Advanced ovarian cancer as a risks of primary multiple malignant tumors after the treatment of extra genital cancer



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CHAPTER II

ETIOLOGY, RISK FACTORS AND PREVENTION OF THE MALIGNANT TUMORS OF FEMALE GENITAL ORGANS
The etiology of malignant tumors of the female genital organs is varied.
Viral etiology of malignant tumors of the female genital organs include HPV (cervical, vaginal and vulva cancer). In the last 25 years, the etiopathogenesis of CIN and cervical cancer is mainly associated with HPV infection. In CIN most commonly found is HPV16/33/31, and in the carcinoma of the cervix - HPV16/18/45 (for squamous cell cancar -HPV16/18/33, and for adenocarcinoma - HPV16/18/45). In patients with carcinoma of the vulva in 30.8% of the case presence of HPV was found (mainly HPV 16). HPV was found in 69.3% of cases of VAIN (primarily HPV 16). Primary prophylactic is to vaccinate against HPV. Secondary prevention is gynecological examinations with Pap (cytology screening) and specifying diagnostic colposcopy with target biopsy.
Hormonal etiology of malignant tumors of the female genital organs (endometrial cancer)
In the etiology of endometrial cancer is estrogen or hormone-related disorders. Obesity, hypertension and diabetes are often seen in patients with endometrial cancer. In 40% of the cases, PE is not hormone-dependent. In the modern interpretation etiology of PE can be represented as a tumor with two different etiologies. Primary prevention of PE boils down to diet. Secondary prevention to early detection of PE include ultrasound of the uterus with endometrial thickness measurement, endometrial biopsy (aspiration, with the help of hysteroscopy and curettage). Examination of tumor markers СА 125 and НЕ 4. Genetic etiology of malignant tumors of the female genital organs (ovary cancer) are BRCA 1 and BRCA 2 mutations. Cumulative risk for ovarian cancer is 40-50% of BRCA 1 and 20-30% for BRCA 2 mutations. It is not established BRCA 1 and BRCA 2 mutations simultaneously in the same patient. The risk of developing ovarian cancer in BRCA 1 and BRCA 2 mutations depends on the age of the patient. Primary prevention of ovarian cancer practically does not exist, except prophylactic ovariectomy. Secondary prevention to early detection of ovarian cancer include ovarian ultrasound and examination of tumor markers CA 125 and НЕ 4.

CHAPTER III

PRIMARY MALIGNANT MULTIPLE TUMORS AND FAMILY CANCER IN ONCOGYNECOLOGY
PMMT (the development of two or more tumors in one patient) is a problem of particular importance in oncology. Mandatory condition for PMMT is the presence of different histological tumor types in various organs. In oncogynecology about 5% of cases are PMMT, it can synchronous and metachronous. More frequent is metachronous (80%) when the second tumor was found more than one year after the first. The presence of HPV in neighboring organs contributes to the development of lower genital tract neoplasia. PMMT combination of hormone dependent cancer tumors from other locations is associated with BRCA-1 and BRCA-2. Most often it is a combination of the tumors with the same etiology, genetic and hormonal (breast cancer, endometrial cancer and ovary cancer) or viral (cervical cancer, vagina cancer and vulva cancer).
Synchronous PMMT
PMMT, which has developed within one year, or both are defined as synchronous PMMT with frequency of about 20%. The most common combination is breast cancer and genital cancer. Rarely is the combination of three or more tumors in the same patient.
Incidence and survival of patients with PMMT in Bulgaria
According to National Cancer Registry in Bulgaria more than 150 women anually are diagnosed with PMMT of female genitalia. In PMMT, when the first tumor was female genitalia, most frequently second tumor is breast cancer - 27.3%, followed by cancer of the colon rectum, ovary and corpus uteri. When the first tumor is breast cancer, lung cancer ranks in the top four and ovary cancer is rare. When PMMT of ЖПО is the second tumor, the most common first is breast cancer tumor - 43.7%, followed by cancer of the colon rectum, ovary cancer and endometrial cancer. In 18.3% of multiple tumors are a combination of breast cancer, cervical cancer, endometrial cancer and ovary cancer. Prolonged survival in these patients increases the likelihood of a second tumor with the diagnosis of a rapidly deteriorating outlook.
Familial cancer in oncogynecology
Most often are ovary cancer and breast cancer, associated with BRCA-1 and BRCA-2. In patients with endometrial cancer in 6% of the cases familial cancer is found, and in patients with ovary cancer, familial cancer is found in 5% of the cases. In genetic consultation, patients who are at high risk for familial cancer are identified.


CHAPTER IV

MALIGNANT TUMORS OF THE VULVA
In 2010, according to the National Cancer Registry in Bulgaria 120 new patients were registered. The actual incidence is 1.27 per 100,000 women.
Early symptoms are unusual and are related to persistent genital pruritus,
burning and dryness in the vulva. Macroscopically, it is manifested in the traditional
forms of protrusion and ulcer. Histologically malignant tumors of the vulva are presented most often as cancers: squamous cell cancer - over 90% of cases, and adenocarcinoma. Forms are rare malignant melanoma and sarcoma. The diagnosis is histologycally. FIGO system is based on surgical staging and TNM stages are determined by clinical and / or pathologo-anathomical classification. Advanced stages are dominating. It is assumed that the prognostic factors associated with the stage of the disease (tumor - above or below 2 cm), depth of invasion (above and below 1 mm stromal invasion), the absence or presence of positive lymph nodes. Treatment is surgical, combined with postoperative percutaneous radiotherapy.
The volume of surgery depends on the stage (size and location of the tumor), the degree of
differentiation and mostly on the condition of the ingvino-femurale limph nodes.
Standard capacity includes radical vulvectomy with unilateral or bilateral liph node dissection. In advanced stages radiation-chemotherapy is used. Local recurrences are common. Treatment of repalses is surgical – large excision of the recurrence, if necessary a resection of urethra or rectum and even evisceration. When properly conducted treatment prognosis in cancer of the vulva is relatively good, the overall 5-year survival according to different authors varies from 35 to 70 percent. Five-year survival in stage І is 79%, in stage ІІ is 59%, in stage ІІІ is 43% and in stage ІV is 13%. For each stage, pooled data show the following: in stage І is 90%, in stage ІІ is 77%, in stage ІІІ is 51% and in stage ІV is 18%.

Post treatment follow-up includes basic and additional tests.
CHAPTER V

MALIGNANT TUMORS OF THE VAGINA
Malignant tumors of the vagina belong to the rare tumors of female genitalia. It is a disease of older women. In about 50% of cases bleeding occurs. Primary adenocarcinoma of the vagina, most commonly is squamous cell cancer - 80%. Adenocarcinoma was found in 10% of the cases. There are clear cell cancer, mucinous cancer, adenosquamous cancerа и papillary cancer, as well sarcoma and malignant melanoma. Regional lymph nodes of the upper two thirds of the vagina are hip, distal to the bifurcation of the aorta, and the lower one-third - inguinal lymph nodes. The histological diagnosis is determining. Tumor extension into cervix and reaching the external axis is classified as carcinoma of the cervix. Tumors involving the vulva are classified as carcinoma of the vulva. TNM and FIGO staging. The prognosis depends on the stage of disease, histological type and degree of differentiation of the tumor, the degree of differentiation of the tumor, presence of metastases in the lymph nodes and tumor emboli in the blood and lymph vessels. Treatment of vaginal cancer is surgical, radiation and combined. For tumors in the upper third of the vagina is applied radical hysterectomy with total abdominal extirpation of the vagina and pelvic lymph dissection. For tumors in the middle third of the vagina is applied total hysterectomy with total extirpation of the vagina and ingvino-femural lymph node dissection by Ducuing (performance of pelvic lymph node dissection depends on the presence or absence of metastases after extirpation of the ingvino-femoral lymph nodes). For tumors in the lower third of the vagina is applied total hysterectomy with total extirpation of the vagina, lymph node dissection and ingvino-femoral partial vulvektomy. Surgical treatment is combined with preoperative and / or postoperative radiotherapy. Chemotherapy is used in the treatment of recurrent, metastatic or locally advanced cancer, alone or in combination with radiotherapy. Most oftena applied are platinum agents. According to FIGO 5-year survival for patients with carcinoma of the vagina in stage I was 53%, in stage II - 43% in stage III - 28% and in stage IV - 12.5%. Five-year survival of squamous cell cancer is 68%, while adenocarcinoma is 22%. Post treatment follow-up is standard.

CHAPTER VI

MALIGNANT TUMORS OF THE CERVIX
Malignant tumors of the cervix are ​​the second most common tumors among female genitalia in Bulgaria. Contact bleeding is leading in 4/5 of the patients. Cervical cancer metastasizes primarily in lymph channels or directly adjacent to, rarely by blood. It is extremely important to determine the extent of tumor spread. The diagnosis is histological. Cervical cancer is keratinizing and non- keratinizing and squamous cell cancer (around 90%) and adeno- carcinoma (around 10%). In staging, the International Classification TNM / FIGO is used. Prognostic factors: tumor size, stage of disease, lymph node involvement and limph-vascular spaces and histological subtype is important, and the degree of differentiation. Treatment of cervical cancer is complex. The therapeutic approach is individually tailored for each patient from an interdisciplinary team - oncogynecologist, radiologist and medical oncologyst. Surgical interventions are conization and trachelectomy for stages IA and IB to extended hysterectomy with extirpation of the upper third of the vagina and pelvic lymph node dissection in stage IB-IIB to IVA in the evisceration stage and recurrence.
Additional indications for surgery were: cervical option with strong bloated neck, lack of opportunity for conducting full brachytherapy, an inflammatory process, pregnancy or other tumor requiring surgical treatment, presence of adenocarcinoma, recurrence and metastases when exhausted ability of RT. Radiation plays an essential role in the combined treatment of cancer of the cervix. Used as preoperative and postoperative radiation therapy, either alone as external beam radiation therapy and brachytherapy. In recent years radiotherapy is increasingly combined with chemotherapy (cisplatin), as well as neoadjuvant and adjuvant therapy, as in the case of definitive radiotherapy. In stage II A, B, IIIA, IIIB, IV A – a standard is synchronous radiotherapy with platinum containing chemotherapy. In stage IA five year survival is 95-100%, in stage IB - 75-90%, stage II - 60-75%, Stage III - 35-40%, IV stage - 0-5%. Survival after radical hysterectomy with or without adjuvant radiotherapy is 85% -95% for patients without metastases in Lymph nodes; in patients with Lymph nodes metastases survival was 45% - 55%. Quality of life depends on the treatment and menopausal status of the patient. Post treatment follow-up is standard.

CHAPTER VII

MALIGNANT TUMORS OF THE UTERUS. ENDOMETRIAL CANCER
Malignant tumors of the corpus uterus are the most common tumors in ЖПО
Bulgaria. The main and most important symptom of РЕ is a genital bleeding.
Histologically adenocarcinoma predominant (70-80% of cases) – well-,
moderate -, and low differentiated. Less frequently encountered: adenoakantoma, adenoscuamous cancer, clear-cell carcinoma, serous carcinoma, secretory adenocarcinoma and undifferentiated carcinoma. Regional lymph nodes are pelvic (obturator, internal
iliac, external iliac and hypogastral, parametrial, sacral and para-aortic. The first and most important diagnostic procedure is separated abrasion test of the cervix and uterine cavity with
histological examination. It is imperative that preoperative loco-regional staging (pelvic lymph nodes). Based on clinical findings and conclusions research is defined TNM and FIGO stage. Endometrial cancer requires surgical staging. On the basis of clinical pathology criteria
Endometrial cancer is divided in 2 types: Type I - mostly endometroid cancer and type-II
non-endometroid cancer. Major prognostic factors were stage, Histological type of tumor, degree of differentiation and the presence of lymph node metastases. Surgical method is the method of choice in the treatment of endometrial cancer treatment is complex. Surgical volume is consistent with the degree of risk in endometrial cancer. Conservative treatment is indicated for young women in Stage I with well-differentiated adenocarcinoma who want to keep their reproductive potential. Radiation therapy is used as part of combination therapy. It is Used alone, in some cases, when there are contraindications for surgery. Radiation can be pre- or after surgery, or external beam and brachytherapy. Adjuvant hormone therapy is not conducted. Chemotherapy is indicated for metastatic disease or used to treat relapses. The overall 5-year survival was 67%, as I stage it is 76.3%, for II-59.2% to 29.4%, III and IV - 10,3%. For patients in the IA stages and highly differentiated carcinoma 15-year survival was 98%. Endometroid adenocarcinoma has 89% 5-year survival clear-and 89% cancer - 81% and adenoscuamous cancer - 80%. Best prognosis has adenoakantoma- 96%. Post treatment follow-up is standard.
CHAPTER VIII

MALIGNANT TUMORS OF THE UTERUS. UTERINE SARCOMAS
Sarcoma of the uterus is 1% of malignant tumors in women and 2% -5% of malignant tumors of the uterine body. The most frequently is found as an in abdominal cavity, which even the patient herself feels. Bleeding in menopause abundant, irregular vaginal bleeding are the most common symptoms suggestive of diagnosis. From a practical perspective, the most commonly found leiomyosarcoma, endometrial stromal sarcoma, and mixed mesodermal carcinosarcoma, also known as mullerian sarcoma. The most often metastasis are hematogenous (lung and liver), but some species such as histological carcinosarcoma is observed lymphogenic metastasis. The most common preoperative carcinosarcoma was diagnosed (93.5%), whereas leiomyosarcoma in 65% of cases the operation was due to uterine fibroids and is only postoperative placed histological diagnosis. Based on clinical findings and conclusions research is defined TNM and FIGO stage, using the international
Classification TNM / FIGO sarcomas of the uterus. Prognosis for uterine sarcoma
mainly depends on the stage, and the second depends on the histological type of
tumor. Mitotic index is also of great importance for the prognosis. Healing tactics depend on the stage of disease, histological type of tumor, local distribution process and the general condition of the patient. Surgical method is principal. Abdominal hysterectomy, bilateral salpingo-oophorectomy and selective pelvic and para-aortic lymph node dissection is performed. Adjuvant therapy has changed from radiation therapy to chemotherapy in recent decades. Radiation therapy applies to local control. Chemotherapy is administered in locally advanced or metastatic disease. Hormone therapy is applied in endometrial stromal sarcoma. Sarcoma of the uterus have a bad prognosis. Five-year survival depends on the stage of disease and histological type of tumor. In the first stage, it reaches 50-60%, while in advanced stages is reduced to 20%. Quality of life is highly dependent on the timely detection, treatment method applications, the stage of disease and treatment outcomes achieved. Post treatment follow-up is standard.

CHAPTER IX

MALIGNANT TUMORS OF THE OVARY
Malignant ovarian tumors are the third most common tumors of female genitalia in Bulgaria. In advanced stages of the disease patients have more symptoms, ascites is a leading symphtom and large tumor masses filling the abdomen. Around 90% of the primary malignant tumors of the ovary are epithelial (carcinoma) - serous, mucinous, endometroid, clear cell, transitory cell and squamous, such as nonepithelial and metastatic. In diagnostics rely on different methods and tumor markers CA 125 and HE4. Staging of ovarian cancer is surgical. It is based on the spread of the disease and includes a full assessment of the peritoneal cavity and omentum, biopsy of the diaphragmatic and pelvic peritoneum; para-aortic and pelvic lymph nodes and peritoneal washing study results. Based on the findings and research done, the TNM and FIGO stage is determined. Classical prognostic factors include the degree of differentiation, stage, histological type, presence or not of ascites formation cystic rupture preoperatively, extracapsular growth, age of the patient. Surgery plays an important role in all phases of the treatment of ovarian cancer. The volume of surgery according to FIGO guidelines include: total abdominal hysterectomy classical, bilateral salpingo-oophorectomy, total omentectomy, cytological evaluation of the pelvis, abdomen and subdiaphragmal, selective lymph node dissection of the pelvic lymph nodes in the surgical field and para-aortic evaluation of abdominal organs. Optimal cytoreduction aims to maximize the reduction of cancer cell mass as the amount of residual tumor after primary surgery is crucial for survival. Combined or monochemotherapy held in adjuvant aspect of radical surgery and patients as neoadjuvant for locally advanced inoperable patients and treatment for metastases. Gold Standard is the application of a combination of carboplatin and paclitaxel. In stages I and II 5-year survival was 82% in stage III was 36%, while stage IV is 18%. Quality of life depends on staging and treatment.

CHAPTER X

MALIGNANT TUMORS OF THE FALLOPIAN TUBE
Malignant tumors of the fallopian (uterine) tubes are one of the rarest tumors of female genitalia in Bulgaria. In 50% of patients with cancer of the uterine tube, leaks or bleeding from the vagina that is bloody or type of amber known as hydrops tubae profluens. Usually the symptoms are similar to the thesis of the ovarian cancer and most patients are diagnosed intraoperatively or in obtaining histological result. We distinguish three major histological types: epithelial, mixed epithelial- mesenchymal and mesenchymal, and resembles that of ovarian cancer. Only in 4% of cases, the diagnosis fallopian tube cancer is placed preoperatively. CA 125 is showing positive for cancer of the fallopian tube in 80% of patients with this tumor is significantly higher markups. Staging of fallopian tube cancer is surgical. It is based on the spread of the disease and includes a full assessment of the peritoneal cavity and omentum, biopsy of the diaphragmatic and pelvic peritoneum; para-aortic and pelvic lymph nodes and peritoneal washing study results. Based on clinical findings and research done to determine the TNM and FIGO stage, using the International Classification of cancer of the fallopian tubes. The most important prognostic factor is the spread of tumor. The extent of invasion is an independent prognostic factor in stage I. Tumor located in the fimbriae is a poor prognostic factor. Vascular invasion and metastasis in Lymph nodes are also a prognostic factors. The volume of surgery include: total abdominal hysterectomy classical, bilateral salpingo-oophorectomy, total omentectomy, cytological evaluation of the pelvis, abdomen and subdiaphragmal, selective pelvic lymph node dissection and para-aortic area and appendectomy, and surgical evaluation of abdominal organs. Chemotherapy is conducted as adjuvant and neoadjuvant therapy with sarboplatin and paclitaxel. Patients in stage I have relatively good prognosis. Fallopian tube cancer have a worse prognosis than ovarian cancer. Post treatment follow-up is standard.
CHAPTER ХІ

TROPHOBLASTIC DISEASE. CHORIOCARCINOMA
Choriocarcinoma is the rarest malignant tumor of female genitalia in Bulgaria. Trophoblastic disease is a condition that is related to pregnancy and has a gestational origin. The clinical picture depends on the type of trophoblastic disease. In Choriocarcinoma, in addition to genital bleeding, the clinical picture is associated with localization of metastases. Gestational trophoblastic neoplasia (GTN) is: trophoblastic tumor of the placenta, invasive mola and choriocarcinoma that has two untypical types - site trophoblastic tumor of the placenta (placental-site trophoblastic tumor-PSTT), and Epithelioid trophoblastic tumor (epithelioid trophoblastic tumor - ETT). βHCG level is directly related to the type of trophoblastic disease. Based on clinical findings and research done to determine the TNM and FIGO stage, using the International Classification TNM / FIGO for trophoblastic disease include an evaluation of the prognostic index. Treatment strategy is determined by the level of risk: low risk GTN and GTN at high risk. In recent years, surgical treatment yielded to chemotherapy. Total hysterectomy is performed only in cases of profuse, unresponsive to conservative treatment, bleeding, and PSTT and ETT. Chemotherapy is the most effective method of treatment for patients with GTN. In prognostic index ≤ 6 can be treated successfully with monotherapy with Methotrexate. In prognostic index ≥ 7 most commonly used is a combination EMA-CO (Etoposide, Dactinomycin, Methotrexate, Folinic Acid, Cyclophosphamide, Vincristine). In recurrences using different combinations and regimens

"salvage" chemotherapy and surgery. Illness in the early stages 5-year survival rate is close to 100%. In localized process, it is 94.5%, regional process - 92.9% and in the presence of metastases - 87.1%. Good therapeutic results in chariocarcinoma determine the quality of life. Most patients after disease have a restored menstrual and reproductive functions. In molar pregnancy, the follow-up period is one year, in invasive mola - two years, and at Choriocarcinoma - 4 years. Meanwhile, the level of βHCG is monitored, radiographs of the lungs are made and is recommended to prevent a new pregnancy within one year.

CHAPTER ХІI

BREAST CANCER IN THE PRACTICE OF GYNECOLOGY
Breast cancer is the most common malignant tumour in women in Bulgaria. The clinical picture is quite varied, but the main is palpation of tumor formation in the mammary gland. Histological classification includes carcinoma in situ disease and Paget, and invasive carcinoma (ductal, lobulalen, medullary, mucinous adenocarcinoma, tubular, inflammatory, undifferentiated, etc.).. Diagnosis includes case history, including family history and palpation of both breast and axillary lymph node. In order to determine the size of the tumor, ultrasound, mammography, tumor marker CA 15-3 are used. It is Necessariy to apply aspiration biopsy and excision biopsy, which is done by sectoral resection. Based on clinical findings and research done to determine the TNM stage, using the International Classification of TNM breast cancer. Prognostic factors: stage of disease, condition of lymph nodes, tumor size, histologic type and nuclear degree of primary tumor, estrogen and progesterone receptors, HER2/neu, BRCA1 and BRCA2, and others. Breast cancer treatment is complex. The therapeutic approach is individually tailored for each patient from an interdisciplinary team – surgeon-mammologyst, radiologist and medical oncologist. Depending on the diagnosis and stage of disease applies surgery, radiation, hormone or chemotherapy, most oftenly combined. The most commonly used surgical treatment is modified radical mastectomy (by Patey) with axillary lymph node dissection at the three levels, or organ-saving operation - quadrantectomy. Patients in stages I and II, in which organ-saving operation has been carried out, the 10-year survival was 82%. In the long run, women breast cancer survivors, reported higher levels of quality of life after primary treatment.
Post treatment follow-up is standard.

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