Cervical cancer

Cervical cancer rarely appears on the background of unchanged epithelium. This disease is naturally preceded by dysplasia and / or pre-invasive cancer. Cervical cancer is the third most common malignant neoplasm in women worldwide, and it remains the leading cause of death in women in developing countries.

[1], [2], [3],

Epidemiology

Deaths from cervical cancer are declining year by year, but in developing countries the disease continues to result in the death of 46,000 women aged 15-49 years, and about 109,000 at the age of 50 years or older each year.

[4], [5],

Causes of the cervical cancer

Human papillomavirus (HPV) is the main cause of cervical cancer.

HPV is a heterogeneous group of viruses that have closed circular double-stranded DNA. The viral genome is encoded by 6 proteins (E1, E2, E3, E4, E6, and E7) that function as regulatory proteins, and two newly discovered proteins (L1 and L2) that form the viral capsid.

To date, about 115 different genotypes of HPV are known. More than 90% of all cervical cancer cases worldwide are caused by HPV 8 types: 16, 18, 31, 33, 35, 45, 52, and 58. Three types - 16, 18, and 45 in 94% of cases are provoked by cervical adenocarcinoma .

[6], [7], [8], [9], [10], [11]

Risk factors

• Type and duration of papillomavirus infection.
• Weakened immunity (eg, poor nutrition, immunosuppression and HIV infection).
• Environmental factors (eg, smoking and lack of vitamins).
• Poor access to routine screening.
• The early age of the first sexual intercourse and a large number of sexual partners.

Genetic predisposition

Genetic changes in several classes of genes are associated with cervical cancer. The tumor necrosis factor (TNF) is involved in the initiation of cell apoptosis, and the TNFa-8, TNFa-572, TNFa-857, TNFa-863, and TNF G-308A genes are associated with a higher incidence. Polymorphism of the TP53 gene is associated with an increased incidence of HPV infection, which is often transformed into cervical cancer.

The chemokines of the receptor-2 (CCR2) gene on the chromosome 3p21 and the gene on the Fas 10q24.1 chromosome can also influence the genetic predisposition to cervical cancer, possibly violating the immune response to HPV.

The Casp8 gene (also known as FLICE or MCH5) has polymorphism in the promoter region, is associated with a decrease in the risk of cervical cancer.

[12], [13]

Symptoms of the cervical cancer

The most common symptoms of cervical cancer:

• Abnormal vaginal bleeding.
• Vaginal discomfort.
• Unpleasant odor and discharge from the vagina.
• Upset bladder.

Preinvasive cervical cancer (Ca in situ) is a pathology of the integumentary epithelium of the cervix, throughout the thickness of which there are histological signs of cancer, loss of stratification and polarity, there is no invasion of the underlying stroma. Ca in situ is in a state of dynamic equilibrium, it is a "compensated" cancer.

The primary localization of the preinvasive cancer is the boundary between the multilayered planar and cylindrical epithelium (in young women - the area of the external throat, the pre- and postmenopausal periods - the cervical canal). Depending on the characteristics of the structure of cells, two forms of cancer are distinguished in situ - differentiated and undifferentiated. With a differentiated form of cancer, cells have the ability to maturation; for the undifferentiated form, there is a characteristic lack of layering characteristics in the epithelial layer.

Symptoms of preinvasive cervical cancer do not have specific signs. In a number of cases, there are pains in the lower abdomen, bleeding, spotting from the genital tract.

Microinvasive cervical cancer is a relatively compensated and less aggressive form of the tumor, which occupies an intermediate position between the intra-epithelial and invasive cancers.

Microcarcinoma, as well as cancer in situ, is a preclinical form of a malignant process and therefore has no specific clinical signs.

The main symptoms of invasive cancer are pain, bleeding, leucorrhoea. The pains are localized in the area of the sacrum, lower back, rectum and lower abdomen. With a common cancer of the cervix with a lesion of parametric tissue and pelvic lymph nodes, pain can be irradiated to the hip.

Bleeding from the genital tract occurs as a result of damage to easily traumatized small vessels of the tumor (during a sweat act, defecation, lifting of gravity, vaginal examination)

Beli have a serous or bloody character, often with an unpleasant odor; the appearance of whites is due to the opening of lymph vessels during the decay of the tumor.

With the transition of cancer to the bladder, frequent urge and frequent urination are observed. The compression of the ureter leads to the formation of hydro- and pionefrosis, and in the future - the development of uremia. When a tumor of the rectum is damaged, constipation develops, mucus and blood appear in the stool, vaginal and rectal fistulas are formed.

[14], [15], [16], [17]

Stages

• 0 stage - pre-invasive cancer (Ca in situ).
• 1a stage - the tumor is limited to the cervix of the uterus and invasion in the stroma no more than 3 mm (tumor diameter should not exceed 1 cm) - microinvasive cancer
• 1b stage - the tumor is limited to the cervix with an invasion of more than 3 mm
• 2a stage - the cancer infiltrates the vagina, not passing to its lower third and / or spreads to the body of the uterus
• 2b stage - the cancer infiltrates the parameter on one or both sides without moving to the pelvic wall
• Stage 3 - cancer infiltrates the lower third of the vagina and / or there are metastases in the appendages of the uterus, regional metastases are absent
• 3b stage - the cancer infiltrates the parameter on one or both sides to the pelvic wall and / or there are regional metastases in the lymph nodes of the pelvis, and either hydronephrosis and a dysfunctional kidney due to stenosis of the ureter
• IVa stage - cancer sprouts the bladder and / or rectum
• IVb stage - distant metastases outside the pelvis are defined

International classification of cervical cancer by TNM (1989)

T - tumor state

• Tis - carcinoma in situ
• T1 - cervical cancer limited to the uterus
  • T1a - cancer is diagnosed only microscopically
    • T1a1 - minimal invasion of the stroma
    • Т1а2 - depth <5 mm, horizontally <7 mm
  • T1b - tumor more than T1a2
• T2 - spread to the uterus, but without the walls of the pelvis or lower third of the vagina
  • T2a - without affecting the parameter
  • T2b - with the defeat of the parameter
• T3 - the lower third of the vagina is affected or spread to the pelvic wall, hydronephrosis
  • T3a - the lower third of the vagina is affected
  • T3b - spread to the pelvic wall (hydronephrosis)
• T4 - the mucous membrane of the bladder, rectum, spread beyond the pelvis

N - Regional lymph nodes

• NX - insufficient data to assess the condition of regional lymph nodes
• N0 - there are no signs of regional metastases of lymph nodes
• N1 - metastases in regional lymph nodes

M - distant metastases

• Mx - insufficient data to determine distant metastases
• M0 - no signs of metastases
• M1 - there are separate metastases

Diagnostics of the cervical cancer

[18], [19], [20], [21], [22], [23], [24], [25], [26]

Diagnosis of preinvasive cervical cancer

The main methods for diagnosing preinvasive cancer are colposcopy, cytological and histological studies.

• Colposcopy. Preinvasive cancer is characterized by changes that correspond to atypical epithelium, and atypical vessels.
• Cytological examination. With cancer in situ, there are signs of severe dysplasia and lymphoid infiltration with atypical flat-epithelial cells.
• Histological examination allows detecting atypical epithelium without violating the integrity of the basal membrane and, thereby, establishing the final diagnosis.

[27], [28], [29], [30], [31]

Diagnosis of microinvasive cervical cancer

• Colposcopy. There are changes in the vaginal part of the cervix by the type of atypical epithelium.
• Cytological examination. With microcarcinoma, signs of severe dysplasia and athenia of the cellular background are diagnosed.
• Histological examination. The study of micro-preparations reveals a violation of the integrity of the basal membrane, the introduction into the underlying layers of individual tumor cells and their groups; invasion of malignant elements does not exceed 3 mm.

[32], [33], [34]

Diagnosis of invasive cervical cancer

Inspection of the cervix in the mirrors. The examination of patients begins with examination of the cervix in the mirrors. To prevent injury to the organ affected by the tumor, the cervix is exposed using a spoon-shaped mirror and lift. In the exophytic form of the cancer, tuberous formations of a reddish color are found, with areas of necrosis having a gray color.

The endophytic form is characterized by an increase and consolidation of the cervix, ulceration in the area of the external throat.

Colposcopy. In the exophytic form of the cancer, yellow-red formations with clearly contoured peripheral vessels having a corkscrew shape are visualized. In endophytic form, the tumor is defined as a crater with uneven edges and a warty bottom covered with necrotic masses.

The Schiller test is not specific for the diagnosis of cervical cancer, since it allows only to differentiate normal and pathologically altered areas of the vaginal part of the cervix.

Colposomyroscopy helps to establish the polymorphism of cells and their nuclei with a disorderly arrangement of cellular elements. Cytological examination reveals a large number of atypical cells.

Histological examination of cervical biopsy is crucial in the diagnosis of malignant process. The accuracy of the pathomorphological examination depends on the method of obtaining the material for study. Therefore, a biopsy should be carried out purposefully under colposcopy control.

Metastases of cervical cancer and their diagnosis. Metastasis of cervical cancer is carried out mainly on the lymphatic system, in the final stage of the disease the lymphatic pathway of the cancer can be combined with hematogenous. Chromolymphography, excretory urography, rectoscopy, computed tomography and NMR spectroscopy are used to detect metastases of cervical cancer.

[35],

Treatment of the cervical cancer

Treatment for cervical cancer varies depending on the stage of the disease:

• Stage 0: Cancer in situ (stage 0) - topical treatment, laser ablation, cryosurgery, excision of the pathological site; surgical removal of the pathological site is preferred.
• Stage IA1: The preferred method of treatment in step IA1 is surgery; total hysterectomy, radical hysterectomy and conization.
• Stage IA2, IB, IIA: Combined remote beam brachytherapy and radical hysterectomy with pelvic lymphadenectomy for patients with stage IB or disease IIA; radical vaginal tracheectomy with pelvic lymphodissection.
• Stage IIB, III or IVA: Chemotherapy with cisplatin and irradiation.
• Stage IVB and relapse of cancer: Palliative personalized therapy; Radiation therapy is used to stop bleeding and reduce pain intensity; Systemic chemotherapy is used for multiple metastases.

Treatment of preinvasive cervical cancer

The method of choice in the treatment of patients with preinvasive cervical cancer is cone electroexcision. Indications for radical surgery - extirpation of the uterus - are:

1. age over 50;
2. preferential tumor localization in the cervical canal;
3. a common anaplastic variant with ingrowth into the gland;
4. The absence in the preparation removed during the previous conization of the sites free of tumor cells;
5. impossibility of wide excision;
6. combination of preinvasive cancer with other genital diseases requiring surgical intervention;
7. relapse of the tumor.

In the presence of contraindications to surgical treatment, intracavitary gamma irradiation is performed.

Treatment of microinvasive cervical cancer

The method of choice in the treatment of microcarcinoma is extrafascial extirpation of the uterus, in the presence of contraindications to surgical intervention - intracavitary uterus. Broad conization for the treatment of pre-invasive cancers is used for a combination of indications:

1. age younger than 40 years;
2. early stromal invasion (up to 1 mm);
3. absence of tumor cells in the distal sections of the biopsy;
4. a highly differentiated form of cancer, limited to ectocervix;
5. the possibility of dynamic, clinical, cytological and colposcopic control.

Treatment of invasive cervical cancer

• 1b stage - combined treatment in two variants: remote or intracavitary irradiation followed by expanded extirpation of the uterus with appendages or expanded extirpation of the uterus followed by remote gamma-therapy. In the presence of contraindications to surgical intervention - combined radiation therapy (remote and intracavitary radiation).
• Stage 2 - in most cases a combined radial method is used; surgical treatment is indicated for those patients in whom radiation therapy can not be carried out in full, and the degree of local spread of the tumor allows for a radical surgical intervention.
• Stage 3 - radiation therapy in combination with general strengthening and detoxification treatment.
• Stage 4 - symptomatic treatment.

In August 2014, the FDA approved bevacizumab (Avastin) for the treatment of late (metastatic) stage of cervical cancer. This drug is approved for combination chemotherapy with paclitaxel and cisplatin or paclitaxel and topotecan.

Prevention

1. Systematic, scientifically based advocacy among women of the need for periodic medical examinations to identify early stages of tumors.
2. Preventive examinations of women, starting from the age of 30, including cytological studies of vaginal smears.
3. Clinical examination of women with background diseases of the cervix.

[36], [37], [38], [39],

Forecast

The prognosis for cervical cancer is individual and depends on the morphological structure of the tumor and the stage of the spread of the malignant process. With the implementation of appropriate medical measures, the five-year survival of patients with microcarcinoma is 80-90%, stage I of cervical cancer 75-80%, stage II 60%, stage III 35-40%.

Treatment of patients with cervical cancer, combined with pregnancy. When choosing a treatment strategy for pregnant women with cervical cancer, it is taken into account that pregnancy stimulates the growth of malignant cells.

The detection of preinvasive cancer in the first trimester of pregnancy is an indication for its interruption, with obligatory scraping of the cervical canal and subsequent conization of the cervix; in the II and III trimesters, pregnancy can be maintained until the term of labor with dynamic colposcopic and cytological control.

In the I and II stages of cancer in I and II trimesters, an extensive extirpation of the uterus with appendages followed by radiation therapy is performed; In the third trimester of pregnancy, cervical cancer treatment is preceded by a cesarean section.

Patients with stage III cancer in the I and II trimesters are interrupted pregnancy or amputation of the body of the uterus followed by radiation therapy; in the third trimester of pregnancy - cesarean section, amputation of the uterus body, combined radiation therapy.

[40], [41],