Endometrial cancer

Endometrial cancer refers to several types of malignancies that arise from the endometrium, or lining, of the uterus. Endometrial cancers are the most common gynecologic cancers in the United States, with over 35,000 women diagnosed each year. The most common subtype, endometrioid adenocarcinoma, typically occurs within a few decades of menopause, is associated with excessive estrogen exposure, often develops in the setting of endometrial hyperplasia, and presents most often with vaginal bleeding. Endometrial carcinoma is the third most common cause of gynecologic cancer death (behind ovarian and cervical cancer). A total abdominal hysterectomy (surgical removal of the uterus) with bilateral salpingo-oophorectomy is the most common therapeutic approach.

Endometrial cancer may sometimes be referred to as uterine cancer. However, different cancers may develop not only from the endometrium itself but also from other tissues of the uterus, including cervical cancer, sarcoma of the myometrium, and trophoblastic disease.

Carcinoma
Most endometrial cancers are carcinomas (usually adenocarcinomas), meaning that they originate from the single layer of epithelial cells that line the endometrium and form the endometrial glands. There are many microscopic subtypes of endometrial carcinoma, including the common endometrioid type, in which the cancer cells grow in patterns reminiscent of normal endometrium, and the far more aggressive papillary serous carcinoma and clear cell endometrial carcinomas. Some authorities have proposed that endometrial carcinomas be classified into two pathogenetic groups:


 * Type I:  These cancers occur most commonly in pre- and peri-menopausal women, often with a history of unopposed estrogen exposure and/or endometrial hyperplasia. They are often minimally invasive into the underlying uterine wall, are of the low-grade endometrioid type, and carry a good prognosis.


 * Type II: These cancers occur in older, post-menopausal women, are more common in African-Americans, are not associated with increased exposure to estrogen, and carry a poorer prognosis. They include:
 * the high-grade endometrioid cancer,
 * the uterine papillary serous carcinoma,
 * the uterine clear cell carcinoma.

Sarcoma
In contrast to endometrial carcinomas, the uncommon endometrial stromal sarcomas are cancers that originate in the non-glandular connective tissue of the endometrium. Uterine carcinosarcoma, formerly called Malignant mixed müllerian tumor, is a rare uterine cancer that contains cancerous cells of both glandular and sarcomatous appearance - in this case, the cell of origin is unknown.

Histological types: I- Endometrial Adenocarcinoma Commonest. 3 grades:- G1: Highly differentiated (composed of glands and 5% of lesion is of solid growth pattern). G2: Moderately differentiated ( 6%-50% of lesion composed of solid sheets of cells). G3: Undifferentiated ( > 50% of lesion composed of solid sheets of cells). Subtypes of endometrial adenocarcinoma: Endometrioma --> most common. Clear cell.--> most malignant. Secretory. Mucinous. Papillary serous.--> common with hereditary types.

II- Adenoacanthoma (adenocarcinoma with squamous metaplasia). Less than 10%. Malignant glandular element + benign squamous element low grade tumour good prognosis.

III- Adenosquamous carcinoma Malignant glandular element + malignant squamous element high grade malignancy poor prognosis.

IV- Carcinosarcoma Highly malignant. Epithelial and stromal malignant elements.

Signs and symptoms

 * Vaginal bleeding and/or spotting in postmenopausal women.
 * Abnormal uterine bleeding, abnormal menstrual periods.
 * Bleeding between normal periods in premenopausal women in women older than 40: extremely long, heavy, or frequent episodes of bleeding (may indicate premalignant changes).
 * Anemia, caused by chronic loss of blood. (This may occur if the woman has ignored symptoms of prolonged or frequent abnormal menstrual bleeding.)
 * Lower abdominal pain or pelvic cramping.
 * Thin white or clear vaginal discharge in postmenopausal women.

Risk factors

 * high levels of estrogen
 * endometrial hyperplasia
 * obesity
 * hypertension
 * polycystic ovary syndrome
 * nulliparity (never having carried a pregnancy)
 * infertility (inability to become pregnant)
 * early menarche (onset of menstruation)
 * late menopause (cessation of menstruation)
 * endometrial polyps or other benign growths of the uterine lining
 * diabetes
 * Tamoxifen
 * high intake of animal fat
 * pelvic radiation therapy
 * breast cancer
 * ovarian cancer
 * anovulatory cycles
 * age over 35
 * heavy daily alcohol consumption (possibly a risk factor)

Clinical evaluation
Routine screening of asymptomatic women is not indicated, since the disease is highly curable in its early stages. Results from a pelvic examination are frequently normal, especially in the early stages of disease. Changes in the size, shape or consistency of the uterus and/or its surrounding, supporting structures may exist when the disease is more advanced.

Diagnostic test study of S-p53 Ab and agreement study for high-risk endometrial cancer Kappa: 0.70  Sensitivity (%): 64   Specificity(%): 96   PPV: 78   NPV: 92
 * A Pap smear may be either normal or show abnormal cellular changes.
 * Endometrial curettage is the traditional diagnostic method. Both endometrial and endocervical material should be sampled.
 * If endometrial curettage does not yield sufficient diagnostic material, a dilation and curettage (D&C) is necessary for diagnosing the cancer.
 * Hysteroscopy allows the direct visualization of the uterine cavity and can be used to detect the presence of lesions or tumours. It also permits the doctor to obtain cell samples with minimal damage to the endometrial lining (unlike blind D&C).
 * Endometrial biopsy or aspiration may assist the diagnosis.
 * Transvaginal ultrasound to evaluate the endometrial thickness in women with postmenopausal bleeding is increasingly being used to evaluate for endometrial cancer.
 * Recently, a new method of testing has been introduced called the TruTest, offered through Gynecor. It uses the small flexible Tao Brush to brush the entire lining of the uterus. This method is less painful than a pipelle biopsy and has a larger likelihood of procuring enough tissue for testing. Since it is simpler and less invasive, the TruTest can be performed as often, and at the same time as, a routine Pap smear, thus allowing for early detection and treatment.
 * Ongoing research suggests that serum p53 antibody may hold value in identifying high-risk endometrial cancer.

Pathology
The histopathology of endometrial cancers is highly diverse. The most common finding is a well-differentiated endometrioid adenocarcinoma, which is composed of numerous, small, crowded glands with varying degrees of nuclear atypia, mitotic activity, and stratification. This often appears on a background of endometrial hyperplasia. Frank adenocarcinoma may be distinguished from atypical hyperplasia by the finding of clear stromal invasion, or "back-to-back" glands which represent nondestructive replacement of the endometrial stroma by the cancer. With progression of the disease, the myometrium is infiltrated. However, other subtypes of endometrial cancer exist and carry a less favorable diagnosis such as the uterine papillary serous carcinoma and the clear cell carcinoma.

Further evaluation
Patients with newly-diagnosed endometrial cancer do not routinely undergo imaging studies, such as CT scans, to evaluate for extent of disease, since this is of low yield. Preoperative evaluation should include a complete medical history and physical examination, pelvic examination and rectal examination with stool guaiac test, chest X-ray, complete blood count, and blood chemistry tests, including liver function tests. Colonoscopy is recommended if the stool is guaiac positive or the woman has symptoms, due to the etiologic factors common to both endometrial cancer and colon cancer. The tumor marker CA-125 is sometimes checked, since this can predict advanced stage disease. In addition to this, both D&C and Pipelle biopsy curettage give 65-70% positive predictive value. But most important of these is hysteroscopy which gives 90-95% positive predictive value.

Staging
Endometrial carcinoma is surgically staged using the FIGO cancer staging system. Although the FIGO staging has recently been updated, the older staging described below is still commonly used.
 * Stage IA: tumor limited to the endometrium
 * Stage IB: invasion of less than half the myometrium
 * Stage IC: invasion of more than half of the myometrium
 * Stage IIA: endocervical glandular involvement only
 * Stage IIB: cervical stromal invasion
 * Stage IIIA: tumor invades serosa or adnexa, or malignant peritoneal cytology
 * Stage IIIB: vaginal metastasis
 * Stage IIIC: metastasis to pelvic or para-aortic lymph nodes
 * Stage IVA: invasion of the bladder or bowel
 * Stage IVB: distant metastasis, including intraabdominal or inguinal lymph nodes

The 2010 Figo staging system is as follows: Carcinoma of the Endometrium
 * IA        Tumor confined to the uterus, no or < ½ myometrial invasion
 * IB        Tumor confined to the uterus, > ½ myometrial invasion
 * II         Cervical stromal invasion, but not beyond uterus
 * IIIA     Tumor invades serosa or adnexa
 * IIIB     Vaginal and/or parametrial involvement
 * IIIC1   Pelvic lymph node involvement
 * IIIC2   Para-aortic lymph node involvement, with or without pelvic node involvement
 * IVA      Tumor invasion bladder and/or bowel mucosa
 * IVB      Distant metastases including abdominal metastases and/or inguinal lymph nodes

Treatment
The primary treatment is surgical. Surgical treatment should consist of, at least, cytologic sampling of the peritoneal fluid, abdominal exploration, palpation and biopsy of suspicious lymph nodes, abdominal hysterectomy, and removal of both ovaries (bilateral salpingo-oophorectomy). Lymphadenectomy, or removal of pelvic and para-aortic lymph nodes, is sometimes performed for tumors that have high risk features, such as pathologic grade 3 serous or clear-cell tumors, invasion of more than 1/2 the myometrium, or extension to the cervix or adnexa. Sometimes, removal of the omentum is also performed.

Abdominal hysterectomy is recommended over vaginal hysterectomy because it affords the opportunity to examine and obtain washings of the abdominal cavity to detect any further evidence of cancer.

Women with stage 1 disease who are at increased risk for recurrence and those with stage 2 disease are often offered surgery in combination with radiation therapy. Chemotherapy may be considered in some cases, especially for those with stage 3 and 4 disease. hormonal therapy with progestins and antiestrogens has been used for the treatment of endometrial stromal sarcomas.

The antibody Herceptin, which is used to treat breast cancers that overexpress the HER2/neu protein, has been tried with some success in a phase II trial in women with uterine papillary serous carcinomas that overexpress HER2/neu.

Complications of treatment

 * Uterine perforation may occur during a D&C or an endometrial biopsy.

Prognosis
While endometrial cancers are 40% more common in Caucasian women, an African American woman who is diagnosed with uterine cancer is twice as likely to die (possibly due to the higher frequency of aggressive subtypes in that population, but more probably due to delay in the diagnosis).

Survival rates
The 5-year survival rates for endometrial adenocarcinoma following appropriate treatment are :

Epidemiology
It's the most frequent cancer occurring in the female genital tract in the United States and many other Western countries. It appears most frequently between ages of 55 and 65, and uncommon below 40. There are two pictures of this disease, perimenopausal women with estrogen excess and in older women with endometrial atrophy.