Endometrial cancer occurs more frequently in women after menopause, it is rare before the age of 40. Prognosis is generally good, endometrial cancer is often diagnosed when it is confined to the uterus. Overall survival is approximately 75% and depends on the stage (representing the spread of endometrial cancer) and histological diagnosis.

STAFF

At the IEO endometrial cancer is treated by a multidisciplinary team consisting of specialists in:

• Gynecologic Cancer Surgery
• Gynecologic Cancer Medical Treatments
• Unit of Preventive Gynecology
• Innovative Therapeutic Strategies in Ovarian Cancer Unit
• Peritoneal Cancer Surgery Unit
• New Drugs and Early Drug Development for Innovative Therapies
• Department of Pathology and Laboratory Medicine
• Department of Medical Imaging and Radiation Sciences

The most frequent type of endometrial cancer (type 1) is often preceded by precancerous forms that go under the name of atypical hyperplasia. These should be distinguished from simple or complex hyperplasia, benign forms that represent a risk factor for the development of endometrial cancer and precancerous lesions. In case of atypical hyperplasia in menopause, removing the uterus is preferred. In the case of young women desiring pregnancy, conservative treatment is possible, based on progestin hormones capable of atypia regression. Simple and complex non-atypical hyperplasia can also benefit from hormone treatment.

Based on a careful evaluation of the results of scientific research, it has been possible to identify specific risk factors and protective nutritional factors for specific types of cancer. Experts have classified the results into four levels: "convincing evidence", "probable evidence", "limited evidence" and one last level that collects the effects for which evidence of association with the cancer is “highly unlikely." The probable and convincing evidence forms the basis for the recommendations:

With regard to endometrial cancer, there is convincing evidence that excess weight and obesity are risk factors, while a high sugar intake in the diet is a likely risk factor. Among the protective factors for this cancer, there is probable evidence for regular physical activity and moderate consumption of coffee

Good prognosis of endometrial cancer is related to multiple favorable factors. The cancer generally occurs in menopause because the menstrual cycle involves a monthly renewal of the endometrium and it is therefore protective. When the endometrial cancer is formed, it typically bleeds. This symptom is abnormal in menopause, so the woman refers to the doctor and receives the diagnosis. The cancer is thus diagnosed because it is early symptomatic. Finally, the uterus is a muscle with very thick walls, and usually when diagnosis occurs, the cancer is still confined to the inner part of the organ and the removal of the uterus leads to healing in most menopausal cases.

Screening for endometrial cancer in asymptomatic women is not recommended since real benefits in terms of mortality reduction have not been observed. However, there are groups of women at high risk for endometrial cancer for which screening is recommended (users of tamoxifen (1), Lynch syndrome (2) based on the supposed benefits of early diagnosis, although there are no studies showing a reduction in mortality associated with the disease. In the case of women at high risk, gynaecological transvaginal ultrasound with the measurement of endometrial fissure and possible endometrial sampling have been proposed for screening.

(1) Tamoxifen or tamoxifen citrate is an anticancer drug taken orally, belonging to the family of oestrogen receptor selective modulators. The drug inhibits the effects of oestrogens, the hormones in women, through histone deacetylation, thus nullifying the effects of oestrogen-receptor binding to DNA. This is useful because breast cancer cells often thrive on these hormones. A number of studies show that tamoxifen increases the incidence of uterine cancers due to its pro-oestrogenic effect on the endometrium. The risk of inducing endometrial carcinoma is more pronounced in women who are post-menopausal, obese and in those previously subjected to HRT (hormone replacement therapy). Endometrial carcinoma develops in 0.5-1% of women taking tamoxifen for five years, with a tripled risk compared to controls. In addition, tamoxifen can induce endometrial hyperplasia and polyps. It is currently believed that tamoxifen-induced endometrial cancer does not possess malignancy features exceeding cancers found in the general population

(2) The Lynch syndrome (or hereditary non-polyposis colorectal cancer, or hereditary colorectal carcinomatosis on a non-polyposis basis, Hereditary Non-Polyposis Colon Cancer - HNPCC) is a hereditary form of colon cancer with dominant transmission, which means it has a 50% probability of occurrence in the children of those affected. Unlike familial adenomatous polyposis, the predisposition to the development of the disease is not manifested by the appearance of polyps, but directly with the development of colon cancer, usually around the age of 45. This is the main manifestation of Lynch syndrome I, while that of type II includes other possible malignancies at endometrium, ovary, stomach, urinary tract, bile ducts, in addition to colon cancer. The syndrome is caused by a mutation in one of the DNA MMR genes, MLH1, MSH2, MSH6 and PMS2. Women with Lynch syndrome (LS) have 40-60% risk of developing endometrial cancer, and about 10-15% risk of ovarian cancer. Several screening strategies have been studied but the real effectiveness of endometrial screening remains uncertain. Screening certainly plays a fundamental role in the group of high-risk women who want to avoid prophylactic surgery. The main guidelines recommend screening starting from the age of 30-35 through TV gynaecological ultrasound and endometrial sampling yearly.

Endometrial cancer symptoms are typically bleeding in postmenopausal or perimenopausal women, and recurrent inter-menstrual bleeding in women aged <40 years. However, there are many benign causes of bleeding in post-menopausal patients, endometrial atrophy (50%), endometrial hyperplasia (13%) or endometrial polyps (10%). There is a 10% chance of endometrial cancer and 1% of cervical cancer. Age is the most important independent risk factor associated with blood loss in menopause. Fifty percent of bleeding in women over 70 years is caused by endometrial cancer.

In cases of atypical blood loss, the diagnostic process includes:

Transvaginal gynecological ultrasound (TVS)

Transvaginal scan (TVS) can be associated with sonohysterography followed by histological endometrial sampling. This sampling can be performed in the doctor’s surgery with a very thin catheter (Pipelle de Cornier). This method is non-invasive and well tolerated and its accuracy is 90-98% (ability to correctly identify the stage of the endometrial cancer).

Hysteroscopy with biopsy

Hysteroscopy with biopsy is a viable and equivalent alternative to transvaginal ultrasound with sonohysterography for the diagnosis of endometrial cancer.

TV gynecological ultrasound

TV gynecological ultrasound is a non-invasive test performed in the doctor’s surgery. The ultrasound allows for the evaluation of endometrial thickness and morphology. The normal post-menopausal endometrium is thin, uniform with a thickness of about 1 mm, while in the cases of endometrial cancer it appears thickened and with different morphological characteristics and specifications, in most cases.

The sonohysterography is an ultrasound vaginal probe using contrast medium consisting of sterile saline solution introduced with a syringe into the uterine cavity via a special catheter. It is a test that is performed in the clinic and is well tolerated. Sonohysterography allows discriminating focal endometrial lesions from those spread to the entire endometrial surface and it shows characteristic features in the presence of an endometrial cancer.

• Irregular thickening of the endometrium with heterogeneous and irregular echogenicity at the endo-myometrial junction.
• Difficulty distending the uterine cavity during SCSH.
• The uneven surface of a focal lesion.

Hysteroscopy

Hysteroscopy is a minimally-invasive endoscopic method for both diagnosis and/or treatment of endometrial cancer through which it is possible to visualise the uterine cavity with an instrument called hysteroscope. Surgery can be performed under general anaesthesia or while awake (in selected cases). The first stage consists of the dilatation of the cervical canal with rigid instruments. Then the hysteroscope is introduced, allowing operations to be carried out in the uterus without leaving wounds and/or scars.

Diagnostic hysteroscopy is when the operator only observes the uterine cavity by performing - if necessary - a targeted biopsy of the endometrium. Instead, Operational Hysteroscopyis whenminor surgical interventions are performed during the procedure, such as removal of endometrial polyps or small intracavitary fibroids.

In the rare cases of endometrial cancer in young patients wishing to become pregnant, it is possible to propose a conservative treatment that allows for the preservation of the uterus, in the presence of favourable conditions. To undertake this course, precise conditions are required:

• Histologically-confirmed diagnosis of well-differentiated endometrial cancer (grade 1).
• Involvement of only endometrium without myometrial infiltration.
• Absence of spreading disease to extra-uterus locations, pelvic lymph nodes and peritoneum of the abdominal cavity.
• Patients motivated and eager for pregnancy.

Conservative therapy is based on the use of progestin-based hormonal therapy that aims to restore normality in the endometrium. Fundamental to this process is a close follow-up with imaging examinations and periodic hysteroscopic evaluations. This type of therapy should be initiated and supervised by a multidisciplinary medical team, with a high competence in conservative cancer treatment. Atypical endometrial hyperplasia also benefits from conservative hormone treatment in young women and requires specific monitoring.

There are several ongoing studies on the diagnosis of endometrial cancer and the treatment of precancerous endometrial lesions at the Unit of Preventive Gynaecology. In particular, a multicentre study on the standardisation of diagnostic endometrial ultrasound (IETA) is ongoing and an innovative protocol on the conservative treatment of endometrial carcinoma and precancerous lesions.

Metastases symptoms and treatment

Distant metastasis was defined according to the International Federation of Gynecology and Obstetrics and included non-regional lymph nodes (including inguinal lymph nodes for endometrial cancer) as well as lesions in the peritoneum, liver, lung and bone. The diagnosis is based on signs, symptoms and imaging. New classes of drugs and new interventions have given a better quality of life to patients and improved their life expectancy. It is necessary a multidisciplinary approach to treat patients with metastasis, in particular bone metastasis. Bone metastases are classified as osteolytic, osteoblastic or mixed, according to the primary mechanism of interference with normal bone remodeling. Bone metastases symptoms are characterized by severe pain, impaired mobility, pathologic fractures, spinal cord compression, bone marrow aplasia and hypercalcemia. Treatment decisions depend on several parameters, for example, whether bone metastases are localized or widespread, whether there is evidence of extraskeletal metastases, the kind of endometrial cancer and its features, prior treatment history and disease response, symptoms and the general state of health. Treatments can often shrink or slow the growth of bone metastasis and can help with the related symptoms but they are not curative. Distant metastasis guides treatment strategy, triggering initiation of chemotherapy or radiation therapy regimens aimed at controlling hematogenous spread of disease and/or targeting individual metastatic lesions for palliation. Thus, pain management with analgesic and radiation should be utilized as indicated during the initiation of these therapies. Radiotherapy is the treatment of choice for both localized bone pain and in presence of poorly localized bone pain or recurrence of pain in previously irradiated skeletal sites.