Cervical cancer

Cervical cancer is extremely rare in the presence of normal epithelium. Dysplasia and/or preinvasive cancer are common precursors to this disease. Cervical cancer is the third most common malignancy in women worldwide and remains the leading cause of death in women in developing countries.

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Epidemiology

Deaths from cervical cancer are declining each year, but in developing countries the disease still kills 46,000 women aged 15-49 and about 109,000 women aged 50 or older each year.

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Causes cervical cancer

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

HPV is a heterogeneous group of viruses that have a 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 recently discovered proteins (L1 and L2) that form the viral capsid.

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

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Risk factors

• Type and duration of papillomavirus infection.
• Weakened immunity (eg, poor nutrition, immunosuppression, and HIV infection).
• Environmental factors (eg smoking and vitamin deficiencies).
• Poor access to routine screening.
• Early age at first sexual intercourse and a large number of sexual partners.

Genetic predisposition

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

The chemokine receptor 2 (CCR2) gene on chromosome 3p21 and the Fas gene on chromosome 10q24.1 may also influence genetic susceptibility to cervical cancer, possibly by impairing the immune response to HPV.

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

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Symptoms cervical cancer

The most common symptoms of cervical cancer are:

• Abnormal vaginal bleeding.
• Vaginal discomfort.
• Unpleasant odor and discharge from the vagina.
• Urination disorder.

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

The predominant localization of preinvasive cancer is the boundary between the stratified squamous and columnar epithelium (in young women - the area of the external os, pre- and postmenopausal periods - the cervical canal). Depending on the structural features of the cells, two forms of cancer in situ are distinguished - differentiated and undifferentiated. In the differentiated form of cancer, the cells have the ability to mature, for the undifferentiated form, the absence of signs of stratification in the epithelial layer is characteristic.

Symptoms of preinvasive cervical cancer do not have specific signs. In some cases, pain in the lower abdomen, leucorrhoea, bloody discharge from the genital tract are noted.

Microinvasive cervical cancer is a relatively compensated and low-aggressive form of tumor that occupies an intermediate position between intraepithelial and invasive cancer.

Microcarcinoma, like 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, and leucorrhoea. The pain is localized in the sacrum, lumbar region, rectum, and lower abdomen. With widespread cervical cancer with damage to the parametrial tissue and pelvic lymph nodes, the pain may radiate to the thigh.

Bleeding from the genital tract occurs as a result of damage to easily injured small vessels of the tumor (during sweating, defecation, lifting weights, vaginal examination)

The leucorrhoea is serous or bloody in nature, often with an unpleasant odor; the appearance of leucorrhoea is caused by the opening of lymphatic vessels during the disintegration of the tumor.

When cancer spreads to the bladder, frequent urges and frequent urination are observed. Compression of the ureter leads to the formation of hydro- and pyonephrosis, and subsequently to the development of uremia. When the rectum is affected by the tumor, constipation occurs, mucus and blood appear in the feces, and vaginal-rectal fistulas are formed.

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Stages

• Stage 0 - preinvasive cancer (Ca in situ).
• Stage 1a - the tumor is limited to the cervix and invasion into the stroma is no more than 3 mm (the tumor diameter should not exceed 1 cm) - microinvasive cancer
• Stage 1b - the tumor is limited to the cervix with invasion of more than 3 mm
• Stage 2a - cancer infiltrates the vagina without extending to its lower third and/or spreads to the body of the uterus
• Stage 2b - cancer infiltrates the parametrium on one or both sides without extending to the pelvic wall
• Stage 3a - cancer infiltrates the lower third of the vagina and/or there are metastases in the uterine appendages, regional metastases are absent
• Stage 3b - cancer infiltrates the parametrium on one or both sides to the pelvic wall and/or there are regional metastases in the pelvic lymph nodes, and/or hydronephrosis and a non-functioning kidney are determined due to ureteral stenosis
• Stage IVa - cancer has spread to the bladder and/or rectum
• Stage IVb - distant metastases outside the pelvis are determined

International classification of cervical cancer according to the TNM system (1989)

T - tumor condition

• Tis - carcinoma in situ
• T1 - Cervical cancer limited to the uterus
  • T1a - cancer is diagnosed only microscopically
    • T1a1 - minimal stromal invasion
    • T1a2 - depth < 5 mm, horizontal < 7 mm
  • T1b - the tumor is larger than T1a2
• T2 - spread to the uterus, but not to the pelvic walls or lower third of the vagina
  • T2a - without damage to the parametrium
  • T2b - with parametrium damage
• T3 - the lower third of the vagina is affected or spreads 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 is affected, spread beyond the pelvis

N - Regional lymph nodes

• NX - insufficient data to assess the state of regional lymph nodes
• N0 - no signs of metastasis of regional lymph nodes
• N1 - metastases to regional lymph nodes

M - Distant metastases

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

Diagnostics cervical cancer

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Diagnosis of preinvasive cervical cancer

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

• Colposcopy. Preinvasive cancer is characterized by changes corresponding to atypical epithelium and atypical vessels.
• Cytological examination. In carcinoma in situ, signs of severe dysplasia and lymphoid infiltration with atypical squamous epithelial cells are revealed.
• Histological examination allows detection of atypical epithelium without damaging the integrity of the basement membrane and, thus, to establish a definitive diagnosis.

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Diagnosis of microinvasive cervical cancer

• Colposcopy. Changes in the vaginal part of the cervix are observed in the form of atypical epithelium.
• Cytological examination. In microcarcinoma, signs of pronounced dysplasia and atynia of the cellular background are diagnosed.
• Histological examination. Study of micropreparations reveals a violation of the integrity of the basement membrane, the introduction of individual tumor cells and their groups into the underlying layers; the invasion of malignant elements does not exceed 3 mm.

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Diagnosis of invasive cervical cancer

Examination of the cervix in mirrors. Examination of patients begins with examination of the cervix in mirrors. To prevent injury to the organ affected by the tumor, the cervix is exposed using a spoon-shaped mirror and a lifter. In the case of an exophytic form of cancer, reddish lumpy formations are found, with areas of necrosis that are gray.

The endophytic form is characterized by enlargement and thickening of the cervix, ulceration in the area of the external os.

Colposcopy. In the exophytic form of cancer, yellow-red formations with clearly contoured peripheral vessels of a corkscrew shape are visualized. In the endophytic form, the tumor is determined 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, as it only allows differentiation between normal and pathologically altered areas of the vaginal portion of the cervix.

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

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

Cervical cancer metastases and their diagnostics. Cervical cancer metastases mainly through the lymphatic system; in the final stage of the disease, the lymphatic route of cancer spread may be combined with the hematogenous route. Chromolymphography, excretory urography, rectoscopy, computed tomography and NMR spectroscopy are used to detect cervical cancer metastases.

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Treatment cervical cancer

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

• Stage 0: Carcinoma in situ (stage 0) - local treatment, laser ablation, cryosurgery, excision of the pathological area; surgical removal of the pathological area is preferred.
• Stage IA1: The preferred treatment for stage IA1 is surgery; total hysterectomy, radical hysterectomy and conization.
• Stage IA2, IB, IIA: Combined external beam brachytherapy and radical hysterectomy with pelvic lymphadenectomy for patients with stage IB or IIA disease; radical vaginal tracheectomy with pelvic lymph node dissection.
• Stage IIB, III, or IVA: Chemotherapy with cisplatin and radiation.
• Stage IVB and recurrent cancer: Palliative personalized therapy; radiation therapy is used to stop bleeding and reduce pain; 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 surgical intervention - extirpation of the uterus - are:

1. age over 50 years;
2. predominant localization of the tumor in the cervical canal;
3. common anaplastic variant with ingrowth into glands;
4. absence of areas free of tumor cells in the specimen removed during previous conization;
5. impossibility of performing wide excision;
6. combination of preinvasive cancer with other diseases of the genital organs requiring surgical intervention;
7. tumor recurrence.

If there are 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 uterine therapy. Wide conization for the treatment of preinvasive cancer is used for a combination of indications:

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

Treatment of invasive cervical cancer

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

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

Prevention

1. Systematic, scientifically based propaganda among women about the need for periodic medical examinations to detect early stages of tumors.
2. Preventive examinations of women, starting from the age of 30, including cytological examinations of vaginal smears.
3. Medical examination of women with underlying diseases of the cervix.

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Forecast

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

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

Detection of preinvasive cancer in the first trimester of pregnancy is an indication for its termination with mandatory curettage of the cervical canal and subsequent conization of the cervix; in the second and third trimesters, pregnancy can be maintained until the due date with dynamic colposcopic and cytological control.

For stages Ib and II cancer in the first and second trimesters, extended extirpation of the uterus with appendages is performed, followed by radiation therapy; in the third trimester of pregnancy, treatment of cervical cancer is preceded by a cesarean section.

Patients with stage III cancer undergo termination of pregnancy or amputation of the uterus with subsequent radiation therapy in the first and second trimesters; in the third trimester of pregnancy - cesarean section, amputation of the uterus, combined radiation therapy.

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