Excess exposure to unopposed estrogen (exogenous or endogenous) is the most common risk factor for uterine cancer.
Obesity is the most common source of endogenous estrogen exposure. Androstenedione is converted to estrogen by aromatase in adipose tissue. Nearly 70% of early-stage endometrial cancer patients are obese. The lifetime risk of developing endometrial cancer is 10% to 15% in women with a body mass index (BMI) of 40 kg/m2 or greater.
Unopposed estrogen replacement, without concomitant progesterone, is the most common form of exogenous estrogen exposure. In women with an intact uterus on estrogen replacement, it is imperative that a progesterone is also administered to prevent the development of endometrial hyperplasia and/or cancer.
Tamoxifen, a selective estrogen receptor modulator, increases the relative risk of developing endometrial cancer. In a postmenopausal female taking tamoxifen who experiences bleeding, the estimated risk of endometrial cancer is approximately 7.8%.
Chronic anovulatory states, such as those seen in polycystic ovarian syndrome (PCOS), lead to constant estrogen stimulation of the endometrium. In addition, lower levels of progesterone are present secondary to absence of a corpus luteum. Nulliparity and infertility have also been linked to endometrial cancer.
Age increases the risk of uterine cancer. Approximately 80% of newly diagnosed cases occur at age ≥55.
Hereditary/familial syndromes predispose individuals to the development of many cancers, including uterine cancer (Table 53-2).
Lynch syndrome accounts for 2% to 5% of all endometrial cancers. It is inherited in an autosomal dominant fashion resulting from a germline mutation in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2). Patients with Lynch syndrome have a 17% to 71% risk of developing uterine cancer depending on the specific gene mutation. These women are also at a significantly higher risk for cancers of colorectal, renal pelvis, ureter, and ovarian origin.
Women with Cowden syndrome, an autosomal dominant condition with a mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor gene, have a 13% to 19% lifetime risk of uterine cancer.
Primary prevention of cancer should be a goal for any health care provider. Given the high rates of cancer development in those with an identified hereditary/familial cancer syndrome, these patients will have unique needs for screening and prevention (Table 53-2).
| Genetic Syndrome | Pathogenesis | Cancer Risk | Screening | Intervention |
|---|---|---|---|---|
| BRCA1 | Mutation in BRCA1 tumor suppressor gene on chromosome 17; autosomal dominant | Breast: 65–74% Ovarian: 39–46% Other: pancreatic | Annual breast MRI age 25–29; alternating breast MRI and mammogram q6mo age 30+ TVUS and CA-125 may be reasonable for short-term surveillancea | Risk-reducing BSO age 35–40; risk-reducing bilateral mastectomy should be offered |
| BRCA2 | Mutation in BRCA2 tumor suppressor gene on chromosome 13; autosomal dominant | Breast: 65–74% Ovarian: 12–20% Other: pancreatic, prostate | Risk-reducing BSO age 40–45; risk-reducing bilateral mastectomy should be offered | |
| Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome) | Mutation in mismatch repair genes (MLH1, MLH2, MSH6, PMS2, EPCAM); autosomal dominant | Colorectal: 52–82% Endometrial: 25–60% Ovarian: 4–24% Other: stomach, small bowel, and others | Colonoscopy q1–2y age 20–25+ (or 2–5 y prior to earliest onset of colorectal cancer in family) Endometrial biopsy q1–2y age 30–35+ | Risk-reducing hysterectomy/BSO after completion of childbearing or age 40–45 Consider progestin-based contraception |
| Cowden syndrome | Mutation in phosphatase and tensin gene (PTEN); autosomal dominant | Endometrial: 5–10% Breast: 25–50% Other: thyroid, colon, and others | Annual mammogram and breast MRI age 30+ (or 10 y prior to earliest onset of breast cancer in family) Consider endometrial biopsy q1–2y age 35 (TVUS screening not recommended) | Discuss risk-reducing hysterectomy upon completion of childbearing (oophorectomy not recommended) Discuss risk-reducing bilateral mastectomy |
| Other recommended screening includes: colonoscopy, thyroid ultrasound, dermatologic exam, renal ultrasound | ||||
| Peutz–Jeghers syndrome | Mutation in serine/threonine kinase 11 gene (STK11); autosomal dominant | Colorectal: 39% Breast: 32–54% Ovary: 21% Cervical: 10% Other: pancreas, small bowel, and others | Annual breast MRI and mammography age 30+ Colonoscopy and endoscopy q2–3y age 18+ Annual pelvic exam and pap (endometrial biopsy if AUB) age 18–20 y+ Annual TVUS 18–20 y+ Annual pancreatic imaging age 30–35+ | Discuss risk-reducing hysterectomy/BSO upon completion of childbearing Discuss risk-reducing bilateral mastectomy |
| Li–Fraumeni syndrome | Mutation in tumor suppressor gene TP53; autosomal dominant | Lifetime cancer risk for females approaches 100% (sarcomas, breast, brain, colon, and others) | Annual breast MRI age 20–29; annual breast MRI and mammogram 30–75 Colonoscopy and upper endoscopy q2–5y age 25 (or 5 y prior to earliest onset of GI cancer in family) Annual dermatologic exams, whole body MRI, brain MRI | Discuss risk-reducing bilateral mastectomy |
aHas not been shown to decrease mortality or increase survival rates.