Guidelines for Diagnosis and Treatment of Cervical Cancer (2022 Edition)

1、 Overview

Cervical cancer is one of the most common gynecological malignancies, and its incidence rate ranks second among female malignancies in China, after breast cancer. In 2018, there were more than 569000 new cervical cancer cases and 311000 deaths worldwide. 85% of these cases occurred in developing countries. In 2015, there were about 111000 new cases and 34000 deaths in China. In general, the death distribution of cervical cancer in rural areas is slightly higher than that in urban areas, and the central and western regions are about twice as large as that in eastern regions. The median onset age of cervical cancer patients in China is 51 years old, but it mainly occurs in two age groups, most of which are 40-50 years old. There is another peak in 60-70 years old, and it is rare before 20 years old. However, it is noteworthy that in recent years, the average age of onset of cervical cancer is gradually decreasing, with a younger trend. Therefore, it is necessary to standardize the diagnosis and treatment of cervical cancer nationwide. On the other hand, the occurrence of cervical cancer can be effectively controlled through the examination and treatment of precancerous lesions. The experience of western countries shows that the incidence of cervical cancer has been reduced by 70% - 90% among closely screened people. On November 17, 2020, WHO launched the global strategy of "accelerating the elimination of cervical cancer".

This guideline is applicable to cervical squamous carcinoma, adenocarcinoma and adenosquamous carcinoma, accounting for more than 90% of all cervical cancers. Some special pathological types, such as small cell carcinoma, clear cell carcinoma, sarcoma and other incidence rate are low. At present, there is no consensus at home and abroad, so this guide is not suitable for these rare pathological types of cervical cancer. This guideline is based on internationally recognized guidelines for diagnosis and treatment of cervical cancer, such as the guidelines of the National Comprehensive Cancer Network (NCCN) and the International Federation of Obstetrics and Gynecology (FIGO), and revised in combination with previous guidelines in China. In clinical practice, the concept of standardized comprehensive treatment is emphasized for cervical cancer, and individualized treatment is also emphasized, which needs to be combined with hospital equipment, technical conditions and patients' conditions. For patients with complicated cervical cancer who are not covered by this guideline, it is recommended to participate in clinical trials.

2、 Etiology

At present, it has been confirmed that persistent infection of high-risk human papillomavirus (HPV) is a necessary factor in the occurrence of cervical cancer and precancerous lesions, that is, HPV infection is the most critical link in the process of cervical carcinogenesis. In women's lifetime, the probability of high-risk HPV infection is more than 70%, but less than 10% of women develop cervical cancer or cervical intraepithelial neoplasia (CIN), mainly because 80% of women's HPV infection is transient. In addition to the role of persistent high-risk HPV infection, other endogenous and exogenous factors also need to participate in and act together to cause cervical cancer. Therefore, the risk factors for cervical cancer can be divided into two categories: one is biological factors, that is, high risk HPV persistent infection; The second is exogenous behavioral risk factors.

（1） HPV infection.

At present, more than 200 subtypes of HPV have been found and identified, and about 54 species can infect genital mucosa. According to the different risk of HPV and cervical cancer, HPV can be divided into high-risk type and low-risk type. High risk types (such as HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) are closely related to cervical cancer, especially HPV16 and 18. Low risk HPV (e.g 6. 11, 42, 43, 44) may cause genital and perianal condyloma. At present, human papillomavirus vaccine has been marketed in China, which can be promoted according to the appropriate age to prevent cervical precancerous lesions and cervical cancer.

（2） Behavioral risk factors.

1. Because HPV is mainly transmitted through sex, some factors that may increase HPV infection, such as young age at the beginning of sexual life, multiple sexual partners or sexual partners with multiple sexual partners, poor sexual hygiene or a history of sexually transmitted diseases, will increase the risk of HPV infection, thus increasing the risk of cervical cancer.

2. Menstruation and maternity factors: early marriage, early childbearing, multiple pregnancies and births, poor hygiene during menstruation and puerperium.

3. Smoking.

4. Oral contraceptives.

5. Autoimmune disease or long-term immunosuppression (for example, renal transplant patients need long-term oral immunosuppressive drugs).

6. Malnutrition: β Deficiency of carotene, folic acid, vitamin A and vitamin C, imbalance of trace elements, etc.

3、 Clinical manifestations

（1） Symptoms.

Cervical precancerous lesions and early cervical cancer may not have any symptoms. With the increase of the severity of the lesions, there will be contact vaginal bleeding, abnormal leucorrhea such as bloody leucorrhea, increased leucorrhea, irregular vaginal bleeding or postmenopausal vaginal bleeding. In the advanced stage of cervical cancer, a large amount of vaginal bleeding may also occur, which may be accompanied by water like or even rice soup like leucorrhea. In addition, there may be corresponding symptoms caused by the tumor invading other organs, such as hematuria if invading the bladder, bloody stool if invading the rectum, fistula if the tumor invading the bladder and rectum, lumbago if invading the periuterine ureter and causing hydronephrosis, and cough, hemoptysis and other related symptoms may be caused by lung metastasis; Tumor associated with infection may cause fever; There may also be renal failure and cachexia.

（2） Physical signs.

Early invasive carcinoma of the cervix (stage Ⅰ A1 and stage Ⅰ A2) may not have any related abnormal signs. Cervical invasive carcinoma (stage Ⅰ B1 and above) can be found by gynecological examination, which can be generally divided into cauliflower type, nodule type, ulcer type and cervical type. The cervical type sometimes shows smooth surface of the cervix, but the cervical tube is significantly thickened and hard in texture. If the vagina is invaded, tumors in the vaginal vault or vaginal wall can be found. Gynecological examination of patients with periuterine involvement can reveal periuterine thickening, such as stage IIIB patients with tumors extending to the pelvic wall; In the late stage, patients may palpate enlarged lymph nodes in the groin or supraclavicular region.

4、 Diagnostic check

（1） Cervical/vaginal cytology smear and HPV detection.

Cervical/vaginal cytological smears and HPV detection are the primary screening methods for the detection of early cervical cancer and precancerous lesions (CIN) at this stage, especially for the diagnosis of early lesions without obvious clinical signs. The material should be taken at the transitional zone of cervical epithelium, that is, the area between the old and new squamous columnar epithelium. At present, thin prep cytology test (TCT) is mainly used. HPV detection can be an effective complement to TCT, and the combination of the two is conducive to improving the screening efficiency. For HPV16 and 18 positive patients, direct referral to colposcopy for histological biopsy is recommended.

（2） Colposcopy.

Colposcopy plays an important role in finding precancerous lesions, early cervical cancer, and determining the location of lesions, which can improve the positive rate of biopsy. In medical units without colposcopy, 3% or 5% acetic acid or iodine solution can also be applied to smear the cervix for macroscopic observation. Biopsy can be taken at the place with white epithelium of vinegar or where iodine is not stained and sent for pathological examination. The importance of cervical curettage should be noted at the same time as colposcopy biopsy, especially when colposcopy shows that squamous intraepithelial lesions extend from the transformation area to the cervical canal, cytological screening indicates atypical glandular cells, and no scale column transformation area is found under colposcopy. Only a professional colposcopy doctor can decide to omit cervical curettage, otherwise cervical curettage should be performed for all patients receiving colposcopy biopsy.

（3） Gynecological examination.

Gynecological examination is the most important means of clinical staging. The clinical staging needs to be decided by two gynecologists with deputy senior titles or above. Once the staging is determined, the staging cannot be changed after treatment.

1. Visual diagnosis

It shall be conducted under sufficient lighting conditions, and the vulva shall be observed directly and through a vaginal speculum

Inspect the vagina and cervix. In addition to general observation, attention should be paid to the scope of cancer invasion and the position of cervical tumor

Position, range, shape, volume and relationship with surrounding tissues.

2. Palpation

The texture of the tumor, the extent of invasion and its relationship with the surrounding must be determined by palpation. For some submucosal and cervical infiltration, palpation is more accurate than visual diagnosis. The triple diagnostic examination can understand whether there is infiltration near the vagina, cervix and uterus, the relationship between tumor and pelvic wall, uterosacral ligament, uterine rectal depression, rectum itself and its surroundings.

（4） Pathological diagnosis.

Pathological examination of cervical biopsy under colposcopy or direct vision is the gold standard for final diagnosis. For rare or difficult pathological types (such as adenocarcinoma or small cell carcinoma), immunohistochemical examination should be performed to assist in differentiation and diagnosis. For those who can not be diagnosed by multiple bite biopsies, the method of cutting can be used when deeper tissues need to be taken further. When cervical surface biopsy is negative, vaginal cytology smear is positive, or imaging examination cannot exclude cervical cancer, cervical conization can be performed for pathological examination. Because of the small size of cervical biopsy tissue, it is impossible to completely determine the depth and scope of invasion of cervical lesions. Therefore, for the diagnosis of stage IA1 and stage IA2 cervical early invasive cancer, the final diagnosis of whether the scope of cervical lesions is early invasive cancer can only be made through the postoperative pathology of cervical conization.

（5） Imaging examination.

Because of the superficial anatomy, most cervical cancer can be diagnosed by gynecological examination and cytopathology. The value of imaging examination in the diagnosis of cervical cancer is mainly to understand the scope and extent of tumor metastasis and invasion (including the evaluation of the scope of local tumor invasion, lymph node metastasis and distant organ metastasis), so as to guide clinical decision-making and evaluate the efficacy. Imaging methods for cervical cancer include:

1. Abdominal and pelvic ultrasound

It is mainly used for observation of local cervical lesions, as well as pelvic and retroperitoneal lymph node metastasis, and other abdominal and pelvic organs metastasis. In addition, it can find superficial lymph node metastasis. Due to the limitation of resolution, the assessment of local cervical lesions and systemic metastasis mainly depends on MRI and CT.

2. Pelvic MRI

Non radiation, multi sequence, multi parameter imaging, with excellent soft tissue resolution, is the best imaging examination method for cervical cancer, which is helpful to detect the lesions and determine the size and location, especially for patients with CIN3 biopsy, it can be used to exclude endogenous lesions; To define the scope of the lesion and provide an important basis for staging before treatment, it can show the depth of the lesion invading the cervical matrix, judge whether the lesion is limited to the cervix, adjacent to the uterus or invading the pelvic wall, and can show the scope of the lesion in the vagina, but sometimes it is difficult to distinguish between the lesion protruding into the vaginal cavity and adhering to the vaginal wall and directly invading the vaginal wall; It can indicate the invasion of bladder and rectal wall, but it needs to be combined with microscopic examination. Lymph node metastasis in pelvic cavity, retroperitoneal region and inguinal region was also detected. For patients without surgical treatment, it can be used to delineate the target area of radiotherapy, monitor the efficacy during treatment, evaluate the efficacy at the end of treatment and follow up after treatment.

3. Abdominal and pelvic CT:

CT soft tissue resolution is low, and the density of plain scan lesions is similar to that of normal cervix, especially for early cervical cancer limited to the cervix; The contrast of enhanced CT is better than that of plain CT, but nearly 1/2 of the lesions are isodense and difficult to define the scope. The advantages of CT mainly lie in displaying the middle and late stage lesions, evaluating the relationship between cervical lesions and surrounding structures (such as bladder, rectum, etc.), lymph node metastasis, and whether other organs in the abdominal and pelvic cavity have metastasis in a large range of scans. CT examination can be selected for patients with MRI contraindications.

4. Chest radiography and chest CT examination

The main purpose is to exclude lung metastasis and mediastinal lymph node metastasis. Chest radiographs can only exclude obvious lung metastasis, and mediastinal lymph nodes cannot be evaluated. Therefore, hospitals with conditions should perform chest CT examination.

5. Nuclear medical imaging examination

Positron emission computed tomography (PET-CT) is not recommended to evaluate the local invasion of cervical cancer, but PET-CT is recommended for the following conditions:

(1) The FIGO stage is the pre treatment stage for patients with stage Ⅰ B1 and above first diagnosis (including patients with stage Ⅰ B1 needs to retain fertility function);

(2) If cervical cancer is found unexpectedly by simple hysterectomy due to other reasons, the patient will be evaluated as a whole body;

(3) The target area of radiotherapy should be delineated with the aid of image;

(4) Follow up monitoring 3 to 6 months after treatment for patients with high risk factors;

(5) Patients suspected of recurrence and metastasis during follow-up, including clinical symptoms or elevated tumor markers. Radionuclide bone scanning is only used for patients with suspected bone metastasis.

6. Endoscopy

Cystoscopy and rectoscopy: Patients suspected of bladder or rectum invasion in clinical practice should undergo corresponding endoscopic examination. Units without conditions shall be transferred to superior hospitals for treatment.

（6） Tumor marker examination.

Abnormal increase of tumor markers can assist in diagnosis, efficacy evaluation, disease monitoring and follow-up monitoring after treatment, especially in follow-up monitoring. Squamous cell carcinoma associated antigen is an important marker of cervical squamous cell carcinoma. Because squamous cell carcinoma is the most common type of cervical cancer, squamous cell carcinoma associated antigen is the most frequently detected serological tumor marker in the diagnosis and treatment of cervical cancer. Cervical adenocarcinoma may have elevated carcinoembryonic antigen, carbohydrate antigen 125 or CA19-9.

5、 Classification and staging of cervical cancer

（1） Histological classification of cervical carcinoma.

Cervical carcinoma mainly includes cervical squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma and other rare types. Among them, squamous cell carcinoma is the most common, accounting for about 80%, and adenocarcinoma accounts for 15%~20%. With the development of the general survey of cervical cancer, the incidence and mortality of cervical squamous cell carcinoma have shown a downward trend, but the incidence of adenocarcinoma has shown an upward trend in the past 30 years. The prognosis of squamous cell carcinoma is the best among various pathological types, while that of cervical adenocarcinoma and adenosquamous carcinoma is relatively poor, and this difference is more obvious in advanced patients. At present, the pathological type of cervical cancer mainly refers to the pathological classification published by the World Health Organization (WHO, 2014)

Epithelial tumours

Squamous tumours and precursors

Squamous cell carcinoma, not otherwise specified 8070/3

Keratinizing 8071/3

Non-keratinizing 8072/3

Basaloid 8083/3

Verrucous 8051/3

Warty 8051/3

Papillary 8052/3

Lymphoepithelioma-like 8082/3

Squamotransitional 8120/3

Early invasive (microinvasive) squamous cell carcima 8076/3

Squamous intraepithelial neoplasia

Cervical intraepithelial neoplasia (CIN 3) 8077/2

Squamous cell carcinoma in situ 8070/2

Benign squamous cell lesions

Condyloma acuminatum

Squamous papilloma 8052/0

Fibroepithelial polyp

Glandular tumours and precursors

Adenocarcinoma 8140/3

Mucinous adenocarcinoma 8480/3

Endocervical 8482/3

Intestinal 8144/3

Signet-ring cell 8490/3

Minimal deviation 8480/3

Villoglandular 8262/3

Endometrioid adenocarcinoma 8380/3

Clear cell adenocarcinoma 8310/3

Serous adenocarcinoma 8441/3

Mesonephric adenocarcinoma 9110/3

Early invasive adenocarcinoma 8140/3

Adenocarcinoma in situ 8140/2

Glandular dysplasia

Benign glandular lesions

Müllerian papilloma 8560/3

Endocervical polyp 8015/3

Other epithelial tumours 8015/3

Adenosquamous carcinoma

Glassy cell carcinoma variant

Adenoid cystic carcinoma 8200/3

Adenoid basal carcinoma 8098/3

Neuroendocrine tumours

Carcinoid 8240/3

Atypical carcinoid 8249/3

Small cell carcinoma 8041/3

Large cell neuroendocrine carcinoma 8013/3

Undifferentiated carcinoma 8020/3

Mesenchymal tumours and tumour-like conditions

Leiomyosarcoma 8890/3

Endometrioid stromal sarcoma, low grade 8931/3

Undifferentiated endocervical sarcoma 8805/3

Sarcoma botryoides 8910/3

Alveolar soft part sarcoma 9581/3

Angiosarcoma 9120/3

Malignant peripheral nerve sheath tumour 9540/3

Leiomyoma 8890/0

Genital Rhabdomyoma 8905/0

Postoperative spindle cell nodule

（2） Staging of cervical cancer.

At present, the clinical staging standard of cervical cancer revised at the FIGO 2018 meeting is adopted. The clinical staging was determined by gynecological examination The staging standard in this version has been greatly changed compared with the previous version. First of all, in Phase IA diagnosis, the width of horizontal interstitial infiltration is no longer considered. The new version of the standard only distinguishes Phase IA1 and Phase IA2 according to the depth of interstitial infiltration, mainly considering that the width may be affected by human factors. Secondly, the sub stages of stage Ⅰ and stage B were refined, from the original 2 sub stages to 3 sub stages, which is more conducive to the selection of postoperative adjuvant treatment and prognosis judgment of patients. The last important change is to include lymph node metastasis into the staging system, define lymph node metastasis as stage IIIC, and add evidence labels for lymph node metastasis (r represents imaging findings of lymph node metastasis, p represents pathological confirmation).

Note.— Imaging and pathologic analysis, where available, can be used to supplement clinical findings for all stages. FIGO = International Federation of Gynecology and Obstetrics. (Adapted, under a CC BY license, from reference 1.)

*Indicates stages that are new from the 2009 FIGO system.

† Stage IIIC should be annotated with r (radiology) or p (pathologic analysis) to indicate the method used to allocate this stage. Imaging modality or pathologic technique should also be documented.