Raised and unopposed (hormone) levels can lead to endometrial cancer.
USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 60-year-old woman comes to the office because of post-menopausal bleeding for the last two weeks. She states that the flow was initially similar to that of her prior menses, but over the last week she only experienced intermittent spotting. Endometrial biopsy shows complex hyperplasia without atypia. Which of the following, if present, is a risk factor associated with her condition?
The uterus is a hollow organ that sits behind the urinary bladder and in front of the rectum.
The top of the uterus above the openings of the fallopian tubes is called the fundus, and the region below the openings is called the uterine body.
The uterus tapers down into the uterine isthmus and finally the cervix, which protrudes into the vagina.
Zooming into the cervix, there are two openings, a superior opening up top, and an inferior opening down below, both of which have mucus plugs to keep the uterus closed off except during menstruation and right before ovulation.
The uterus is anchored to the sacrum by utero-sacral ligaments, to the anterior body wall by round ligaments, and it’s supported laterally by cardinal ligaments as well as the mesometrium, which is part of the broad ligament.
The wall of the uterus has three layers: the perimetrium, which is a layer continuous with the lining of the peritoneal cavity, the myometrium, which is made of smooth muscle that contracts during childbirth to help push the baby out, and the endometrium, a mucosal layer, that undergoes monthly cyclic changes.
The endometrium is itself made up of a single layer of simple columnar epithelium, which has ciliated and secretory cells, that sit on top of connective tissue, or stroma.
There any many grooves in the stroma which is lined by the epithelium and these are the uterine glands which secrete a glycogen rich fluid that’s essential for the developing embryo during early pregnancy.
Endometrial carcinoma involves the abnormal growth of the epithelial cells that make up endometrial glands, and there are two main types.
The most common is Type 1 endometrial carcinoma, which is also called endometrioid carcinoma because the tumours grow in a way that looks like normal endometrial glands.
It usually involves several genetic mutations in endometrial cells, including of PTEN, a tumor suppressor gene; PIK3CA, an oncogene; and ARID1A, a gene regulating chromatin structure.
All of these mutations increase signaling in the PI3K/AKT pathway, which promotes growth and replication of endometrial cells.
More signaling in the PI3K/AKT pathway also enhances the expression of genes which are linked to estrogen receptors.
Now, excessive estrogen can come from obesity, because fat cells convert adrenal precursors into sex hormones; taking tamoxifen, a breast cancer medication that blocks estrogen receptor in the breasts, but stimulates them in the uterus; and postmenopausal estrogen therapy given without a progestin to “balance” it out.
Other risk factors related to high estrogen levels are never having been pregnant; chronic anovulation, when the ovaries don’t release an egg during a menstrual cycle; and having many menstrual cycles.
Finally, a hereditary condition called Hereditary nonpolyposis colorectal cancer, also called Lynch syndrome, causes a high risk of developing certain cancers, including colon cancer and endometrial carcinoma.
The good news is that there are actually factors that protect against Type 1 endometrial carcinoma!
Taking hormonal contraceptives, being older at the time you give birth, and breastfeeding all reduce the risk of developing this type of cancer.
Now, type 2 endometrial carcinoma is more rare, and it has a number of subtypes.
The most common subtype is serous carcinoma.