notes by dr Claudio Italiano
Ovarian cancer is the leading cause of death for gynecological neoplasms in the United States. In 1996, 26700 new cases were diagnosed and 14800 deaths registered. This disease is responsible for 5% of all female cancer deaths in the United States; more women die for this type of neoplasia than for carcinoma of the cervix and endometrium considered together. The age-specific incidence of the most common ovarian malignant tumors increases progressively and reaches its peak in the eighth decade of life. Ovarian cancer is quite rare before age 40. Epidemiological studies indicate higher incidences in industrialized nations and an association with disorders of ovarian function that include fertility, nulliparity, repeated abortions and the use of ovulation-inducing drugs such as clomiphene. Each pregnancy reduces the risk of ovarian cancer by about 10% and breastfeeding and ligation also appear to reduce the risk. oral contraceptives reduce the risk of ovarian cancer both in patients with a family history of cancer and in the general population. Many of these risk reductions are in support of the "ovulation incessant" hypothesis underlying the etiology of ovarian cancer, which implies that an aberrant process of superficial epithelium repair is essential for the development of ovarian carcinoma. estrogen replacement after menopause does not appear to increase the risk of ovarian cancer, although a study has found a modest increase in risk for hiring above 11 years.
Family cases represent about 5% of all ovarian malignancies and a family history of ovarian cancer is a major risk factor. Women with an affected first-degree family have a risk of 5% compared to 1.6% of the general population. In families with two or more first-degree family members, the risk may exceed 50%. We recognize three types of malignant tumors with family recurrence and autosomal dominant inheritance:
1) site-specific, in which only ovarian cancer is evident;
2) family member associated with breast cancer;
3) Lynch's type 11 neoplastic family syndrome, which includes non-polypomatous
colorectal carcinoma, endometrial cancer and ovarian cancer.
In women with hereditary forms of ovarian-mammary cancer, the susceptibility locus, BRCA-1, is located on chromosome 17q12-21. It is probable that BRCA-1 is a tumor suppressor gene and the synthesized protein acts as a negative regulator of tumor growth. A large number of BRCA-1 mutations have been described; in most cases they are "frameshift" or nonsense mutations and in 86% of cases there is the production of truncated proteins. The exact implication of the myriad of other mutations, including the numerous missense mutations, is not known. Male subjects belonging to such families have an increased risk of prostate cancer. Cytogenetic analysis of sporadic ovarian malignant tumors usually shows complex chromosomal rearrangements. Structural abnormalities frequently appear on chromosomes 1 and 11 and loss of heterozygosity (LOH) is quite common on chromosomes 3q, 6q, 1 lq and 17. There are also frequent oncogenes that include c-myc. , Il-ras, K-ras and neu. Ovarian tumors (usually non-epithelial) are sometimes components of complex genetic syndromes. Peutz Jeghers syndrome (intestinal polyps and mucocutaneous pigmentation) is associated with tumors of the sexual stromal strings of the ovary and Sertoli cell tumors in humans. Patients with gonadal dysgenesis (46XY genotype or mosaics of cells containing Y lines) develop gonadoblastomas and women with basocellular nevoid carcinomas have an increased risk of ovarian fibromas.
Clinical picture and differential diagnosis In most ovarian cancer patients the diagnosis is made when the disease has already spread beyond the pelvis. The appearance of abdominal pain, distention of the abdomen and urinary symptoms usually indicate an advanced stage of the disease. Localized ovarian cancer is generally asymptomatic.
However, the progressive increase of a localized ovarian tumor may result in the appearance of voiding frequency and constipation, while rarely the torsion of an ovarian mass causes the appearance of acute abdominal pain or surgical abdomen. Unlike cervical carcinoma or endometrial cancer, bleeding or vaginal discharge are rarely present in the early stages of ovarian cancer. Early diagnosis of the disease usually occurs following palpation of an asymptomatic adnexal mass during a routine pelvic exploration. However, the majority of the ovarian masses identified for the objective examination is represented by functional benign cysts that characteristically disappear over three menstrual cycles. Adrenal masses that occur in women before menarche or after menopause are more frequently pathological and usually require surgical exploration. The three causes of adnexal masses include pedunculated uterine fibroids, endometriosis, benign ovarian neoplasms and inflammatory bowel lesions. Evaluation of patients with suspected ovarian cancer should include measurement of serum CA125 tumor marker levels. The determinants of CA-125 are glycoproteins with molecular dimensions ranging from 220 to 1000 kDa and radioimmunoassays are used to determine their levels in the circulation. Approximately 80-85% of patients with ovarian cancer have levels of CA-125 equal to or greater than 3 5 U / ml. Other malignancies can also result in elevated CA-125 levels, such as endometrial cancer, cervix, tuba, pancreas, breast, lung and colon cancer. Non-malignant conditions sometimes characterized by high CA125 values include pregnancy, endometriosis, pelvic inflammatory disease and uterine fibroids. About 1% of normal women have serum CA-125 levels above 35 U / ml. However, in postmenopausal women with asymptomatic pelvic mass and CA125 levels of 65 U / ml or higher the sensitivity of the test is 97% and its specificity is 78%.
Unlike patients with advanced disease at the time of diagnosis, patients with early-stage ovarian cancer (stages I and II) are commonly treatable with conventional therapy. For this reason screening procedures should have an impact on the rate of cure of the disease. Although pelvic exploration can sometimes identify the disease at an early stage, it is a very sensitive screening procedure. A transvaginal ultrasound has replaced the abdominal ultrasound, which is slower and less sensitive, but has a significant number of false positive results, particularly in premenopausal women. Images obtained with Doppler color in association with transvaginal ultrasound can improve accuracy and reduce the high risk of false positive results. The use of CA-125 as a screening medium has been studied. Unfortunately, half of the women with stage 1 or IL disease have CA-125 levels below 65 U / ml. Other non-malignant diseases may present with high CA-125 values and false-negative and positive results have been reported in most of the screening studies. Attempts have been made to improve sensitivity and specificity with the combination of different procedures, usually transvaginal ultrasound and CA-125 levels. In a screening study conducted on 22,000 women, 42 were screened positive and I I had ovarian cancer (including 7 at an advanced stage). Furthermore, 8 women with negative screening developed ovarian cancer. So, if on the one hand the screening allows to diagnose malignant ovarian malignancy at an early stage in asymptomatic women, on the other hand the percentage of false positive results would be such as to lead to a large number of unnecessary laparotomies (ie negative) in the hypothesis that Positivity to screening involved a surgical exploration. The Consensus Conference of the National Institutes of Health advised against the use of ovarian cancer screening in the general population in the absence of known risk factors for the disease.
Epithelial tumors represent the majority (85%) of ovarian neoplasms. They may be
benign (50% of cases), malignant (33% of cases) or low malignant potentiality
(16% of cases), the latter also called borderline "in relation to malignancy."
Malignant carcinomas with low malignant potential have characteristics cytology
of malignancy but do not invade the ovarian stroma More than 75% occur at an
early stage and generally occur in young women.
Apart from benign tumors, such as ovarian cyst, the malignant tumors of the
ovary are of three types:
- epithelial tumors
- germ cell tumors
- stromal tumors.
Epithelial tumors originate from epithelial cells that superficially coat the
ovaries. They constitute more than 90% of malignant ovarian neoplasms.
Germ cell tumors originate from germ cells (those that give rise to eggs); they
represent about 5% of malignant ovarian neoplasms, are almost exclusive of young
age (childhood and adolescence) and are differentiable from other malignant
tumors of the ovary because they produce tumor markers found in the blood (such
as alfaprotein or chorionic gonadotropin) different from those produced by
tumors of epithelial origin.
Stromal tumors originate from the gonadal stroma (ovary supporting tissue). In
theory they constitute an easily diagnosed group since the symptoms common to
all ovarian tumors combine hormonal effects (ie linked to an excessive
production of both female and male hormones, because part of the cells is able
to produce testosterone). Most of these tumors are characterized by low
malignancy. They represent about 4% of malignant ovarian neoplasms.
The most recent classification of Kurman distinguishes ovarian carcinoma in two
groups, defined as type I and II.
Type I tumors arise from well-differentiated cells, such as borderline tumors (ie,
the border between malignancy and benignity); some of these may be slow-growing
(low-grade serous carcinomas). Type I tumors are correlated with a certain type
of mutations affecting specific genes (including KRAS, BRAF, PTEN and b-catenin).
Type II tumors, on the contrary, are high-grade, rather aggressive, tumors that
arise directly from the epithelial tissue of the organ, without going through a
precancerous phase. These tumors are very unstable from the genetic point of
view and show mutations in the P53 gene. Hereditary tumors related to BRCA1 and
BRCA2 genes are type II.
Natural history is clearly better for the benign, obviously, than the malignant
counterpart. There are five main subtypes of epithelial ovarian tumors: serous
(50%), mucinosis (25%), endometriosis (15%), clear cell (5%) and Brenner's tumor
(1%), the latter deriving from the urothelium. Benign epithelial tumors are
almost always serous or mucinous and develop in women between the ages of 20 and
60. They are frequently large (20-30 cm), bilateral and typically cystic.
Malignant epithelial tumors occur in individuals over 40 years. They are solid masses with areas of necrosis and haemorrhage. In the presence of masses larger than 10-15 cm the disease has already spread in the intra-abdominal spaces. Dissemination can be peritoneal carcinomatosis, which leads to renal or intestinal obstruction and cachexia.
Although the prevalence of ovarian tumors is epithelial, two other major categories of ovarian tumors include stromal cell tumors and germ cell tumors. These tumors, distinguished by their cellular origin, clinical presentation and natural history, are often managed differently. Ovarian metastases can originate from carcinomas of the breast, color, stomach and pancreas and Krukenberg's tumor has been classically described as bilateral ovarian masses resulting from gastrointestinal carcinomas.
|
|
ovary | surliving at 5 years |
endometrial | surliving at 5 years | cervical | surliving at 5 years |
| I | Confined to the ovary | 90% | Confined to the body | 89% | Carcinoma in situ | 100% |
| II | Confined at the pelvis | 70% | Body and cervix | 80 | Confined to the uterus no to the pelvis | 85 |
| III |
Intra diffusion |
15-20% | Beyond the uterus but not beyond the pelvis | 30 | Extended to the pelvis and the lower third of the vagina | 33 |
| IV |
Extra distribution |
1-5% | at the rectum and bladder | 9 | Diffused to the mucosa of the bladder or rectum | 7 |
Although laparotomy is often the primary procedure used to define the diagnosis, less invasive investigation techniques can help in defining the extent of disease extension. They include chest radiography, computed tomography (CT) of the abdomen and abdominopelvic ultrasound. If the patient has specific gastrointestinal symptoms, opaque enema should be performed or serial x-rays of the gastrointestinal tract. Symptoms related to changes in bladder or renal function can be assessed by cystography or intravenous pyelography. An accurate laparotomy performed for staging purposes allows to establish the stage and extent of the disease and allows to perform a cytoreduction of the tumor mass in patients with advanced disease. An appropriate laparotomy involves a longitudinal incision of appropriate length to ensure accurate examination of the abdominal viscera. The presence and quantity of ascitic fluid should be evaluated by studying its cytology. The primary tumor must be examined for the presence of growths, thick adhesions and rupture. Careful visual and manual inspection of the diaphragm and peritoneal surface is required. In addition to total abdominal hysterectomy and bilateral salpingo-oophorectomy, a partial homologectomy is required and paracolic lodges must be inspected. 1 pelvic lymph nodes, as well as paraaortic lymph nodes in the renal hilar region, must be biopsied. Since the surgery defines the stage, establishes the prognosis and provides the indications for the subsequent therapy, it must be performed by a surgeon with specific expertise in the staging of ovarian cancer. Some studies have shown that in patients operated by an oncologist gynecologist the disease had been correctly staged in 97% of cases against 52% and 35% of cases in which the disease had been staged, respectively, by obstetricians / gynecologists and general surgeons. At the end of the staging process, in 23% of women the disease is in stage I (cancer limited to ovary or ovaries); in 13% in stage II (disease confined to the actual pelvis); in 47% in stage RI (diffuse disease but confined to the abdomen) and in 16% in stage IV (extrapelvic and extraddominal diffusion). The 5-year survival is related to the stage of the disease, resulting equal to 90% in stage 1, 70% in stage 11, 15-20% in stage 111, and -1-5% in stage IV. The prognosis of ovarian cancer depends not only on the stage, but also on the extent of the residual disease and the histological degree. Patients presenting with advanced disease but who lack significant disease residues after surgery have a mean survival of 39 months compared to 17 months of patients with suboptimal tumor mass resection. The prognosis in epithelial tumors also depends greatly on the histological grade and to a lesser extent on the histotype. Studies in patients with early-stage disease have associated longer survival with mucinus adenocarcinomas than with endometrioid or serous histotypes and a worse prognosis for clear cell carcinomas. Although anatomopathologists use different grading systems, in every grading system the best prognosis is reserved for well or moderately differentiated tumors and the worst prognosis for poorly differentiated histological subtypes. The typical 5-year survival, regardless of the stage of the disease, turns out to be the following: well-differentiated carcinoma, 88%; moderately differentiated carcinoma, 58%; poorly differentiated carcinoma, 27%. The prognostic significance of the pre- and post-operative CA-125 levels is poorly defined
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