Endometrial carcinoma arises from the cells that make up the glands of the uterus. It usually arises when estrogen stimulates the glandular tissue in an uncontrolled fashion; however, estrogen independent forms of endometrial cancer also exist. Endometrial cancer usually arises on a background of both hyperplasia and atypical cellular features.
When too much estrogen is present, endometrial tissue undergoes a process known as hyperplasia. Hyperplasia refers to excessive proliferation of the cells that compose the endometrium. Hyperplasia can be either simple or complex. Simple hyperplasia occurs when both the glands, and the tissue surrounding the glands (aka: stromal tissue), proliferate equally. Complex hyperplasia occurs when the glands proliferate more than the surrounding tissue.
In addition to hyperplasia, the cells that make up the glands can start to look "atypical". The atypical appearance is manifested by irregular cell shapes, decreased cytoplasm to nucleus ratio (ie: the nucleus takes up more space in the cell), crowding of the normal glandular architecture, and prominent nucleoli. Cellular atypia is an ominous sign of cancer.
Therefore, there are different classifications of endometrial hyperplasia depending on whether or not atypical features are present, and weather or not the hyperplasia is simple or complex. The different classifications are outlined in the table below:
|Classification of endometrial hyperplasia:|
|Simple hyperplasia without atypia|
|Complex hyperplasia without atypia|
|Simple hyperplasia with atypia|
|Complex hyperplasia with atypia|
The importance of the atypia is that it predicts progression to cancer. Once complex hyperplasia with atypia is present, the risk of progressing to cancer is approximately 30%. By comparison, the risk of complex hyperplasia without atypia is only 3%.
Why cancer develops in some, but not all patients with complex hyperplasia is not entirely known, but may be due to inactivation of the tumor suppressor gene PTEN. When the PTEN gene is mutated (or absent) the glandular cells are more sensitive to estrogen stimulation.
The second form of endometrial adenocarcinoma is estrogen independent. It is a rarer form of the disease, and the pathology is not entirely understood.
The most common symptom of endometrial cancer is abnormal uterine bleeding. If this occurs in a post-menopausal woman cancer of the endometrium must be ruled out. Non-specific signs of cancer such as weight loss, fatigue, and malaise can also occur.
Risk factors for developing endometrial cancer are related to the amount of a woman's life that estrogen has been able to stimulate the endometrium.
For example, menopause occurring at the age of 52 or older increases risk. Estrogen replacement therapy during, or after menopause increases risk. Having had no children (aka: nulliparity) increases the risk (ie: in essence, a women who has had a child has had 9 fewer cycles of estrogen stimulation on the endometrial tissue compared to a patient who has never been pregnant). Obesity also increases the risk because fat tissue converts adrenal hormones (ie: androstenedione) into estrogens (ie: estrone), which can lead to endometrial hyperplasia. In addition, rare ovarian tumors that secrete estrogen can also cause endometrial carcinoma.
Diagnosis is via biopsy of the endometrial tissue. In general, all women greater than 35 years of age with abnormal bleeding, or atypical glandular cells on Pap smear should have a biopsy of the uterine tissue.
Biopsy is the only way to tell if endometrial cancer is present. Biopsy will also show hyperplasia and/or atypia, which are considered pre-cancerous. There is about a 10% false negative rate with biopsy; therefore, if patients continue to have symptoms they should be watched closely and/or re-biopsied at a later date.
Treatment depends on biopsy results. If the biopsy returns as simple hyperplasia without atypia, medical therapy with hydroxyprogesterone (a progestin) is usually started. If atypical cells are seen, then post-menopausal women usually undergo hysterectomy (surgical removal of the uterus).
However, in pre-menopausal women who may not be done childbearing, dilation and curettage and progestin therapy is usually recommended.
If the biopsy returns as cancer then hysterectomy with or without radiation and progestins is initiated depending on the stage of disease.
A very crude outline of treatment options is shown in the flow chart to the left.
Endometrial carcinoma occurs most commonly after excessive estrogen stimulation. Endometrial hyperplasia with atypia is considered a pre-cancerous lesion. Symptoms are generally limited to abnormal uterine bleeding. However, risk factors include anything that can lead to increased estrogen stimulation of the endometrium. Diagnosis is based on biopsy of the tissue. Treatment is based on biopsy results and ranges from progestin therapy to hysterectomy and radiation.
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