I. Concept of cervical carcinoma in situ
Cervical carcinoma in situ is a progression from cervical intraepithelial neoplasia and is included in the classification of severe atypical hyperplasia or CIN III, which refers to when the cancer cells occupy the whole or near whole layer of the epithelium and have not yet penetrated the epithelial basement membrane to invade the underlying lamina propria. The heterogeneous cells of cervical carcinoma in situ have more significant pleomorphism than those with atypical hyperplasia at all levels, and the epithelial layer is completely replaced by cancer cells, with cells of different sizes, shapes, disorderly arrangement, unclear hierarchy, and disappearance of polar orientation. The nuclei were large and densely stained, the nucleoplasm ratio increased, the cell membrane, intercellular bridges and cell boundaries were unclear, and nuclear fission images were scattered throughout the layer, and pathological nuclear fission images were seen.
Carcinoma in situ of the uterine cervix can spread from the surface along the periphery of the endocervical glands, encircle the ducts, and even replace part or all of the columnar epithelium, and sometimes the cancer cells can also invade the glandular lumen and fill it up.
The epithelial package of the uterine cervix is divided into squamous epithelium and columnar epithelium, so cervical carcinoma in situ actually includes two types: squamous carcinoma in situ and adenocarcinoma in situ of the uterine cervix. The incidence of adenocarcinoma in situ of the cervix is reported to be less than 1%, so this section focuses on the diagnosis and treatment of squamous carcinoma in situ of the cervix.
Etiology of cervical carcinoma in situ
There are few studies specifically on the etiology of cervical carcinoma in situ, which are mostly combined with CIN or invasive carcinoma of the cervix.
1.Population and geographical related factors
Similar to the incidence factors of cervical invasive carcinoma, the geographical distribution of the incidence of cervical carcinoma in situ and CIN has certain characteristics. Globally, the low incidence rate is in Europe, and the incidence rate is higher in developing countries. Among them, the lowest incidence rate is in the Ardabil area in northwestern Iran, which may be related to the level of economic development, sanitary conditions and religious beliefs in the area.
There is a lack of uniform survey data in China, and it is currently found that the incidence is more concentrated in the central and western regions of China and some coastal areas. There is also a correlation between occupation and socioeconomic status, with HPV infection being more prevalent in women with low education and low income, and the onset of CIN/CIS.
The age of onset of patients has a different distribution from that of cervical invasive carcinoma. The peak age of onset of cervical carcinoma in situ is 30-34 years old, which is 20 or more years earlier than that of cervical invasive carcinoma. This age distribution characteristic reflects that patients with cervical carcinoma in situ need a period of progression after exposure to the onset factors before they can develop into cervical invasive carcinoma.
2.HPV infection and other biological factors
There is a consensus on the relationship between HPV infection and cervical cancer, that is, high-risk HPV infection can lead to the development of cervical cancer, so HPV infection and cervical cancer in situ are closely related. Among them, horizontal transmission is through direct sexual contact, which is the main influencing factor of oncogenic HPV transmission. Vertical transmission refers to mother-to-child transmission. It has been found that at least 30% of HPV-positive mothers transmit the infection to their infants through vertical transmission, leading to persistent infection in children.
The incubation period of HPV infection is an unstable period, with an average incubation period of 1-8 months. During the initial years of infection, most women experience regression and clearance of symptoms. When there is severe cell-regulated immune damage, it can contribute to massive HPV replication, followed by the gradual appearance of large amounts of viral DNA in the nuclei of superficial and intermediate cells, thus increasing the likelihood that the individual will develop new or repetitive damage. The most common clinical manifestations of persistent HPV infection in the reproductive tract are warts, high levels of CIN/CIS, and cervical cancer, so most scholars agree that persistent infection with a particular type of HPV is critical to the development of CIN/CIS.
In addition, some scholars have studied and found that some other biological factors may also influence the development of CIN/CIS. Chlamydia trachomatis infection was found to increase the risk of cervical cancer by 2 or 5 times; the presence of herpes simplex virus-II in women with high-risk HPV infection increased the risk of cervical squamous cancer by 2 or 19 times; thus suggesting that herpes simplex virus-II is a synergistic factor in the development of cervical cancer due to high-risk HPV infection. It is also believed that infection with mycoplasma and trichomonas can also promote the development of cervical cancer.
3.Behavioral factors
There are several behavioral factors related to the development of cervical cancer.
(1) Sexual behavior: A large number of epidemiological studies have confirmed that factors such as early sexual life, multiple sexual partners and sexual confusion increase the risk of cervical cancer.
(2) Oral contraceptive pills: The relationship between oral contraceptive pills and cervical lesions was once controversial. Some scholars believed that it might be because oral contraceptive pills reduce the use of contraceptives, which artificially increases the chance of HPV transmission and therefore increases the chance of cervical lesions accordingly. Later, some scholars further studied that after excluding HPV infection, oral contraceptives still increased the chance of cervical lesions, and the analysis suggested that oral contraceptives may work through two links: one is to artificially increase the level of estrogen in women, which may cause HPV DNA to integrate into the host’s genome and contribute to the malignant transformation of cervical lesions; the other is that oral contraceptives may increase the chance of cervical lesions during sexual intercourse. Another aspect is that the contact of sexual organs in oral contraceptive users may increase the chance of HPV infection.
(3) Multiple pregnancies and multiple births: Multiple pregnancies and multiple births affect changes in hormone levels in women, delaying the body’s immune response to HPV infection and further affecting the progression of persistent HPV infection or cervical lesions. Another mechanism is related to the body’s post-injury repair. Multiple pregnancies and multiple births increase the chance of cervical injury, which increases the chance of repair errors during the body’s repair process, leading to cervical lesions.
(4) Smoking: Smoking as a synergistic factor of HPV infection can increase the risk of cervical cancer. Nicotine and other carcinogenic components in tobacco can be detected in the cervical mucus of smokers, which directly increases the chance of cancer; in addition, some scholars believe that smokers have an open mind and a higher chance of persistent HPV infection.
Pathological characteristics of cervical carcinoma in situ
The basic pathological characteristics of squamous carcinoma in situ of the uterine cervix are that the cancer cells are confined to the epithelium, the basement membrane is intact, and there is no interstitial infiltration.
(i) Disordered cell arrangement with no polarity.
(ii) Large cell nuclei with increased nucleoplasmic ratio.
(iii) large nuclear heterogeneity with different shades of staining.
④heterogeneous nuclear schizophrenic phase is common and can be found in the epithelial lattice. It is very common for in situ carcinoma to involve the gland, but it still has the characteristics of intact basement membrane without mesenchymal infiltration.
Pathological features of adenocarcinoma in situ of the uterine cervix.
(i) It often occurs in the vicinity of the migrating zone of the lower part of the cervical canal.
(ii) It may also be confined within a single cervical canal mucosal polyp.
(3) It may involve groups of glandular structures or a single gland that grows buddingly into the interstitium, causing sieve-like changes in the gland, and papillae composed of epithelial cells may also penetrate into the gland or protrude from the surface of the cervical canal, but are not infiltrative.
(4) Adenocarcinoma in situ consists of pseudostratified columnar epithelium.
There is now further understanding about the pathological features of carcinoma in situ. Most scholars believe that the integrity of the basement membrane is not a reliable indicator to distinguish infiltrating carcinoma from carcinoma in situ, because both value-added basement membrane cells and inflammatory cells can disrupt the basement membrane, which can disappear around benign epithelial pedicles, while intact basement membrane can be seen at the margins of infiltrating carcinoma. The important feature is now considered to be the interstitial reaction, which is an important indicator to distinguish in situ carcinoma from infiltrating carcinoma. The interstitial fibrous tissue around the infiltrating lesion appears lax, with fibrous contraction breaks and interstitial stromal alterations. Due to the stromal alterations, there is a certain degree of basophilia on HE-stained sections, with unequal amounts of protoplasmic cell infiltration in the interstitium; whereas in carcinoma in situ, there are no interstitial alterations around the lesion, although there is an obvious inflammatory cell reaction in cocoa. In addition to interstitial changes, the morphology and arrangement of tumor cells are also of reference value.
4.Diagnosis of cervical carcinoma in situ
The diagnosis of cervical carcinoma in situ follows the three-step procedure of cervical cancer diagnosis, namely cytological examination, colposcopy-guided cervical tissue biopsy to cervical conization diagnosis.
Since 1941, vaginal cervical exfoliation cytology has become the preferred tool for cervical lesion screening because of its simplicity, cost-effectiveness and repeatability. The correct rate of cervical exfoliation cytology fluctuates, and there are some false positives and false negatives. The correctness of the diagnosis is related to the site and method of sampling and the technique of production. The more commonly used and recommended method is liquid-based thin-layer cytology, which can reduce the interference of impurities, blood and other factors and improve the correct diagnosis.
Colposcopy is an important auxiliary diagnostic method to diagnose CIN and early cervical cancer. Colposcopy can detect the more hidden lesions and improve the detection rate. Biopsy under the guidance of colposcopy can greatly improve the accuracy of blind biopsy. If the cytological diagnosis and colposcopy results are inconsistent, cervical scraping can also be performed if necessary to clarify the possibility of a cervical canal lesion.
Cervical conization Cervical conization is a very traditional diagnostic method, which was once neglected due to the widespread use of colposcopy. After continuous clinical practice, it was found that colposcopy-guided cervical biopsy still has its limitations. The literature reports that the correct diagnostic rate of colposcopy-guided cervical biopsy is 75% to 90%, which is related to the limitations of the examination technique itself, in addition to the experience and quality of the examiner. Nowadays, the use of cervical conization is more commonly used due to the promotion of Leep technology
In conclusion, due to the characteristics of cervical lesions, most cases can be diagnosed promptly and accurately. It should be emphasized that the diagnosis of cervical carcinoma in situ is based on the pathological diagnosis of cervical conization. Therefore, strictly speaking, the diagnosis of cervical carcinoma in situ obtained by colposcopy-guided cervical biopsy is not very reliable, and the diagnosis after cervical conization is more credible.
V. Treatment of cervical carcinoma in situ
The treatment of cervical carcinoma in situ depends on the patient’s wishes, age, fertility requirements, compliance, follow-up conditions, and the equipment and technical conditions of the hospital where the patient is seen. At present, most scholars advocate that the treatment of cervical carcinoma in situ should be excisional surgery, choosing cervical conization surgery or hysterectomy surgery.
1.Cervical conization
Cervical conization is both a reliable diagnostic method and an effective treatment means, so it is the preferred method for the treatment of cervical carcinoma in situ. If the pathological examination result after cervical conization is confirmed as in situ cancer, hysterectomy can be performed after follow-up or 4-6 weeks; if the pathological result is invasive cancer, effective treatment measures need to be taken early according to specific conditions. The common methods of cervical conization include cold knife conization, laser conization and LEEP conization. During the conization procedure, attention needs to be paid to.
(i) The procedure should be performed under iodine staining or colposcopy to clarify the extent of the lesion.
(ii) The extent of resection should include the abnormal lesion seen colposcopically, the entire transformation zone, the entire squamocolumnar junction and the lower part of the cervical canal, not exceeding the endocervical opening.
③The width of resection is 0,5 cm outside the lesion, and the cone height extends to 2-2,5 cm of the cervical canal. when the lesion is on the surface of the cervix, the cone cut should be wide and shallow, if the lesion involves the cervical canal, the cone cut should be narrow and deep to avoid leaving the lesion behind. Also need to pay attention to the age of the patient, the resection should be deep for elderly women with squamocolumnar junction moving into the cervical canal, and shallow for pregnant women with squamocolumnar junction moving outward.
④ Conization samples need to be examined in detail and comprehensively and marked if necessary.
⑤ If hysterectomy is required after cervical conization, an interval of 4-8 weeks should be appropriate.
The complications after cervical conization are mainly bleeding, infection, cervical stenosis and cervical insufficiency.
2. Hysterectomy
Hysterectomy is the removal of the entire uterus including the cervix. Patients with cervical carcinoma in situ should be able to undergo total hysterectomy if they do not have fertility requirements. Hysterectomy can be performed directly or after cervical conization, and the latter is recommended. If direct surgery is chosen, a detailed colposcopic evaluation is necessary. Whether total hysterectomy requires removal of the vagina is still debated. Most scholars now believe that in principle, extrafascial hysterectomy should be performed, and since approximately 2-3% of lesions in CIS involve the vaginal vault, vaginal resection should be 0,5 cm, and if the lesion involves the vagina, hysterectomy should be expanded.
3. Management of CIS during pregnancy
CIN lesions in pregnant women can regress in 75% of patients after delivery, so conservative observation is advocated. Since cytologic changes during pregnancy can return to normal at 6 weeks postpartum, the review should be started again at 6 weeks postpartum and treated according to non-pregnancy principles. For pregnant women with CIN III/CIS, the decision should be based on the number of weeks of pregnancy and the urgency of the patient’s fetal requirements. In principle, termination of pregnancy is not necessary and no special treatment is required, and close follow-up, including colposcopic biopsy if necessary, is mandatory. Diagnostic conization should be performed only when infiltrating carcinoma is suspected. Although most scholars believe that conization during pregnancy is safe, the depth of conization should not exceed 1 cm, and if the pathology is still diagnosed as carcinoma in situ after conization, it can be followed up until 6 weeks after delivery.
4.Special treatment If patients diagnosed with CIS are combined with serious diseases and there are contraindications for surgery, intracavitary radiotherapy can be considered.
Follow-up of cervical carcinoma in situ
Follow-up after treatment of cervical carcinoma in situ is very important. Although the risk of recurrence or invasive cancer is reduced after treatment, it is still much higher compared with the general population. The first review is usually performed 3-6 months after surgery to determine the follow-up plan. The more common method of follow-up is cytology-based, with colposcopy considered if available, once every 4-6 months, with repeat cytology for a full 2 years, and then once a year.
Following successful treatment, the clearance rate of cervical HPV infection is high; therefore, HPV DNA testing can be used as one of the follow-up tests. To provide sufficient time for clearance of HPV infection, HPV DNA testing should be started again 6 months after treatment.
After many years of treatment, recurrent lesions or the development of cervical invasive cancer may also occur, so follow-up should be at least 10 years and preferably lifelong.