectocervix, regardless of size, the excision depth must be at least 7 mm. For type 2 TZ, the excision depth is increased to up to 10 mm. If visualization of the squamocolumnar junction (type 3 TZ) is difficult or impossible, the excision depth must be at least 15 mm (conization) [3], [11], [12].

In young women with a diagnosis of CIN II on biopsy with a p16-negative IHC result, active surveillance is acceptable, similar to LSIL, using cytological control, HPV testing, and colposcopy every 6 months for 2 years [8], [50], [51].

In the absence of regression, switch to active management (cervical excision). In patients with a diagnosis of CIN II on biopsy with a p16-positive IHC result, prompt cervical excision is necessary [8], [52].

Comments: The conditions for destructive methods (cervical radiofrequency therapy, argon plasma coagulation (CME — Surgical treatment of cervical diseases using various energies), cervical cryodestruction, cervical laser vaporization) are: complete visualization of the transformation zone (type I TZ—lesions limited to the ectocervix); absence of colposcopic signs of ectocervical glandular involvement with aceto-white epithelium extending into them; no evidence of endocervical involvement in the pathological process; no history of prior cervical surgery; no discrepancies between the findings of cervical cytology, colposcopy, and histopathological examination of uterine biopsy material [65], [66].

Comments: Upon histopathological confirmation of the diagnosis and the absence of tumor cells at the resection margins and in the curettage from the remaining part of the endocervical canal, the extent of the surgical intervention performed is considered adequate. If HSIL is detected at the cervical resection margins or in the curettage from the remaining part of the endocervical canal, repeat surgical treatment is advisable [3], [11], [12], [49], [68].

Patients after supracervical hysterectomy are monitored according to the standard schedule depending on age. When HSIL diseases of the cervical stump are detected, surgical treatment should preferably be performed in level 2-3 inpatient facilities (hospitals providing specialized, including high-tech, medical care and developing new methods for diagnosing and treating gynecological pathologies) due to altered topographic-anatomical relationships and potential intraoperative complications.

Algorithms for physician actions in detecting specific types of abnormal smears and in specific groups of patients are presented in Appendix B.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specific rehabilitation has not been developed.

5. Prevention and Dispensary Observation

5.1 Prevention

Comments:

Prevention of cervical cancer (WHO, 2014) [21]:

1. Primary prevention: human papillomavirus vaccination targeting girls aged 9-13 years and prior to sexual debut (Appendix A3.3).

2. Secondary prevention: availability of screening followed by treatment of detected cervical precancer (cervical cancer screening is presented in Appendix A3.4) [12].

Screening strategies [19], [21][1]:

• 21-29 years:

1. cytology/liquid-based cytology (cytological examination of a cervical smear) once every 3 years.

2. Cytological examination of a cervical smear (Pap test) NILM – repeat cytological examination (Pap test) in 3 years.

3. In the presence of smear abnormalities of ASCUS and worse, HPV testing is indicated:

4. In the presence of ASCUS and a negative HPV test (-) – repeat co-testing in 3 years; positive HPV test (+) – colposcopy with possible cervical biopsy.

• 30-65 years

1. Preferred option – co-testing (cytology/liquid-based cytology and HPV test).

2. Cytological examination of a cervical smear (Pap test) NILM and

HPV (-) – repeat co-testing in 5 years.

3. Cytological examination of a cervical smear (Pap test) = ASCUS and

HPV (-) – repeat co-testing in 3 years.

4. Cytological examination of a cervical smear (Pap test) NILM and

HPV (+) – repeat co-testing in 1 year.

5. Cytological examination of a cervical smear (Pap test) ≥ASCUS and HPV (+) – colposcopy and cervical biopsy.

ASC-H and HPV (+/-) – colposcopy with possible biopsy.

HSIL and HPV (+/-) over 25 years of age – colposcopy and loop excision (Medical Service Nomenclature - electrosurgical excision of a cervical neoplasm) or conization.

HSIL and HPV (+/-) under 25 years of age – colposcopy, targeted uterine tissue biopsy, or loop excision (Medical Service Nomenclature - electrosurgical excision of a cervical neoplasm).

AGC and HPV (+/-) – colposcopy with possible uterine (cervical) tissue biopsy, fractional diagnostic curettage of the cervical canal; in women over 35 years of age – uterine (endometrial) tissue biopsy.

Acceptable option – HPV testing as the first step.

HPV (-) – repeat HPV test in 5 years.

If HPV (+) is detected, a cytological examination of a cervical smear (Pap test) is necessary.

Preventive medical examinations or health check-ups for health groups should be carried out⁹:

Health group I – 21-29 years – cytological examination of a cervical smear at least once every 3 years.

Ages 30-65: performing cervical cytology and HPV testing once every 5 years

Health group II - in the presence of risk factors, HPV-positive patients: cervical cytology (Pap test) is recommended. If ≥ASCUS is present — colposcopy; if NILM is detected — repeat co-testing in 1 year.

Health group III - in the presence of benign cervical diseases: treatment in accordance with the guidelines.

Comment: The first co-test (cytology and HPV testing) should be performed 3 months after surgical treatment, then every 6 months for 2 years, and then annually for 20 years [12], [68], [69], [70]. The criterion of cure (absence of residual disease) is a negative HPV test, absence of abnormalities in smears and on colposcopy. In case of suspected residual disease (recurrence), an expanded colposcopy and reconization with pathomorphological examination are recommended [68]; consultation with an oncologist to determine the scope of surgery. For the treatment of recurrent CIN II/III, cervical amputation or hysterectomy is the preferred method [12], [49], [68], [69].

5.2 Dispensary monitoring

Comments: In young patients with a histologically confirmed diagnosis of LSIL (signs of HPV infection, koilocytosis, CIN I), an expectant management strategy with active surveillance of the cervix for 18–24 months, cytologic control once every 6 months, and molecular biological testing of a cervical scrape for human papillomavirus once every 12 months is preferred. If LSIL does not regress within 18–24 months, surgical treatment is recommended [3], [12], [49], [64].

After surgical treatment for LSIL, cervical cytology and HPV testing are performed in 6-12 months.

After surgical treatment for HSIL, cervical cytology and HPV testing are performed [67]. The first co-test (cytology and HPV testing) should be performed 3 months after surgical treatment, then every 6 months for 2 years, and then annually for 20 years [12], [69], [70]. Patients with microinvasive cervical cancer must be consulted by an oncologist with further evaluation and follow-up.

6. Organization of Medical Care

Excisional and ablative treatment methods are preferably performed in outpatient settings or day care settings.

Indications for hospitalization:

- cold-knife conization of the cervix with diagnostic curettage of the cervical canal and uterine mucosa;

- cervical excision when outpatient execution is impossible (e.g., cervical lesions extending to the vaginal fornices, extreme shortening of the cervix, severe extragenital pathology, refusal of local anesthesia, etc.).

Patient discharge criteria: Recovery.

7. Additional Information

None.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Leyla V. Adamyan – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Deputy Director of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Honored Worker of Science of Russia, Head of the Department of Obstetrics, Gynecology and Reproductive Medicine at the Russian University of Medicine, Chief Gynecologist of the Russian Ministry of Health, member of the Society for Reproductive Medicine and Surgery, Russian Association of Endoscopic Gynecologists, Russian Association for Endometriosis, Russian Society of Obstetricians and Gynecologists.

Inna A. Apolikhina – Doctor of Medical Sciences, Professor, Head of the Gynecological Department of Reconstructive Treatment at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health (Moscow).

Natalia V. Artymuk – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology named after Professor G.A. Ushakova at Kemerovo State Medical University of the Russian Ministry of Health, Chief freelance specialist in obstetrics and gynecology of the Russian Ministry of Health in the Siberian Federal District (Kemerovo), member of the Presidium of the Board of the Russian Society of Obstetricians and Gynecologists, President of the Kemerovo Regional Public Organization "Association of Obstetricians and Gynecologists".

Alexandra V. Asaturova – Doctor of Medical Sciences, Head of the 1st Pathological Anatomy Department at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

Levon A. Ashrafian – Academician of the Russian Academy of Sciences, Professor, Head of the Oncoginethology Department at the Russian Scientific Center of Roentgenoradiology, Honored Doctor of the Russian Federation, member of the American Association of Gynecologic Laparoscopists (Moscow)

Igor I. Baranov – Doctor of Medical Sciences, Professor, Head of the Organizational and Methodological Department of the Scientific and Organizational Support Service at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, member of the Russian Society of Obstetricians and Gynecologists (Moscow)

Gyuldana R. Bayramova – Doctor of Medical Sciences, Head of Clinical Work at the Scientific and Polyclinical Department at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, member of the Russian Society of Obstetricians and Gynecologists (Moscow)

Tatyana E. Belokrinitskaya – Doctor of Medical Sciences, Professor, Honored Doctor of the Russian Federation, Head of the Department of Obstetrics and Gynecology of the Faculty of Advanced Training and Professional Retraining of Specialists at Chita State Medical Academy, Chief freelance specialist in obstetrics and gynecology of the Russian Ministry of Health in the Far Eastern Federal District, member of the Board of the Russian Society of Obstetricians and Gynecologists, President of the Transbaikal Society of Obstetricians and Gynecologists (Chita)

Natalia V. Dolgushina – Doctor of Medical Sciences, Professor, Deputy Director – Head of the Department of Scientific Activity Organization at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health (Moscow).

Nina V. Zarochentseva – Doctor of Medical Sciences, Professor of the Russian Academy of Sciences, Deputy Director for Research at the Moscow Regional Research Institute of Obstetrics and Gynecology, Professor of the Department of Obstetrics and Gynecology of the Faculty of Advanced Medical Training at the M.F. Vladimirsky Moscow Regional Research Clinical Institute, member of the Association for Cervical Pathology and Colposcopy, member of the Russian Society of Obstetricians and Gynecologists (Moscow)

Anna G. Kedrova - MD, PhD, Professor, Laureate of the Russian Government Prize, Head of the Department of Obstetrics and Gynecology at the Academy of Postgraduate Education of the FSCC of the Federal Medical-Biological Agency, Chief External Oncologist of the FMBA of Russia.

Lyubov I. Korolenkova - MD, PhD, Professor, Senior Researcher at the National Medical Research Center for Oncology named after N.N. Blokhin of the Ministry of Health of the Russian Federation (Moscow)

Igor N. Kuznetsov – Deputy Director of the Institute of Onkogynecology and Mammology at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after V.I. Kulakov of the Russian Ministry of Health, Member of the Russian Society of Obstetricians and Gynecologists (Moscow)

Galina N. Minkina – MD, PhD, Professor, Professor at the Department of Obstetrics, Gynecology and Reproductive Medicine of the N.A. Semashko Research and Educational Institute of Clinical Medicine at the Russian University of Medicine; Member of the Association for Cervical Pathology and Colposcopy, Member of the Russian Society of Obstetricians and Gynecologists (Moscow)

Natalia V. Mingaleva – MD, PhD, Professor at the Department of Obstetrics, Gynecology and Perinatology of the Faculty of Advanced Training and Professional Retraining of Specialists at Kuban State Medical University of the Russian Ministry of Health, Chief External Specialist in Outpatient Obstetric and Gynecological Care of the Ministry of Health of Krasnodar Krai, Member of the Russian Society of Obstetricians and Gynecologists (Moscow)

Nazarova Niso Mirzoevna – MD, Professor, Leading Researcher of the Scientific Policlinic Department at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Member of the Russian Society of Obstetricians and Gynecologists (Moscow)

Vera N. Prilepskaya - MD, PhD, Professor, Honored Scientist of the Russian Federation, Deputy Director for Research at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after V.I. Kulakov of the Russian Ministry of Health, Member of the Presidium of the Russian Society of Obstetricians and Gynecologists, President of the Russian Society for Contraception, President of the Association for Cervical Pathology and Colposcopy, Board Member of the European Society of Contraception and the European Cervical Cancer Prevention Council, Member of the European Federation for Colposcopy (Moscow)

Elena V. Uvarova - MD, PhD, Professor, Honored Scientist of the Russian Federation, Head of the 2nd Gynecological Department (Children and Adolescents) at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after V.I. Kulakov of the Russian Ministry of Health, Professor at the Department of Obstetrics, Gynecology, Perinatology and Reproductology of the Institute of Professional Education of Physicians at the I.M. Sechenov First Moscow State Medical University, Chief External Specialist in Pediatric and Adolescent Gynecology of the Ministry of Health of the Russian Federation, President of the Interregional Public Organization "Association of Pediatric and Adolescent Gynecologists", Member of the Russian Society of Obstetricians and Gynecologists (Moscow)

Filippov Oleg Semenovich – D.Sc. in Medicine, Professor, Honored Doctor of the Russian Federation, Chief freelance Obstetrician-Gynecologist of the Federal Medical-Biological Agency (FMBA) of Russia, Deputy Director of the Federal Scientific and Clinical Center of Children and Adolescents of FMBA of Russia, Professor at the Department of Obstetrics, Gynecology and Reproductive Medicine, Russian University of Medicine.

Irina P. Shabalova - MD, PhD, Professor, Professor at the Department of Clinical Laboratory Diagnostics of the Russian Medical Academy of Continuous Professional Education, President of the Association of Clinical Cytologists (Moscow)

Conflict of interest: none declared

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Medical specialists: obstetrician-gynecologists; oncologists, pediatric oncologists; urologists, including pediatric urologists-andrologists; pediatricians, dermatovenerologists, etc.

2. Residents, postgraduate students, and trainees of advanced training courses in the specified specialties.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1 Instructions for performing cytologic examination of exocervical and endocervical scrapings

To obtain adequate material, it is necessary to:

1. Use modern instruments — combined brushes with an endocervical component or two separate brushes. All spatulas (Ayre, wooden, and metal) and curette spoons frequently included in disposable gynecological kits should be excluded from use, as they do not allow obtaining a proper scraping from the transformation zone and transitional zone and damage cellular elements when spreading the material onto the glass slide.

2. Obtain the material as a scraping down to "bloody dew" to ensure the sample is as rich in cells as possible.

3. Due to the fact that some lesions may be located outside the ectocervix, a full-fledged cervical sample must be obtained from the cervical canal and endocervical crypts.

Figure 1. Appearance of the working part of brushes for obtaining adequate material from both the ectocervix and endocervix. The material must be obtained either using two brushes (A, B) or a combined brush with an endocervical component (C).

Rules for sampling a conventional smear for oncocytology:

1. The cervix is exposed using specula.

2. The material is sampled from the transformation zone and its surface — the transitional zone of the epithelial junction and from the endocervical crypts, i.e., from the ectocervix and endocervix. Since the neoplastic process initially and most actively develops at the epithelial junction site (transitional zone) and transformation zone, the scraping (smear) must necessarily include the epithelium of these zones. Due to the involvement of endocervical crypts, the presence of the endocervical component in the material is important.

3. It is necessary to use a special disposable instrument that guarantees the collection of material from all specified zones and ensures the informative value of the specimen.

The use of non-standardized instruments is unacceptable as it leads to a decrease in the diagnostic efficacy of the cytological examination.

4. The smear must be taken before colposcopy and various tests, as well as bimanual examination, to avoid lysis and deformation of cellular elements.

5. Biomaterial for cytological examinations is always and exclusively collected first. Biomaterial for molecular biological and/or microbiological examinations is collected strictly after obtaining the material for cytological examination. Biomaterial for general clinical microscopic examination is collected last.

6. Material collection is performed after removing mucus with a sterile dry soft cotton swab, without applying rough pressure to the cervix to avoid loss of epithelium.

7. Material collection for cytological examination is performed using a cytobrush (exocervix) and an endocervical brush (endocervix) and consists of obtaining a scraping-scarification. When obtaining clinical material for cytological examinations, preference should be given to consumables (cytobrushes, universal urogenital probes) with stiff bristles.

8. Recommended sampling technique: rotate the cytobrush, positioned predominantly on the ectocervix, 5 times clockwise by 360° (Fig. 2). If sampling is performed with a cytobrush having an endocervical pin, it is recommended to rotate it at least 3 times by 360°.

Figure 2. Rules for sampling material for cytological examination using a cytobrush and smear preparation technique.

9. To take material from the endocervix, the endocervical brush, after insertion, should be rotated at least three times counterclockwise (Fig. 3b). The appearance of "bloody dew" is expected, which indicates the acquisition of an informative cervical sample where, in addition to mucus, cells from practically all layers of the epithelial sheet are present.

Figure 3. Rules for sampling material for cytological examination using an endocervical brush and smear preparation technique (mandatory: the brush performs rotational movements).

10. An adequate smear must be as thin as possible and must not contain "thick areas" including "unviewable" clusters or complexes of cells. Rules and options for smear preparation are shown in Figures 2 and 3.

11. The material must be distributed evenly along a degreased, dry glass slide (not across or in circles) over the entire surface of the slide with an even distribution of the maximum amount of the obtained scraping (Fig. 2).

12. When using May-Grünwald-Giemsa (Romanowsky-Giemsa) staining, special fixatives are not used; the specimen is air-dried.

13. When using hematoxylin and eosin staining, the standard technique is applied.

14. Smears must be labeled: the patient's last name, sampling location (ecto-, endocervix), and the registration number of the study are indicated on the back of the specimen slide laterally along the short edge (Fig. 2, 3).

15. If Papanicolaou staining is planned, the smear should be fixed with an alcohol solution.

16. In the Russian Federation, the referral form attached to the specimen is standard form No. 446/y, approved by the Order of the Ministry of Health of the Russian Federation dated April 24, 2003, No. 174 "On approval of accounting forms for cytological examinations." All items on the front side of the form must be completed (in the "Treatment administered" column, it is mandatory to indicate what treatment was performed, e.g., electrosurgical conization [DEC] 2002).

A smear for cytological examination should not be taken:

• earlier than 24 hours after sexual intercourse;

• during menstruation;

• during the treatment of genital infections;

• less than 48 hours after expanded colposcopy with application of 3-5% acetic acid solution (FS-001785) or Lugol's solution (ATC: Antiseptics), after the use of lubricants, tampons, or spermicides;

• after vaginal examination or douching. 

Appendix A3.2 Types of HPV tests (For all types of tests - NMU molecular-biological study of a cervical canal scraping for human papillomavirus (Papilloma virus)) [71], [72].

1. Polymerase chain reaction (PCR) – multiple copying of a specific region of viral DNA using type-specific and species-specific primers – qualitative determination of high-risk HPV (HR-HPV) with virus genotyping. Testing for 13-14 types of HR-HPV is recommended.

2. RT (real-time) PCR – real-time PCR – viral load is assessed in logarithms; clinically significant amounts of HPV associated with the risk of neoplasia are differentiated from insignificant amounts corresponding to transient and resolved HPV infection.

3. Qualitative DNA PCR tests for 14 types of HR-HPV with partial genotyping of the most "dangerous" HPV types (types 16 and 18, and others). Test systems have been developed and are used that allow the identification of HPV genes of types 16, 18, 31, 45, 51, 52, and 59; other HR-HPV types are detected in two groups: 33, 56, 58, 66, and 35, 39, 68.

4. Hybrid Capture II (HC2) test = Digene HPV test. The test is based on the hybridization of HR-HPV DNA fragments with RNA probes captured by fluorescently labeled antibodies. A positive result indicates a clinically significant concentration of 13 HR-HPV types in copies of HPV DNA per 1 ml of sample. A negative result practically rules out the presence of CIN2-3.

5. HPV RNA-based tests: PreTect HPV-Proofer (amplification of E6/E7 mRNA of five high-risk HPV types (16, 18, 31, 33, and 45)) and Aptima (Gen-Probe), based on target capture and hybridization of E7 mRNA to detect E7 mRNA expression of 14 HR-HPV types with partial genotyping.

Technique for collecting material for HPV testing

1. Using a brush, take a scrape-smear from the transformation zone including the squamocolumnar junction and the crypts of the cervical canal: rotating the brush, treat the ectocervix first, then insert it into the lower third of the canal and perform 3-5 rotations.

2. Place the brush into a special container with a preservative.

3. Label the container: write the patient's name, outpatient card or medical history number, and the date.

When self-collecting an HPV test sample, the patient must follow the instructions provided with the self-sampling device [32], [35], [36], [72].

Appendix A3.3 Basic principles of HPV vaccination, indications, and contraindications

Two vaccines are registered in the Russian Federation: Human Papillomavirus Vaccine, Recombinant, Adsorbed, containing the AS04 adjuvant (types 16 and 18), and Human Papillomavirus Quadrivalent Vaccine, Recombinant (types 6, 11, 16, 18).

WHO vaccination schedules (2017)

For girls under 15 years of age (optimally at 9-13 years of age, before the onset of sexual activity): two-dose vaccination schedule with an interval of 6 months (the interval can be extended to 12-15 months). If the interval between the 1st and 2nd dose is less than 5 months, a 3rd dose is recommended no later than 6 months after the start of vaccination [73], [74].

For girls over 15 years of age: a three-dose vaccination schedule at 0, 1-2, and 6 months is recommended [73], [74].

Contraindications to vaccination include hypersensitivity to vaccine components, the development of severe systemic allergic reactions or post-vaccination complications following the previous administration of an HPV vaccine. Acute infectious and non-infectious diseases, as well as exacerbations of chronic diseases, are temporary contraindications; immunization is carried out 1–2 weeks after recovery, or during convalescence or remission. In mild forms of respiratory, intestinal, and other infections, vaccination can be performed after normalization of body temperature [74].

If pregnancy occurs after the start of a vaccination series, administration of the remaining dose should be postponed until the end of the pregnancy [75], [74]. There is no need to restart the full course of vaccination in the postpartum period.

Breastfeeding is not an absolute contraindication for vaccination with the quadrivalent HPV vaccine [74]. However, given the preventive nature of HPV vaccines and the very low probability of primary HR-HPV infection during lactation, vaccination should be deferred, as the risks of harm to the infant outweigh the anticipated benefits.

Adolescent girls do not need a special gynecological examination before vaccination. HPV testing prior to vaccination is not recommended [74], [76].

No association has been established between HPV vaccination and an effect on fertility, the development of autoimmune diseases, or death – the incidence of these complications did not differ from that in the general population [77].

Women should be informed that vaccination [74] does not eliminate the need for regular gynecological examinations for secondary prevention, since the vaccine does not protect against all diseases caused by different HPV types [21], [78].

Post-vaccination follow-up

Vaccination is carried out in immunoprophylaxis centers, vaccination rooms of outpatient clinics, and medical institutions, including pediatric ones.

Following vaccination, girls and women are also subject to standard cervical screening, including a cytological examination and an HPV test, in accordance with current orders [21], [78].

Revaccination

Data have been published on effective protection for 9.4 years for the bivalent vaccine and at least 10 years for the quadrivalent vaccine [79], [80]. Currently, there are no recommendations for revaccination.

Adjuvant HPV vaccination in previously unvaccinated individuals undergoing treatment for CIN II+

The American Society for Colposcopy and Cervical Pathology (ASCCP) recommends HPV vaccination for individuals aged 9 to 26 years, as well as, considering the potential benefit of adjuvant HPV vaccination, for unvaccinated individuals aged 27 to 45 years who are undergoing treatment for CIN II+ [81].

Appendix A3.4 Recommended cervical cancer screening algorithm [33], [19]:

• Start of screening – 21 years of age (cervical cytological examination may be performed if a patient under 21 presents and has had sexual activity for more than 3 years).

• End of screening – 65 years of age (provided there is an adequate prior screening history for 10 years and no CIN II-III for 20 years).

• Ages 21-29 – cervical cytological examination at least once every 3 years.

• Ages 30-65 – cervical cytological examination + HPV test at least once every 5 years.

Comment: the key to screening effectiveness is population coverage (at least 70%). This issue can be addressed through active mailing of screening invitations via email and mobile communications, as well as using self-sampling technology for HR-HPV, which has similar effectiveness compared to physician-collected material [38], [39].

Patients with immunosuppression (HIV infection, long-term corticosteroid use, immunosuppressants after organ transplantation, etc.) may require more frequent testing [49].

Screening of patients after hysterectomy

In patients after hysterectomy with no history of HSIL (CIN II+), sampling from the vaginal vault is not recommended.

Patients who have undergone hysterectomy for HSIL (CIN II+) may be at increased risk of developing vaginal cancer. These patients must undergo three consecutive annual HR-HPV and/or cytological tests of the vaginal vault before transitioning to long-term surveillance. Patients with abnormal cytology and/or a positive HPV test should be referred for vaginal colposcopy [49], [82].

Appendix A3.5 Schematic representation of two options for excision of the affected transformation zone and overlying crypts — LLETZ and conization.

Appendix A3.6 Table 4. Correlation of classifications of precancerous cervical lesions [9].

The table demonstrates the correlation of cytological conclusions according to various classifications.

The Bethesda System for Reporting Cervical Cytology, 2014 (complete version)

Smear type (mandatory): conventional smear, liquid-based cytology, or other

Smear adequacy (mandatory): adequate/inadequate for evaluation

General categorization (optional)

1) Negative for intraepithelial lesion or malignancy (NILM)

2) Epithelial cell abnormalities: see "interpretation/result" section, specify if possible whether the pathology involves glandular or squamous cells

3) Other: see "interpretation/result" section (e.g., presence of endometrial cells in women aged 45 years)

Interpretation/result (mandatory)

1) Negative for intraepithelial lesion or malignancy (NILM)

2) Non-neoplastic findings

· Squamous metaplasia

· Keratotic changes

· Tubal metaplasia

· Atrophic changes

· Pregnancy-related changes

· Reactive cellular changes associated with: specify cause:

o inflammation (with or without reparative changes),

o lymphocytic (follicular) cervicitis

o radiation-related changes

o intrauterine device (IUD)-related changes

· Presence of glandular cells post-hysterectomy

· Presence of infectious agents:

o Trichomonas vaginalis

o Fungal organisms morphologically consistent with Candida species

o Flora changes suggestive of bacterial vaginosis

o Cellular changes associated with herpes simplex virus

o Cellular changes associated with cytomegalovirus

· Other

· Presence of endometrial cells (in women ≥ 45 years)

3) Epithelial cell abnormalities

· Squamous cell abnormalities

o Atypical squamous cells

- of undetermined significance (ASC-US)

- cannot exclude a high-grade squamous intraepithelial lesion, HSIL (ASC-H)

o Low-grade squamous intraepithelial lesion (LSIL)

o High-grade squamous intraepithelial lesion (HSIL)

- With features suspicious for invasion (if present)

o Squamous cell carcinoma

· Glandular cell abnormalities

o Atypical

- Endocervical cells (NOS / not otherwise specified, or specify in comments)

- Endometrial cells (NOS, not otherwise specified, or specify in comments)

- Glandular cells (NOS, not otherwise specified, or specify in comments)

- Endocervical cells, suspicious for neoplasia

- Glandular cells, suspicious for neoplasia

o Endocervical adenocarcinoma in situ

o Adenocarcinoma

- Endocervical

- Endometrial

- Extrauterine

- NOS, not otherwise specified, or specify in comments

4) Other malignant neoplasms (specify)

5) Additional findings

o Ancillary testing: specify the method and result (e.g., immunocytochemistry or cell block)

o Automated computer-assisted cytology evaluation and result

o Educational notes and comments (e.g., references to current publications or guidelines)

Appendix B. Physician Action Algorithms

Diagnostic and management algorithm for patients with cervical pathology detected during screening

Appendix C. Patient Information

Cervical cancer is one of the leading malignancies in the structure of female reproductive system diseases. Therefore, understanding the mechanisms of development and identifying pathological conditions of the cervix is of paramount importance. Early detection of pathological processes in the cervix helps preserve reproductive function, prevent the development of serious oncological diseases, and in some cases, even save lives. It has long been established that human papillomavirus plays a role in the development of cervical cancer. Early onset of sexual activity and frequent changes of sexual partners increase the risk of human papillomavirus infection. It is important to note that precancerous conditions and early cervical cancer are usually asymptomatic.

In this regard, regular preventive gynecological examinations, examination of the cervix, cytological examination of cervical scrapings, and testing for human papillomavirus are extremely important. After receiving laboratory test results, in some situations, additional in-depth diagnostics are required—colposcopy (examination of the cervix under magnification using a special optical device) and biopsy. In cases where severe lesions, up to and including cervical cancer, are detected, therapeutic measures are carried out, ranging from excision (removal of pathological areas on the cervix using an electrosurgical loop) or cervical conization (a surgical treatment method allowing excision of the outer surface of the cervix and a portion of the cervical canal) to hysterectomy. In some cases of mild cervical lesions, active surveillance may be possible. It is important to note that treatment does not exclude the risk of reinfection with the human papillomavirus. For this reason, preventive examinations should be performed regularly, at least once every 5 years. On the other hand, vaccination against the human papillomavirus is of equal importance. It is advisable to vaccinate before the onset of sexual activity, optimally at the age of 9–13 years.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not used.