Hereditary ovarian cancer is a malignant epithelial tumor of the ovaries, the genetic predisposition to which is transmitted to descendants. Ovarian carcinoma is accompanied by nonspecific signs – decreased appetite, weakness, gastrointestinal discomfort, vague pain in the abdomen and lower back, in the later stages – ascites. The diagnosis is established according to gynecological examination, radiation methods, laboratory blood tests and biopsies. Treatment is combined or complex, the main methods are surgery and polychemotherapy, radiation therapy can also be used.
C56 Malignant neoplasm of the ovary
Hereditary (family) ovarian cancer is a carcinoma of the female gonads associated with generative (germinal) gene mutations. The frequency of such mutations among Europeans averages 0.2–0.5% and is sharply (4-10 times) increased among Ashkenazi Jews. Hereditary forms account for 10-19% of all malignant epithelial neoplasms of the ovaries. The average age of patients is 48 years (versus 56 years for sporadic cancer), often hereditary cancer manifests in younger women. The risk of developing a cancerous tumor in women carrying the mutation is 11-40%, and with a burdened family history increases by 1.1-1.5 times. The tumor process in the ovaries is often combined with carcinomas of other organs – both the reproductive system and extragenital.
The cause of familial cancer of the female gonads is a generative mutation – damage to certain genes in the chromosomes of germ cells, transmitted to subsequent generations. Gene disorders can be caused by exposure to ionizing radiation, pesticides and agricultural fertilizers, solvents, alkaloids, a number of drugs, infectious agents.
The germinal mutation that has arisen for the first time manifests itself only in the next generation, that is, siblings (siblings) of this generation and their children will be at increased risk of cancer, but not probands (parents who have a genetic mutation). Currently, the following hereditary conditions are known, one of the manifestations of which is ovarian carcinoma:
- Breast and ovarian cancer syndrome. It is caused by a mutation in the BRCA1 and BRCA2 genes and is the main cause of hereditary ovarian cancer (the proportion of BRCA-associated carcinomas is 90-95% of all familial malignant ovarian tumors). The risk of ovarian cancer with germinal mutation BRCA1 reaches 44%, and BRCA2 – 27%. Other clinical manifestations of the syndrome include malignant tumors of the digestive system, melanoma. One of the varieties of the syndrome is familial organ-specific ovarian cancer, occurring in isolation, not combined with primary multiple neoplasms of other organs.
- Lynch syndrome of the second type (hereditary non-polypous colorectal cancer). It is mainly associated with mutations in the MLH1, MSH2 genes. Clinical manifestations include tumors of the gastrointestinal tract, the female reproductive system and a number of others.
At risk of developing hereditary ovarian cancer are women whose close blood relatives have registered carcinomas of the mammary glands, ovaries, uterus, colon and pancreas, melanoma, and in the male line – these extragenital tumors, prostate cancer and primary peritoneal cancer. A special role in terms of risk is assigned to breast carcinoma in male blood relatives, early (up to 40-50 years) episodes of cancer and their primary multiple (synchronous or metachronous) form – the defeat of several different or paired organs.
The risk of developing neoplasia in carriers of the mutation accumulates with age and has a direct dependence on the prevalence of hereditary syndromes among relatives. Risk factors significant for most types of sporadic ovarian cancer (ovarian dysfunction, unrealized reproductive potential, drug stimulation of ovulation, hyperestrogenism) practically do not affect the development of hereditary carcinomas, since 80-90% of these tumors lack estrogen, progesterone and epidermal growth factor receptors.
Mutations associated with hereditary predisposition to ovarian cancer affect genes that carry the function of suppressing tumor growth. Clinically significant “breakdowns” lead to disruption of DNA breakage repair mechanisms and accumulation of multiple errors in its structure. As a result, the body’s ability to timely identify and destroy altered cells is lost, which leads to a violation of their differentiation, uncontrolled proliferation, invasion into neighboring structures and forms a high-quality tumor phenotype. Violation of the synthesis of the protein responsible for DNA repair is also due to the vulnerability of cells to treatment with antiblastoma drugs.
The pathogenesis of hereditary ovarian cancer has not been fully studied, however, the results of recent studies suggest that the source of the tumor is not the epithelium of the ovarian capsule, as previously thought, but the epithelial lining of the fallopian tubes and peritoneum (which can explain the morphological and clinical similarity of ovarian cancer with primary peritoneal carcinoma). The main and earliest way of metastasis of ovarian cancer is implantation, with damage to the peritoneum, large omentum, pelvic organs and capsules of the liver, spleen. Another characteristic way of spreading metastases is lymphogenic – retroperitoneal lymph nodes are first affected, then peripheral. Hematogenous metastasis is extremely rare, while the lung, liver, and brain are affected.
The most complete assessment of the anatomical prevalence of the tumor in order to correctly diagnose, determine the prognosis and develop a rational treatment allows the classification of TNM. Along with TNM, the classification of neoplasias developed by the International Federation of Gynecologists and Obstetricians (FIGO) is actively used in oncology and gynecology, which reflects the consistent development of the tumor process by stages. Below is the FIGO classification of the 2014 revision (the corresponding TNM values are shown in parentheses):
- Stage I (T1N0M0). The tumor process is limited to the ovaries. There are 5 sub-stages depending on the one- or two-sided localization of the process, the presence of cancer cells in flushes from the peritoneum, damage to the ovarian capsule in the pre- or intraoperative period.
- Stage II (T2N0M0). The tumor spreads to the pelvic organs. It includes two sub–stages – the defeat of only the genitals and the involvement of other structures in the process.
- Stage III (T3N0M0 or T1-3N1M0). The tumor affects the peritoneum outside the pelvis or (and) regional lymph nodes (morphological confirmation is necessary). Depending on the size of metastases and their localization within the stage, 5 sub-stages are distinguished.
- Stage IV (T1-3N0-1M1). There are metastases in distant organs (excluding intraperitoneal) and peripheral lymph nodes. It includes 2 options – the presence of malignant cells in the pleural effusion and the involvement of other distant organs.
The first subjective signs of a tumor may be manifestations of paraneoplastic syndrome – decreased appetite, weakness and fatigue, general malaise, subfebrility. As the tumor grows, the symptoms become more pronounced, dull bursting pains in the navel, lower abdomen, epigastrium, hypochondrium join. Compression of the intestines is accompanied by nausea, vomiting, constipation, bloating, unpleasant sensations in the mouth, and compression of the urinary tract – frequent urge to urinate, difficulty in passing urine. With ascites, the volume of the abdomen increases, the accumulation of effusion in the abdominal cavity and in the pleura is manifested by increasing shortness of breath, cough, palpitations, a feeling of nausea in response to previously habitual loads. The spread of the process to the fallopian tubes and uterus may be accompanied by serous-bloody discharge.
The skin first has a pale appearance, then acquires an earthy gray color with a yellowish tinge (due to the addition of hemolytic anemia, compression or germination of the tumor of the biliary system). Weight loss is most often observed, but cachexia is not typical for patients even with advanced ovarian cancer, their appearance may not always correspond to the severity of the disease. Often ovarian cancer is accompanied by thrombophlebitis and phlebothrombosis of the pelvis and lower extremities, manifested by pain, compaction, hyperemia along the affected vein. Sometimes, with ovarian carcinoma, there is a characteristic protrusion of the navel – the appearance of an umbilical hernia is due to the exit beyond the umbilical ring of the tumor-affected large omentum.
Complications may be associated with the local spread of the tumor, vascular manifestations of paraneoplastic syndrome, distant metastases. In young patients, there is often a twist of the legs of the neoplasm, accompanied by a picture of an acute abdomen. This condition can lead to necrosis, peritonitis, rapid progression of cancer. Similar consequences threaten and infringement of the omentum. Thrombosis can lead to pulmonary embolism. As a result of prolonged accumulation of ascitic fluid, severe cardiopulmonary insufficiency develops. Compression of the colon can result in complete intestinal obstruction and death. Metastases in the liver, lungs, brain cause serious disorders and significantly worsen the quality of life, the spread of the process leads to death.
The diagnosis of ovarian cancer is complicated by the inaccessibility of the tumor and the absence of specific gynecological symptoms. As a result, patients are treated for a long time and unsuccessfully for non-existent internal diseases, and the tumor is detected too late. The diagnostic search is aimed at determining the BRCA status, morphological verification of neoplasia, assessment of the prevalence of the tumor process and includes the following studies:
- Gynecological and physical examination. During bimanual rectovaginal examination, it is possible to detect a tumor of the appendage and, by the nature of the changes (irregularities, mobility, density, fixation to neighboring organs), to assume a primary malignant neoplasm. With a general examination for indirect signs (ascites, enlargement of peripheral lymph nodes), ovarian cancer can also be suspected.
- Radiation methods. Abdominal ultrasound of the genitals with the additional use of transvaginal, intrauterine and rectal sensors, color Dopplerometry allows you to detect signs of malignant growth (unevenness of the structure, the presence of many randomly arranged partitions, indistinctness of the contour, hypervascularization, ascites). For a more accurate examination of the primary tumor, as well as to detect metastases in the uterus, liver, lungs, spleen, CT and MRI of the pelvis, abdominal cavity, chest can be prescribed. Colonoscopy is used to detect a tumor lesion of the colon.
- Blood tests. The level of the tumor marker (ELISA analysis) and gene dysfunction of hereditary syndromes (PCR test) are determined. An increase in the level of the Ca-125 antigen associated with ovarian cancer indicates a high probability of ovarian carcinoma, and the detection of mutations in BRCA1, 2 indicates the hereditary nature of the pathological process.
- Morphological analyses of biopsies. Cytological examination of punctates of the Douglas space, abdominal and pleural cavities makes it possible to detect cancer cells, verify the diagnosis and clarify the stage of the tumor process.
- Laparoscopy. In some cases (obesity, adhesions in the patient), an accurate diagnosis can only be established by surgical method. Diagnostic laparoscopy allows you to most accurately diagnose an ovarian tumor and determine the stage.
Differential diagnosis is carried out with the participation of oncogynecologist, doctors of laboratory and ultrasound diagnostics, medical geneticist, radiologist, pathologist. Ovarian cancer is differentiated with ovarian and retroperitoneal cysts, benign and other malignant ovarian tumors, Meigs syndrome, neoplasia of neighboring organs, metastases of stomach and colon cancer, purulent-inflammatory diseases of appendages, umbilical hernia, gastroenteric, cardiological, pulmonological pathology.
In the early stages, the main goal of treatment is radical removal of the tumor and achieving stable and long-term remission without relapse. However, the prevalence of initially diagnosed neoplasia in most cases does not allow destroying all cancer cells in the body, so treatment in such cases is aimed at stabilizing the process and lengthening the period without progression. To achieve these goals, a combination of two methods is used – surgical and medical, which can sometimes be supplemented with radiation therapy.
- Cytoreductive surgery. In ovarian cancer, unlike most other malignant neoplasias, the removal of any technically possible tumor volume can improve the prognosis, so surgery is performed at any stage. If the tumor has not been completely removed, the interventions are repeated after several courses of chemotherapy.
- Polychemotherapy. Hereditary ovarian cancers are more sensitive to chemotherapy than sporadic ones, so drug treatment can also be considered the main method used for partial regression of neoplasia. In the presence of ascites or pleurisy, chemotherapy is performed before surgery, in other cases – after. Treatment is carried out with platinum preparations and taxanes.
- Radiation therapy. Treatment is mostly ineffective in epithelial tumors and is prescribed after surgery only in case of carcinoma resistance to drugs.
Prognosis and prevention
The prognosis of relapse-free and overall survival in familial cancer is more favorable than in sporadic. The average five-year survival rate is 36-40%. At the I stage of the process, this indicator is 70-100%, at II – 45%, at III – 35-40%, at IV – 5-10%. More than half of relapses are registered within a year after treatment. The recurrence rate averages 20-50%. The five–year threshold of relapse-free survival is exceeded by 27% of patients, the ten-year threshold is 7%.
The preventive program includes medical and genetic counseling for women at risk to calculate the likelihood of developing ovarian cancer, DNA testing to detect BRCA mutations. In the presence of a hereditary predisposition, young (up to 35-40 years old) patients are recommended to undergo an annual thorough examination (gynecological ultrasound, rectovaginal examination, determination of the level of CA-125) in order to detect possible neoplasias early. After the realization of the reproductive function, women may be offered preventive tubovariectomy, which reduces the risk of ovarian tumors by 95%, and breast tumors by 50%, or an alternative is tubal ligation (reduces the risk by 60-70% due to atrophy of the epithelium, which is the source of the pathological process). Patients who have been treated for ovarian cancer need lifelong dynamic monitoring by an oncogynecologist for timely diagnosis of a possible relapse.