Endometrial carcinoma is the most common malignancy of the female genital tract, usually appearing in postmenopausal women. Estrogen excess is the most significant risk factor. Clinical presentation involves postmenopausal bleeding, while premenopausal women report recurrent bleeding between cycles. The diagnosis is made by biopsy and treatment usually, depends on the stage at diagnosis. Total hysterectomy, bilateral salpingo-oophorectomy as well as proximal lymphadenectomy is usually performed, together with adjuvant therapy.
In virtually all patients with endometrial carcinoma, bleeding is the primary and most often the only symptom. In postmenopausal women, vaginal bleeding occurs in more than 90% of patients , while perimenopausal women may experience recurrent bleeding episodes during regular menstrual cycles. Bleeding occurs as a result of ulceration and erosion of the endometrium and in addition to bleeding, uterine enlargement may be observed in some cases. Vaginal bleeding unrelated to any physiologic process should be considered as a sign of endometrial cancer, which is why a full workup should be conducted to exclude this potentially life-threatening disease. Sometimes the patient may have complaints of abdominal pain, cramps in pelvic region and pain during sexual intercourse.
The diagnostic workup starts with a thorough physical and gynecological examination, which can reveal some important information such as the size of uterus or presence of a mass either in the endometrium, vagina, or in the adnexa. If there is strong suspicion of a malignancy, endometrial biopsy is the recommended procedure, as it yields a very high rate of accuracy. In some cases, curettage and hysteroscopy may be performed to confirm the diagnosis. Once the obtained sample undergoes microscopic examination, several pathological changes may be clearly observed. Endometrioid carcinoma appears strikingly similar to normal endometrial glands and may have several forms, including squamous, ciliated and mucinous.Nonendometroid types include serous and clear-cell variants, the serous type being characterized by the appearance of small papillae with much greater cytologic differentiation . Depending on the stage of the tumor, malignant cells may infiltrate various layers of the uterus, which is why the use of imaging techniques, such as computed tomography (CT) or magnetic resonance imaging (MRI) should be performed to assess potential presence of metastases. Surgical staging of endometrial carcinoma is frequently the recommended diagnostic method as it can clearly show the extent of malignant infiltration of the tumor and is favored over imaging and clinical studies . Other supporting procedures may include Papanicolaou (Pap) smear, which can reveal endometrial cells in postmenopausal women, or atypical cells of the endometrium in any patient .
Treatment may depend on the stage of the tumor at diagnosis, but in the vast majority of patients, surgical treatment is the method of choice. Total hysterectomy, together with bilateral salpingo-oophorectomy and sometimes para-aortic and pelvic lymphadenectomy is recommended for stages I, II and III. Laparoscopy, laparotomy, or the use of robotic surgery, are all methods that are used depending on tumor staging . Radiation and chemotherapy are indicated in patients with stages II, III and IV, which often proves better prognosis than surgery alone. Various chemotherapeutic agents, such as cisplatin, doxorubicin, carboplatin, and paclitaxel are all used in various combinations and have shown good results . The use of progesterone is advocated in patients with advanced stages of the disease, which is also favorable in the setting of endometrial hyperplasia.
In addition to I-IV staging system, tumors are also graded according to the degree of nuclear atypia, which is sometimes more important in prognosis, especially for some rarer forms such as squamous clear cell adenocarcinomas. Tumors are divided into G1 (≤ 5% of tumor presents with a nonsquamous or nonmodular growth pattern), G2 (6-50%) and G3 (more than 50%). Vascular invasion of the tumor is also an important prognostic factor .
Fortunately, almost 75% of patients are diagnosed with endometrial carcinoma in its early stages, which significantly improves long-term survival rates . 5-year Survival rates are over 80% for patients with stage I or II, while stages III and IV carry a significantly poorer prognosis, with approximately 30% of patients achieving 5-year survival. For these reasons, an early diagnosis is detrimental for achieving good patient outcomes.
There are two main forms of endometrial carcinoma. Endometrioid (adenocarcinoma) form, because of its striking histological similarity to endometrial glands,is the common form of EC. This type of tumors most commonly occurs due to increased levels of estrogen in circulation. Obesity, nulliparity, diabetes mellitus and ovulatory dysfunction have all been recognized to increase circulating estrogen levels, all occurring in the absence or very low levels of progesterone . Iatrogenic factors may also cause excess estrogen, such as the use of tamoxifen , which reduces estrogen levels in breast tissue, but significantly increases its concentrations in the uterus. The use of hormone replacement therapy has also shown to pose a significant risk for developing endometrioid carcinoma . The other form, known as nonendometroid carcinoma, develops more commonly in postmenopausal women on the grounds of endometrial atrophy. Several mutations have been identified in this malignancy, most notably in p53, which is a tumor suppressor gene. In addition, two familial syndromes, Hereditary nonpolyposis colon cancer syndrome (HNPCC) and Cowden's syndrome were shown to significantly increase the risk of development of endometrial carcinoma. In HNPCC, mutations of DNA mismatch repair genes has been established, including mutS homolog 1 and 2 (MSH 1 and 2) and post-meiotic segregation family of genes (PMS1). Cowden's syndrome, which includes the formation of numerous hamartomas, is known to occur partly due to mutations in PTEN gene, which is also a tumor suppressor gene, in addition to the mutation in DNA mismatch repair genes.
Endometrial carcinoma is the most common gynecological malignancy worldwide and it is the fourth most common cancer in women according to certain studies . Recent data indicate that approximately 43,000 women were diagnosed in the United States in 2010, while almost 8,000 women died from this malignancy . European studies established a crude incidence rate of 16 per 100,000 women per year, with a mortality rate of 4-5 per 100,000 women per year, with a lifetime risk of developing endometrial carcinoma established to be between around 2%, both in the US and in Europe . Risk factors include obesity, diabetes mellitus, infertility, nulliparity, but also hypertension, use of tamoxifen and hormone replacement therapy. Family history positive for endometrial carcinoma is also known to be a risk factor, especially in families with HNPCC.
The pathogenesis of endometrial carcinoma starts with increased estrogen stimulation of endometrial tissue without accompanying effects of progesterone, which leads to endometrial hyperplasia. This lesion is though to be the first step in development of endometrioid form of this malignancy in the majority of cases. Estrogen is known to be a potent mitogen and stimulates transcription of various growth factors and proto-oncogenes. Additionally, gene defects in tumor suppressor genes, such as p53 and PTEN, but also mutations in DNA mismatch repair genes have all been identified in patients with endometrial carcinoma , which leads to a significant disruption of normal mitotic activity of endometrial cells. Consequently, malignant alterations occur, and in about 80% of cases, adenocarcinoma occurs. On the other hand, serous endometrial carcinoma develops independently of estrogen stimulation. Endometrial atrophy is one of the key events in this type of tumor, together with suppression of p53 .
Because several risk factors are responsible for developing endometrial carcinoma, appropriate steps in prevention can be made. Diabetes and hypertension can be reduced through adequate dietary habits and exercise, aided by proper pharmacologic therapy when necessary. Patients in whom a familial component increases the risk of this malignancy, such as family history of HNPCC (also known as Lynch syndrome), may favor from prophylactic hysterectomy, as well as bilateral salpingo-oophorectomy once childbearing age passes . In terms of reducing the risk for iatrogenic causes, patients should carefully use hormone replacement therapy and drugs such as tamoxifen, which is sometimes used for prophylaxis against breast cancer.
Endometrial carcinoma is one of the forms of uterine cancer and is established to be the most frequent malignancy of the female genital tract . There are two main forms, endometrioid and nonendometroid. Endometrioid carcinoma is characterized by malignant cells which closely resemble normal endometrial glands and most commonly occurs on the ground of endometrial hyperplasia. On the other hand, type II EC is characterized by poor differentiation and significant aggressiveness, occurring more commonly in the setting of endometrial atrophy. Several risk factors have been established, with excess estrogen being the most significant one. Obesity, diabetes mellitus, hypertension, infertility, and use of tamoxifen are also recognized risk factors for this malignant tumor, but genetic factors are thought to be implicated as well  . Hereditary nonpolyposis colon cancer syndrome (HNPCC) and Cowden's syndrome are two familial syndromes in which increased rates of this tumor are observed. In these syndromes, mutations of genes responsible for DNA mismatch repair and defects in tumor suppressor genes are observed, specifically the phosphatase and tensin homolog (PTEN) genes. Mutations in other tumor suppressor genes, primarily p53, have been reported in many patients. This malignancy is most commonly diagnosed in postmenopausal women between 55-65 years of age, while cases in premenopausal women below 40 years of age have been documented as well. The main clinical presentation is bleeding in postmenopausal women. In perimenopausal women, recurrent episodes of bleeding between cycles are frequently reported. The diagnosis of this tumor is made by endometrial biopsy, with surgical and imaging techniques used to establish the staging of the tumor, which is shown to directly reflect the prognosis. Endometrial carcinoma is classified in stages I (the tumor is confined to the body of uterus), II (involvement of the uterus and the cervix), III (invasion to other structures in the pelvis) and IV (distant metastasis or bladder involvement), with 5-year survival rates ranging between 70-95% for stage I and 10-60% for stages III and IV . Treatment in virtually all cases includes total hysterectomy together with the bilateral removal of ovaries and fallopian tubes (salpingo-oophorectomy). Proximal lymphadenectomy is indicated in stages II and III, but also in stage I when there is extensive involvement of the uterus. In patients with distant metastases, chemotherapy, and/or radiation therapy may be combined with surgery .
Endometrial carcinoma is one of the most common malignant tumors in women and is the most common malignancy of the female genital tract worldwide. There are several distinct subtypes of this tumor, but by far the most common form is endometrioid (around 80%), named because of its very similar appearance to normal endometrial glands, while nonendometroid carcinoma is the second most common form, established in around 10% of patients. In most cases, the cause is excessive amounts of estrogen in the absence of progesterone, which leads to the extensive proliferation of the endometrium and creates favorable conditions for the development of malignant cells. Tumors may also occur on the grounds of endometrial atrophy, which is why this tumor most commonly occurs in postmenopausal women between 55 and 65 years of age. However, it may be seen in perimenopausal women younger than 40 years, although in much smaller rates. Several risk factors have been established, such as obesity, hypertension, diabetes mellitus, infertility, nulliparity and use of hormone replacement therapy. The use of tamoxifen, a drug often given as a preventive measure for breast cancer, is shown to significantly increase the risk for endometrial carcinoma. The family history of endometrial cancer is also shown to be a significant risk factor. Certain inherited conditions such as Cowden's syndrome and Hereditary nonpolyposis colon cancer syndrome carry much higher risks for developing this type of tumor. A lifetime established risk for developing endometrial carcinoma worldwide is established to be about 2%. Virtually all patients present with vaginal bleeding, either during menopause or between regular menstrual cycles and no other symptoms need to be examined. This symptom should always include endometrial carcinoma in the differential diagnosis because an early discovery significantly improves survival rates of patients. Based on its growth and involvement of other tissues and organs, endometrial carcinoma is staged from 1 to 4, 1 implying only endometrial involvement and 4 indicating presence of distant metastases. Initial diagnosis can be made during the gynecological examination, but a definite diagnosis is made by performing a biopsy of the endometrium, with a subsequent microscopic examination. Based on tumor staging, treatment includes surgery, chemotherapy, radiation and the use of chemotherapeutic agents. In the majority of patients, however, complete removal of the uterus, ovaries, and fallopian tubes is recommended for all stages of endometrial carcinoma. Chemotherapy and radiation may be used as adjuvant therapy in patients with the more severe disease. Significant steps in terms of prevention can be made, such as proper management of diabetes and hypertension through good dietary habits and regular exercise, while the use of hormonal therapy needs to be carefully evaluated by the physician. Certain studies have recommended preventive removal of the uterus in women who have a positive family history of endometrial cancer, but only after their childbearing age has passed. Overall, this form of cancer carries a very good prognosis if caught early and fortunately the majority of women are diagnosed in early stages.