Uterine Cancer (Endometrial Carcinoma): Causes

Pathogenesis (development of disease)

Endometrial carcinoma is a malignant neoplasm (malignant neoplasm) of the epithelial portion of the endometrium (lining of the uterus). Two types are distinguished:

  • Estrogen-associated type I carcinoma [estrogen and/or progesterone receptors: usually positive].
  • Estrogen-independent type II carcinoma [estrogen and/or progesterone receptors: mostly negative or weakly positive]

Type I

Estrogen-associated type I carcinoma (90% of all endometrial carcinomas) belongs histopathologically to the endometrioid adenocarcinomas (possibly with a squamous component). Continuous stimulation with endogenous or exogenous estrogens leads to increased proliferation (“rapid growth”) of the endometrium i.e. to hyperplasia (“excessive cell formation”) and possibly to malignant (“malignant”) altered cells via atypical endometrial hyperplasia. This mechanism is exacerbated by the absence of progestogens. Age of patients: 55-65 years. Endometrial hyperplasia is subdivided as follows:

  • Simple hyperplasia (carcinoma risk <1%).
  • Complex hyperplasia without atypia (carcinoma risk about 2%).
  • Complex hyperplasia with atypia (carcinoma risk about 30%).

Typical diseases leading to this carcinoma via atypical endometrial hyperplasia are obesity and anovulatory cycles (in e.g., PCO syndrome) or use of partial estrogen agonists (e.g., tamoxifen) or estrogen hormone replacement therapy. (The former nomenclature of endometrial hyperplasia – “high-grade or atypical adenomatous hyperplasia” – is obsolete.) Atypical endometrial hyperplasia is considered a precancerous condition (tissue change or a tumor that is a possible precursor to cancer) of endometrioid adenocarcinoma (type I carcinoma)

Type II

About 10% of endometrial carcinomas belong to estrogen-independent type II carcinoma. This belongs histopathologically to the serous or clear cell carcinomas, which by definition are classified as poorly differentiated. It usually arises from endometrial intraepithelial carcinoma (EIC) in the atrophic endometrium (“atrophied” endometrium).Patients with type II carcinoma are usually older, usually slender, and thus do not have the risk factors of estrogen dominance. Risk factors for type II carcinoma are age and previous radiatio (radiotherapy) of the uterus (e.g. due to cervical carcinoma). Age of patients: 65-75 years. Carcinoma in situ (Tis) of the endometrium is considered a precancer of type II serous clear cell carcinoma. Note: Type II endometrial carcinomas, unlike type I endometrial carcinomas, have a very poor prognosis even at early tumor stages.

Etiology (causes)

Biographic causes

  • Genetic burden from parents, grandparents (positive family history regarding endometrial cancer and/or colon cancer/colorectal cancer)
    • HNPCC syndrome (engl. hereditary non-polyposis colorectal cancer; hereditary colorectal cancer without polyposis, also known as “Lynch syndrome“) – genetic disorder with autosomal dominant inheritance; in addition to the increased risk of early colorectal carcinomas (carcinomas of the colon (intestine) and rectum (rectum)), mutation carriers are more likely to develop endometrial and ovarian carcinomas (cancer of the endometrium and ovaries). Note: The median risk of developing endometrial cancer in such cases is about 45 years.
    • It is estimated that about 5-10 percent of all patients with endometrial cancer have an increased genetic risk. An increased risk exists if a woman has previously had colon cancer or breast cancer (breast cancer; BRCA gene).
  • Age – older age (for type II endometrial cancer).
  • Socioeconomic factors – high socioeconomic status.
  • Hormonal factors
    • Early menarche (first menstrual period)
    • Frequent cycle abnormalities [esp. anovulatory cycles/cycles without ovulation].
    • Nulliparity (childlessness)
    • Long life phase with menstrual bleeding / late menopause (last menstrual period).

Behavioral causes

  • Nutrition
    • Foods containing acrylamide (Group 2A carcinogen) – this is metabolically activated to glycidamide, a genotoxic metabolite; an association between exposure to acrylamide and risk of endometrial carcinoma (type I carcinoma) has been demonstrated for patients who are neither smokers nor have taken oral contraceptives
    • Micronutrient deficiency (vital substances) – see prevention with micronutrients.
  • Physical activity
    • “Frequent sitters” (66% higher risk from sitting while watching TV; 32% increase in risk for total sitting time)
  • Psycho-social situation
    • Night work
  • Overweight (BMI ≥ 25; obesity), obesity.
    • Increase in BMI (body mass index) by 5 kg/m2 increases risk by a relative 59
    • Obesity is associated with earlier age at diagnosis of endometrioid endometrial cancer

Disease-related causes

  • Atypical endometrial hyperplasia (pathological changes in the endometrium, with atypical changes at the cellular level), which in circa one-third of cases progresses to endometrial carcinoma
  • Diabetes mellitus (diabetes).
  • Infertility
  • Liver dysfunction
  • Mammary carcinoma (breast cancer)
  • Metabolic syndrome – clinical name for the symptom combination obesity (overweight), hypertension (high blood pressure), increased fasting glucose (fasting blood sugar) and fasting insulin serum levels (insulin resistance) and lipid metabolism disorder (increased VLDL triglycerides, decreased HDL cholesterol). Furthermore, a coagulation disorder (increased tendency to clotting), with an increased risk of thromboembolism can often be detected.
  • Estrogen- and androgen-producing tumors.
  • PCO syndrome (polycystic ovary syndrome or Stein-Leventhal syndrome) – refers to a complex of symptoms characterized by hormonal dysfunction of the ovaries (ovaries), including cyst formation in the ovaries and anovulatory cycles (cycles without ovulation).

Laboratory diagnoses – laboratory parameters that are considered independent risk factors.

  • Impaired glucose tolerance
  • Estradiol ↑
  • Fasting insulin ↑

Medication

Other causes

  • Radiation therapy to the pelvis and abdomen (abdominal cavity) (for type II endometrial cancer).