The uterus is the organ that nurtures the embryo, the fetus and produces menstruation. At the same time, the uterus is also an organ prone to malignant tumors. Malignant tumors can occur in all parts of the uterus, from the cervix to the body of the uterus, and from the endometrium to the myometrium. Cervical cancer is the most common gynecologic malignancy, and persistent infection with high-risk papillomavirus (HPV) is the underlying cause of cervical precancerous lesions and cervical cancer. The main pathological types are squamous cell carcinoma and adenocarcinoma. Confirmation of diagnosis relies on biopsy of cervical lesions, and the clinical staging of the extent of lesions is determined by FIGO. HPV vaccine has been applied in the prevention of cervical cancer.
Cervical cancer
Cervical cancer is the most common gynecologic malignancy. The incidence and mortality rate of cervical cancer has decreased significantly in the past 40 years due to the widespread use of cervical cytology screening, which has enabled early detection and treatment of cervical cancer and precancerous lesions. In recent years, there is a trend of younger cervical cancer incidence. Human papillomavirus (HPV) infection, especially persistent infection with high-risk types, is currently considered the main cause of cervical precancer and cervical cancer, and other related influencing factors include early childbirth, multiple births, high-risk male partners, and suppression of machine immune function. Screening and diagnosis of cervical cancer
Three-step diagnostic technique
Cervical cancer develops over a long period of time from cervical intraepithelial neoplasia (CIN), so early detection and timely interruption of cervical precancerous lesions is an effective means to reduce the incidence of cervical cancer. The three-step diagnostic technique is a routine diagnostic technique used worldwide specifically for the screening and diagnosis of cervical cancer and its precancerous lesions, including cervical cytology, colposcopy and cervical pathology.
In 1996, the U.S. Food and Drug Administration (FDA) approved an improved filming technique, thin-layer liquid-based cytology, with a view to improving the 50% to 60% false negatives caused by the presence of large numbers of red blood cells, white blood cells, mucus and exfoliated necrotic tissue on traditional Pap smears. Two methods, Thinprep and AutoCyte Prep, are currently available. The sensitivity and specificity of identifying highly diseased cervical lesions can be increased to about 85% to 90%. TBS classification is now overwhelmingly used for the evaluation and reporting of cervical cytology at home and abroad.
Liquid-based thin-layer cytology is a primary screening tool for cervical lesions. Colposcopy is valuable for early detection of cervical cancer and precancerous lesions by observing the epithelial and vascular morphology on the surface of the cervix, vagina and vulva after magnification and acetic acid test to initially determine the nature of the lesions and taking biopsies from severe lesions. Histopathological diagnosis by cervical cytology and colposcopy, multi-point cervical biopsy or cervical conization is the “gold standard” of the three-step diagnostic technique.
Descriptive diagnoses associated with squamous epithelial abnormalities in the TBS report include: atypical squamous cell (ASC), low grade squamous intraepithelial lesion (LSIL), high grade squamous intraepithelial lesion (HISL), squamous cell carcinoma (SCC), atypical glandular epithelium (AGC), atypical glandular epithelial tropism (AGC
favor neoplasia), adenocarcinoma in situ (AIS), adenocarcinoma (ACA). Another important concept in the TBS reporting system – atypical squamous epithelial cells of undefined significance (ASCUS), which are neither diagnostic of infection, inflammation, reactive changes, nor precancerous or malignant squamous epithelial cells, can be used as a minimal indication for colposcopy and High-risk HPV-DNA can be detected on the basis of liquid-based cytology.
HPV testing
Most HPV infections are transient, and only persistent HPV infection leads to cervical cancer, which is divided into two categories, low-risk and high-risk, depending on the viral pathogenicity. Low-risk HPV, such as HPV6, 11, 42, 43, 44, etc., mainly cause external genital warts; the 15 types of high-risk HPV tumor-causing viruses, such as HPV16, 18, 31, 33, 35, etc., mainly cause cervical cancer, vulvar cancer and other malignant tumors, among which HPV16 and 18 are the two most common subtypes causing cervical cancer, HPV16 is closely related to cervical squamous cancer and HPV18 is prone to cause cervical cancer. HPV16 is closely related to cervical squamous cancer and HPV18 is prone to cervical adenocarcinoma.
In 2005, the World Health Organization (WHO) issued a statement that there is sufficient evidence that HPV-DNA testing can be used as a primary screening tool for cervical cancer and can reduce the incidence and mortality of cervical cancer. Combining some studies in recent years, there are several insights into the role of HPV-DNA testing in clinical practice: ① Further determination of atypical squamous epithelial cells/glandular cells of unclear significance (ASCUS/AGUS) is an effective reclassification method to effectively detect cervical intraepithelial neoplasia from cytologic results of ASCUS/AGUS, reducing colposcopic number of patients with definite cervical precancerous lesions by subsurface biopsy. (②Predict the risk level of the subject based on the type of HPV infection and determine their screening interval. For those who are cytology negative but high-risk HPV positive, the risk level is higher and they should be followed up regularly; for those who are negative for both, the risk level is lower and the screening interval can be extended appropriately. ③ Monitoring of cervical precancerous lesions and after cancer treatment. High preoperative HPV load and still persistent postoperative HPV infection, especially type 16/18, are high-risk factors for cervical precancer and cervical cancer recurrence. Therefore, HPV testing is important for postoperative follow-up.
Screening for cervical cancer with HPV testing should vary by population. Younger women are sexually active and have a high rate of viral infection, but it is usually transient, so HPV-DNA testing is most effective in women at higher ages (>30 years). More work is needed on the current cost-benefit analysis of HPV testing and its ability to become a more rational screening tool to ultimately reduce cervical cancer incidence and mortality.
Cervical cancer FIGO 2009 New clinical staging
The updated clinical staging by the International Federation of Gynecology and Obstetrics (FIGO) in 2009 has two main changes: (i) Stage 0 has been eliminated. ② Stage IIA is subdivided into IIA1 tumor diameter ≤ 4.0 cm and IIA2 tumor diameter > 4.0 cm.
The application of imaging examination in cervical cancer
Magnetic resonance imaging (MRI) plays an important role in the diagnosis, staging, treatment planning and efficacy evaluation of cervical cancer because of its high tissue resolution and multi-directional and multi-sequence imaging.
The sagittal plane of MRI can not only show the whole cervical and uterine body, but also clarify their relationship with vagina and bladder, which can show whether cervical cancer invades vagina and uterine body, and has greater value in determining whether bladder and rectum are invaded; the cross-sectional plane is good for showing parametrial tissues, which is good for observing the invasion of tumor into the cervical part, parametrium, adjacent organs and pelvic wall, as well as the invasion of pelvic lymphatic cavity. The coronal plane is good for displaying the cervix, lateral wall of uterus and vaginal vault, which can directly show the relationship between tumor and surrounding tissues and the exact size and location of the lesion. Transverse and sagittal T2W TSE is the most important scan sequence for the diagnosis of cervical cancer, and the results are reliable.
PET, known as positron emission tomography (PET), is a device that reflects the genetic, molecular, metabolic and functional status of the lesion. CT (Computed Tomography) is an X-ray tomography technique. It can clearly obtain the anatomical structure information of the lesion. At that time, it was difficult to make accurate judgments on the nature of some lesions, such as the benignity and malignancy of tumors and the recurrence of tumors after surgery, and could not accurately reflect the physiological metabolic status of the disease.
PET-CT can detect early tumors as small as 3mm.
The 2012 National Comprehensive Cancer Network (NCCN) guidelines for cervical cancer point out that the role of imaging, especially PET-CT, in pre-treatment evaluation should be emphasized, and in the United States, PET-CT is almost routinely done before treatment for patients with stage IB1 or higher. However, in China, due to its very expensive examination cost, PET-CT has not become a routine examination for cervical cancer, and is mainly used for the evaluation of advanced stage and recurrent disease.
2 Treatment of cervical cancer
Appropriate individualized treatment plan is formulated based on clinical stage, patient’s age, fertility requirements, general condition, medical technology level and equipment conditions. A comprehensive treatment plan based on surgery and radiotherapy, supplemented by chemotherapy, is adopted.
2.1 Surgical treatment
2.1.1 Surgery for early cervical cancer According to Piver Rutledge surgical staging, the types of surgery for early cervical cancer can be divided into the following three categories, namely: ①Type I Extrafascial Hysterectomy. ②Type II hysterectomy or subextensive hysterectomy (Modified Radical Hysterectomy, i.e. Wertheim’ surgery). (iii) Type III hysterectomy or extensive hysterectomy (Radical
Hysterectomy, i.e. Meigs’ surgery). The surgery is mainly indicated for patients with cervical cancer before stage IIa. The surgical routes include transabdominal, transvaginal and laparoscopic routes.
2.1.2 Surgery to preserve reproductive function: extensive cervical resection Extensive cervical resection preserves the body of the uterus, with extensive excision of the cervix and paracervical tissue and the upper third of the vagina. 80% of the cervix is removed and the residual cervical mesenchyme is anastomosed to the vaginal mucosal margin. The available data suggest that extensive hysterectomy is a feasible procedure to preserve fertility, but there is still a lack of evidence at the primary level of evidence-based medicine and it is not the standard of care at this time.
The surgical approach is transvaginal with laparoscopic pelvic lymphadenectomy followed by extensive cervical hysterectomy via the vagina. In open cases, both pelvic lymphadenectomy and extensive hysterectomy are performed via the abdomen. It is also possible to perform the entire procedure laparoscopically.
A careful clinical examination of all patients should be performed before surgery, applying palpation, visualization, colposcopy, endocervical scraping, CT, MRI, etc. for accurate clinical staging. In addition to strict indications for the procedure, the following conditions must also be met in order to perform the procedure: (i) Preservation of fertility is required. ②No clinical evidence of infertility and age <40 years. The indications are generally considered to be stage Ia with vascular infiltration and stage Ia2~Ib1 tumor diameter <2 cm.
③No endocervical canal invasion. ④No evidence of lymph node metastasis on CT, MRI. ⑤ Fully explain the surgical approach and prognosis to the patient and sign the informed consent form.
Some complications may occur after extensive hysterectomy, such as infertility, cervical adhesions, accumulation of blood in the uterine cavity leading to periodic lower abdominal pain, miscarriage or preterm delivery; if stillbirth occurs after 20 weeks, a cesarean section is required to retrieve the fetus and many other problems, which need to be fully communicated with the patient and family members who agree to take the risk. Extensive hysterectomy for adenocarcinoma has limited information, but is not a contraindication.
2.1.3 Surgery for recurrent cervical cancer: pelvic contouring The surgical indication for total pelvic contouring is a patient who has developed a central recurrence after radiotherapy or surgery combined with radiotherapy without finding distant metastases. The entire bladder, uterus, rectum, vagina, and sometimes even part of the vulvar tissues need to be removed during surgery. The scope of surgery needs to be determined according to the extent of recurrence and the location of the lesion. This procedure can be divided into anterior pelvic contouring, which requires removal of the patient’s bladder, and posterior pelvic contouring, which requires removal of the rectum. In the treatment of central recurrence of cervical cancer, total pelvic contouring is the most commonly used procedure. The 5-year survival rate of patients after surgery has been reported to be 40%, with 5-year survival rates ranging from 18% to 70% in different reports. Although total pelvic contouring is rarely used now that radiotherapy is available for stage IV-A cervical cancer, it is still the procedure of choice.
Reconstruction is a part of total pelvic dissection in which the urethra is reconstructed and the intestinal canal (ileum, transverse colon, and sigmoid colon) is chosen as the lumen to drain the urine, and muscle flaps (rectus abdominis or femoralis), colon (rarely used), or omentum are used during vaginal and pelvic reconstruction. Depending on the extent of resection of the tumor location, anastomosis of the rectum and colon can be performed above the plane of the anal raphe or a permanent colostomy can be performed.
Pelvic contouring is an extremely invasive surgical procedure and should only be used in patients with local recurrence. Pelvic wall invasion, distant metastases, and hydronephrosis are contraindications to total pelvic contouring. Despite adequate preoperative evaluation, 25% to 50% of patients undergoing this procedure are unable to complete it due to the discovery of tumor metastases and locally advanced lesions. A very important aspect of the preoperative period is to adequately assess the physical, psychological and social status of the patient. It is essential to inform the patient what the outcome will be after undergoing this procedure and the patient must be made aware of the consequences of the procedure. Perioperative complications include bleeding, infection, cardiopulmonary complications, gastrointestinal fistula, urinary fistula, fistula formation, intestinal obstruction, and flap necrosis. Sexual dysfunction and psychosocial disorders are distant postoperative complications that may persist over time. Even after adequate patient selection, surgical mortality can reach 5%.
2.2 Radiation therapy
In 1898, Wertheim performed extensive hysterectomy + pelvic lymphadenectomy for cervical cancer. In the same year, the Curie couple discovered radium and soon used it in the treatment of cervical cancer. The results of radium treatment were so good that surgery was halted for a time. In the 1920s, external irradiation was used for cervical cancer treatment, which further improved the efficacy.
2.2.1 Types of radiotherapy techniques ① Conventional radiotherapy: conventional positioning and treatment methods, conventional/near-conventional segmentation dose, two-dimensional thinking and calculation of the control target area for dose prediction. Conventional radiotherapy still has about 30% of patients who are not cured, and about 20%-30% of patients have post-radiotherapy complications, including about 10%-20% of radioactive proctitis and 3%-5% of radioactive cystitis. ②Precision Radiotherapy: including Stereotactic Radiotherapy (SRT) and Intensity modulated Radiotherapy (IMRT). Intensity modulated radiotherapy belongs to the category of precision radiotherapy, which is a treatment method integrating clinical radiotherapy, medical image processing technology, computing technology, gas pedal engineering technology, etc. It is one of the milestones in the progress of radiotherapy technology. The main disadvantages of conventional radiotherapy are that it cannot confine the radiation to the tumor area, the irradiation gain is relatively low, the single irradiation dose is not high, and the local control ability of the tumor is poor. In some cases, the tumor target area itself contains sensitive normal tissues that are difficult to treat using conventional radiotherapy. By adjusting the intensity distribution in multiple irradiation fields, a highly conformal three-dimensional dose distribution of the target area can be obtained, thus achieving the purpose of increasing the target area dose and improving the treatment gain ratio without increasing or even decreasing the dose to the surrounding normal tissues.
2.2.2 Radiotherapy methods ① Preoperative radiotherapy aims to shrink the local tumor, reduce the vitality of the tumor, avoid tumor spread during surgery and reduce the chance of local recurrence. Intracavitary radiotherapy is mainly used for: large ectopic tumors of the cervix; stage IIa vaginal invasion; mucinous adenocarcinoma, squamous adenocarcinoma, clear cell carcinoma; pathological grade II or above, and the dose should be 1/3 to 1/2 of the full amount of intracavitary radiotherapy, and surgery should be performed within 4-6 weeks after the completion of radiotherapy. Intraoperative Radiation Therapy (IORT): Although IORT has been carried out earlier in foreign countries, it has just started in China. It is mainly used for primary advanced or recurrent cervical cancer with poor response to chemoradiotherapy before surgery, but not for patients with distant metastases (metastasis in the lymph nodes adjacent to the abdominal aorta is not an absolute contraindication). The characteristic of intraoperative radiotherapy is that a high dose (10-25Gy) can be directly irradiated to the dangerous areas that are prone to recurrence after tumor resection, while the surrounding normal tissues or organs can be excluded or shielded from the irradiation field to the maximum extent, which is helpful to improve the resection rate and local control rate of surgery. (iii) Postoperative radiotherapy to supplement surgical deficiency, mainly using intracavitary brachytherapy, is indicated for those without lymph node metastasis but combined with the following high-risk factors such as large primary tumor size, deep interstitial infiltration and/or lymphovascular interstitial infiltration. Lymph node positive and/or margin positive and/or parametrial infiltration need to be supplemented with pelvic radiotherapy; due to the anatomical variation and tissue adhesions caused by surgery which add difficulties to postoperative radiotherapy, gastrointestinal imaging should be performed before radiotherapy to understand the relationship between the tumor and surrounding organs, especially with the intestine, in order to select the most appropriate treatment plan. It can be performed 2 weeks after surgery. ④Radical radiotherapy is adapted to the treatment of patients with stage IIb or above.
2.3 Chemotherapy
2.3.1 Indications for chemotherapy ①Advanced, extensive systemic metastasis cases. ②Pre-operative chemotherapy for locally huge tumor. ③Middle and late stage cervical cancer with radiotherapy for sensitization. ④Adjuvant chemotherapy after surgery for cervical cancer with high-risk factors, which include: retroperitoneal lymph node metastasis; hypofractionated and tumor diameter ≥2
These high-risk factors include: retroperitoneal lymph node metastasis; hypofractionated and tumor diameter ≥2 cm; vascular involvement; postoperative pathological examination reveals tumor diameter of 4 cm. ⑤ Histopathological types with high malignancy: clear cell carcinoma, small cell carcinoma and undifferentiated carcinoma.
2.3.2 Chemotherapy regimens include carboplatin + paclitaxel, cisplatin + paclitaxel, cisplatin + topotecan, cisplatin + gemcitabine; the available first-line single agents are cisplatin (preferred), carboplatin, and paclitaxel. The recommended second-line therapeutic agents are bevacizumab, polyene paclitaxel, 5-Fu, gemcitabine, isocyclophosphamide, irinotecan, mitomycin, topotecan, pemetrexed, and vincristine.
2.4 Targeted therapy
Traditional treatment methods have not achieved satisfactory results in some cases, especially in patients with locally advanced, metastatic and recurrent cervical cancer; therefore, more and more research has focused on targeted therapy for cervical cancer, and molecular targeted therapy has become the future development trend. The following targeted therapeutic agents are currently being studied.
2.4.1 Epidermal growth factor receptor antagonist (EGFR) EGFR, also known as HER-1, is a member of the tyrosine kinase growth factor receptor family and belongs to the type I tyrosine kinase receptor subfamily (ErbB1-4) with tyrosine kinase activity. EGFR is overexpressed in many human solid tumor tissues, including cervical cancer, and EGFR mediates multiple cell blades through EGFR is overexpressed in many human solid tumor tissues, including cervical cancer, and EGFR mediates multiple cellular edges by mediating EGFR. Herceptin)], cetuximab [Cetuximab (IMC-C225, Ebitus)], etc.; small molecule compounds mainly include Gefitinib [Gefitinib (Eressa, Iressa, ZD1839)], Imatinib [ Imatinib (Glivec, Glivec, STI51)] and Erlotinib [ Erlotinib (Tarceva, OSI-774)], etc.
2.4.2 Vascular endothelial growth factor (VEGF) VEGF is a multifunctional cytokine that is secreted by different tumor cells and can also be expressed in developing normal cells and tissues. It is a potent vascular permeability inducer and a member of the cystatin growth factor superfamily that plays a key role in tumor angiogenesis, and its structural and biological characteristics are important for tumorigenesis, tumor metastasis and prognosis, and is an important target for angiogenesis inhibition therapy. There are the following;
Alpha interferon (INF-α): INF-α is a cytokine, a group of structurally similar and functionally similar low-molecular glycoproteins produced by host cells through antiviral response when the body is infected with virus. INF-α can significantly inhibit TNF-α-induced expression of nuclear factor kB (NF-kB) in cervical cancer HeLa cells and enhance T NF-α-induced apoptosis in HeLa cells. The effect of The use of recombinant IFN-α for the treatment of cervical malignancies can directly inhibit the growth of cervical cancer cells and may achieve tumor suppression by inhibiting the molecular mechanism of HPV-16E6 and E7 gene expression, which can be used as a sensitizer for cervical cancer radiotherapy, and more randomized controlled clinical trials are still needed to confirm the research in this field.
Zoledronic acid (ZA): matrix metalloproteinase-9 (MMP-9) is a pro-angiogenic protease secreted by tumor-infiltrating macrophages, whose function involves the activation of VEGF and appears in the extracellular mesenchyme along with the initiation of angiogenic mechanisms. preclinical trials targeted MMP-9 and neovascularization by typical MMP inhibitors and its diphosphate compound zoledronic acid, typical MMP Both the typical MMP inhibitor and ZA turned off the angiogenic switch, inhibited precancerous lesion progression and suppressed tumor growth, an effect that was equipotent with knockdown of MMP-9. ZA increased apoptosis of tumor epithelial and endothelial cells, but had no effect on proliferation, suggesting that ZA does not possess antimitotic activity. Regarding the possible cellular and molecular mechanisms of action of ZA, ZA reduces VEGF and its receptor-associated tumor vascular endothelial cell generation by inhibiting the expression and suppressing the activity of MMP-9 in tumor-infiltrating macrophages, and can be used as an anti-angiogenic agent targeting MMP-9 given that it was found to have a small toxic response in clinical applications.
Bevacizumab (Avastin, rhuMAb-VEGF): is a humanized monoclonal antibody IgG1 that inhibits angiogenesis by inhibiting VEGF
Biological activity inhibits angiogenesis, and bevacizumab monotherapy or in combination with other chemotherapeutic agents can reduce tumor angiogenesis.
Sunitinib: Sunitinib is an oral multi-targeted tyrosine kinase inhibitor that inhibits VEGF-R2, -R3
It inhibits the tyrosine kinase activity of VEGF-R2, -R3 and -R1 and platelet-derived growth factor (PDGFR-b), KIT, FLT-3 and RET, and achieves antitumor effects by specifically blocking these signaling pathways.
2.4.3 The ET axis is composed of endothelin ET-1, ET-2, ET-3 and their receptors ET(A)R and ET(B)R, which are expressed in a variety of cells and tissues. ET-1 plays an important role in physiological and pathophysiological processes, including histogenesis, cell proliferation, apoptosis and angiogenesis, and is mediated by ET(A)R. Activated ET(B)R prevents apoptosis, inhibits ECE expression and regulates ET-1 clearance in tissue cells. The activation of intracellular signaling pathways caused by ET-1 activation of ET(A)R in cervical cancer tissues is a key mechanism of tumorigenesis and progression. inhibitors of the ECE).
3 Prevention of cervical cancer
In June 2006, the U.S. FDA officially approved the marketing of HPV vaccine for cervical cancer prevention, which is the world’s first tumor vaccine and a milestone in the fight against cancer. 2008, the vaccine has been approved for use in more than 100 countries worldwide. The two HPV vaccines approved by the FDA have not yet been approved in China, and the development of a domestic HPV vaccine is underway. HPV vaccines are also working to expand their indications due to the relationship between HPV infection and more than 20 types of tumors, including vulvar, penile, and anal cancers.
Vaccines include both prophylactic and therapeutic vaccines. The HPV vaccine is classified by the FDA as a Class B drug, but is not recommended for use in women during pregnancy. Prophylactic vaccines take 10 to 20 years to show definite results. Since the HPV vaccine has been in use for less than 10 years, the long-term effects have yet to be proven.