Description and Epidemiology
Uterine cancer is among the most prevalent gynecologic carcinomas affecting women worldwide. It involves invasive neoplasms of the corpus uteri that originate from either the endometrial (innermost) or myometrial (middle) layers of the uterus (Malpica et al., 2019). The disease has multiple etiologies with two major subgroups recognized based on tumor origin: endometrial cancer (endometrium) and sarcoma (myometrium). Endometrial carcinoma is the most prevalent type of uterine cancer in North America and Europe. A less common but more aggressive subtype is the malignant mixed Müllerian tumor (MMMT), a uterine carcinosarcoma.
The uterine cancer incidence varies globally, reflecting differential exposure to risk factors – overweight and reproductive health. The most affected are countries in Northern Europe and North America. In the United States, uterine malignancy is the fourth most prevalent cancer, with 63,230 new cases diagnosed in 2018 (Felix & Brinton, 2018). Age is also a risk factor in the development of this disease. Uterine cancer is rare among women aged below 45 years but more common in the 40-60 years age bracket (Felix & Brinton, 2018). Globally, the disease is the sixth most diagnosed cancer based on age-adjusted incidence rates.
In the United States, uterine cancer incidence has shown rising trends over the years. The disease peaked in 1975 due to increased hormone (estrogen) therapy in the 1970s and obesity prevalence (Henley et al., 2018). The incidence rate declined in the subsequent decades until recently, when it began to rise in response to overweight trends. The age-standardized mortality rate is higher in the United States than in Europe, at 4.6 versus 2 per 100,000 females (Passarello et al., 2019). Racial disparities exist in disease incidence, with minority women being disproportionately affected. A two-fold increase in mortality is found in black women diagnosed with endometrial cancer compared to their white counterparts (Malpica et al., 2019). Advanced stage disease is associated with low survival rates and outcomes. Among the risk factors associated with this disparity in survival are socioeconomic disadvantages, comorbidities, and limited access to quality treatment.
Normal Physiology of the System
The uterus is a hollow muscular organ located in the female pelvis. Its histological structure comprises three tissue layers: the endometrium, myometrium, and serosa or perimetrium (Passarello et al., 2019). The endometrial thickness changes in response to hormonal stimulation and estrogen exposure. The uterus is anatomically divided into three components: the fundus, body (corpus), and cervix, with ligaments holding it in position (Henley et al., 2018). The most common uterine cancers affect the endometrial and myometrial layers of the corpus. In normal cases, after fertilization, the embryo implants and develops in the uterine body through the fetal stage. The placenta is embedded into the endometrium and nourishes the fetus. If the ovum is not fertilized, the endometrial layer is shed monthly as menstrual flow between menarche and menopause.
The ovulation phase precedes a menstrual cycle, and the entire process is under hormonal control. Elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) induce follicular maturation and increase estrogen levels (Malpica et al., 2019). The endometrium proliferates and thickens in response to high estradiol concentration to prepare for implantation of the embryo. Critical estrogen levels have a positive feedback effect on LH, resulting in the release of an ovum. If the egg is not fertilized, LH concentration drops, causing the estrogen and progesterone levels to also decrease (Henley et al., 2018). However, if fertilization occurs, implantation of the embryo into the endometrium occurs, triggering more progesterone release to prevent uterine wall shedding. The proliferative effect of estradiol causes hyperplasia, which increases the risk of endometrial cancer.
Pathophysiology and Effects on the Body System
Endometrial cancers are classified as type I and type II based on their pathophysiological features. Type I is the most common type, accounting for 70-80% of uterine cancer diagnoses (Passarello et al., 2019). An unopposed estradiol exposure induces endometrial hyperplasia, which, if untreated, develops into adenocarcinoma. Thus, type I carcinomas are estrogen-dependent and involve the proliferative effect of this hormone on the endometrium and myometrium.
Type II endometrial cancers are less common than type I carcinomas. Overall, they account for 10-20% of all diagnoses but present as high-grade, advanced-stage, and serious malignant cells (Henley et al., 2018).). Estradiol exposure is not implicated in type II cancer development. This disease is linked to atrophic endometrium, especially in old age, with precursor endometrial intraepithelial carcinomas involved in its etiology (Passarello et al., 2019). MMMTs also belong to this category and develop from mixed cell carcinosarcomas. Estrogen and progesterone receptors that are highly expressed in type I adenocarcinomas remain repressed in type II cancer development.
The onset and progression of endometrial cancer have adverse effects on the uterus in postmenopausal women. In asymptomatic cases, the endometrium becomes atrophic, resulting in the undifferentiated inner basal layer and superficial stratum functional (Passarello et al., 2019). The uterine mucosa also becomes inactive because endometrial glands fail to express estrogen receptors in response to estradiol exposure. Thus, estrogen stimulation does not increase endometrial proliferative activity in uterine cancer diagnoses.
Genetic Influences and Related Risk Factors
Various genetic alterations, including sporadic mutations, are involved in endometrial cancer development. One genetic predisposition that precedes disease onset is the lynch syndrome (LS), an autosomal dominant condition caused by “germline mutations occurring in any of the mismatch repair genes (MLH1, MSH2, MSH6, or PMS2)” (Passarello et al., 2019, p. 163). LS elevates the risk of gastric, colorectal, ovarian, and types I endometrial cancers. Therefore, screening for alterations in mismatch repair genes can help for early uterine cancer diagnosis and treatment. Mutations in the gene that encodes phosphatase and tensin homolog (PTEN) also increase endometrial cancer risk. They cause loss of PTEN phosphatase activity (Cowden syndrome), which leads to aberrant cell proliferation and spread, causing adenocarcinomas (Passarello et al., 2019). Promoter methylation also alters PTEN expression, contributing to type II endometrial cancer development.
Mutations in the KRAS oncogene are associated with tumor growth in the endometrium. This gene codes for a GTPase that acts as a molecular switch, activating factors involved in cell-signaling pathways connected with uterine carcinogenesis (Passarello et al., 2019). KRAS alterations have been detected in most endometrial hyperplasias. P53 gene mutations have also been found in 80% of endometrial intraepithelial carcinomas that advance into serious type II cancers (Henley et al., 2018). Alterations in two other genes encoding transmembrane proteins, HER2 and E-cadherin, have been implicated in cellular proliferation, and metastasis, and inhibited apoptosis.
A key epigenetic mechanism involved in endometrial cancer development is DNA methylation. MLH1 methylation is associated with a buildup of incorrect nucleotide insertions or deletions inactivating this mismatch repair gene (Passarello et al., 2019). Therefore, hypermethylation causes MLH1 silencing, which is implicated in type I endometrial cancer. The loss of expression in MLH1 is associated with PTEN and KRAS mutations, suggesting that the carcinomas are multifactorial.
Other related risk factors for uterine cancer besides genetic predisposition include age, obesity, racial background, and estradiol exposure. Postmenopausal women aged 60 and above are at a higher risk of endometrial cancer than young, premenopausal females are – 85% of diagnoses versus 5% of cases (Henley et al., 2018). The higher incidence in the older population is linked to overweight and anovulatory cycles at this age. In North America, racial disparities in uterine cancer exist, with white women having a greater lifetime risk than black females (2.88% versus 1.69%) (Henley et al., 2018). However, the latter are disproportionately affected by serious type II endometrial cancer due to differences in healthcare access. Metabolic syndromes, especially obesity and type 2 diabetes, are linked to an elevated risk of malignant carcinomas. In obese, postmenopausal women, peripheral androgen is converted to estrogen in adipose cells, and anovulation is high, increasing the predisposition to endometrial cancer. Unopposed estradiol exposure due to hormone replacement therapy to manage menopausal complications also increases the risk of carcinomas.
Clinical Presentation of the Disease
A primary assessment is performed to identify risk factors and evaluate presenting symptoms. The patient’s medical and family history should also be reviewed to determine genetic predisposition and inform therapy and interventions. The most frequent primary indicator for uterine cancer is abnormal uterine bleeding or spotting, especially in postmenopausal women. About 90% of female patients present with this symptom and atypical vaginal discharge and a biopsy test should be done to eliminate endometrial cancer as the probable cause (Henley et al., 2018). Another primary indicator is pyometra, a life-threatening uterine infection. Histologically, this condition is characterized by the accumulation of lymphocytes and pus in the endometrium. The symptoms occur at the early stage of the disease.
A typical late indicator of uterine cancer is chronic abdominopelvic pain. Women with advanced disease may also experience abdominal distension or bloating and drastic weight loss. Other presenting complaints include early satiety, bowel and bladder problems, and dyspnea (Henley et al., 2018). In the advanced disease stage, women may complain of pain during intercourse. Abnormal cytology is a late indicator of endometrial cancer in postmenopausal females. It may entail the occurrence of endometrial cells or adenocarcinoma on pap smears. Hysterectomy is indicated for late-stage uterine cancer after the pelvic exam and biopsy confirmation of the disease.
A comprehensive physical exam can reveal early or late-stage disease, with asymptomatic patients having normal findings. Suspected supraclavicular lymph nodes should be examined by palpation (Denschlag & Ulrich, 2018). A speculum exam is performed to evaluate the condition of the cervix and vagina and ensure that the adenocarcinoma is not spreading to the cervical tissues. Another diagnostic tool is a pelvic examination, which assesses the position of the uterine corpus or the extension of the parametria. An endometrial biopsy (EMB) procedure is a confirmatory test for uterine cancer diagnosis. A negative EMB result for symptomatic individuals warrants further investigation by hysteroscopy (Denschlag & Ulrich, 2018). The goal is to establish the cause of uterine bleeding in the patient.
Imaging provides another diagnostic tool for evaluating abnormal uterine bleeding. Transvaginal ultrasound can indicate the structure of the endometrium and uterine size. According to Denschlag and Ulrich (2018), and endometrial thickness of 5 mm or less is not indicative of type I adenocarcinoma. However, type II carcinomas may occur in thin endometria; hence, biopsy tests are recommended in symptomatic patients. Computerized tomography (CT) can help evaluate the disease stage and metastasis. This imaging tool is useful for detecting type II tumors and the extent of myometrial invasion for chemotherapy considerations (Denschlag & Ulrich, 2018). A chest x-ray is done to eliminate metastatic lung disease as the cause of pain before performing CT.
Imaging studies may not identify lymph node involvement in suspected stage I-III disease. However, CT or magnetic resonance imaging (MRI) may be useful when a biopsy test has confirmed type II endometrial tumors. These serious carcinomas increase the risk of the disease spreading beyond the uterus before symptom onset. Imaging can detect inoperable cancer that requires radiation treatment or chemotherapy (Passarello et al., 2019). It may also provide a basis for recommending invasive procedures such as laparotomy to remove the growth. MRI is used to assess the extent of myometrial invasion and tumor extension to the cervix to inform fertility-preserving treatments for pre-menopausal patients.
Preoperative assessments are performed to determine the risk of heart disease in symptomatic patients and select the surgical procedure – laparotomy or cytoreduction. Laboratory tests can help indicate comorbid conditions and tumor markers associated with endometrial cancer. Complete blood count and kidney function are routinely assessed before invasive procedures. Assays for a tumor marker of endometrial cancer, serum CA-125, can be performed to determine if the disease has spread to organs other than the uterus (Denschlag & Ulrich, 2018). Positive results will indicate late-stage type II endometrial carcinoma and extra-uterine cancer.
Treatment and Management
Various treatment modalities are indicated for patients diagnosed with endometrial cancer. The most recommended option is surgery – total hysterectomy (TH) to lower the risk of uterine carcinoma and metastasis. According to the National Comprehensive Cancer Network [NCCN] (2019) guidelines, TH with bilateral salpingo-oophorectomy (BSO) is the first treatment option for cancer that has not spread to the pelvis or abdomen. TH and BSO entail removing the entire uterus and adnexa (through ovariectomy and salpingectomy), respectively.
For women with unresectable tumors, a non-surgical treatment, which includes radiation therapy combined with chemotherapy, is provided. In addition to these two procedures, the NCCN (2019) endorses hormone therapy for extra-uterine diseases or inoperable patients who do not respond to chemotherapy. This method may also be useful for pre-menopausal women diagnosed with early-stage disease. TH/BSO and evaluation of the lymph nodes in the first-line treatment for uterine-restricted endometrial cancer (Passarello et al., 2019). An abdominal assessment is required to determine if the disease is only localized in the uterus. The procedure entails examining the diaphragm and peritoneal membrane and performing a biopsy for high-risk individuals.
Surgical procedures can be used to remove the uterus, cervix, ovaries, and fallopian tubes. Robotic laparoscopy is a minimally invasive method for uterine removal, ovariectomy, or salpingectomy (Passarello et al., 2019). Such approaches often result in reduced postoperative hospitalization period and lower infection rates. Thus, minimally invasive procedures are recommended to remove smaller endometrial tumors. On evaluation, extended pelvic lymph nodes should be excised to avoid cancer spread. This assessment is recommended as a basis for indicating adjuvant therapy followed by radiotherapy or chemotherapy (Denschlag & Ulrich, 2018). TH/BSO and lymphadenectomy are useful for uterus-confined cancer, while radical hysterectomy and BSO may be considered in cases where the cervix is affected.
Another treatment for all endometrial cancer diagnoses is sentinel lymph node (SLN) mapping. This approach allows a more exhaustive evaluation of the pelvic and para-aortic nodes in cases than when lymphadenectomy is used (Denschlag & Ulrich, 2018). In this procedure, a dye is injected into the cervical lumen to detect the uterine lymphatic pathway and metastasis using an infra-red camera. SLN mapping is a more accurate approach to the identification of metastatic lymph nodes than lymphadenectomy.
Adjuvant therapy is recommended for early-stage endometrial cancer to prevent relapse and reverse the pathophysiology of the disease. The treatment is indicated for elderly patients, with high-risk histology, lymphovascular invasion, high-grade tumors, and affected cervix (Passarello et al., 2019). Adjuvant chemotherapy is usually considered for patients with invasive myometrial cancer, while chemo-radiation or radiotherapy (RT) is recommended for unresectable tumors at stage III. The use of adjuvant RT in early-stage endometrial cancer is not beneficial (Denschlag & Ulrich, 2018). It reduces disease recurrence but does not improve survival rates. The International Society of Gynecologic Pathologists’ indication for adjuvant RT includes grade III tumors with no myometrial invasion for which brachytherapy may be needed (Malpica et al., 2019). The treatment is also considered for grade I or II carcinomas with extensive myometrial invasion. Adjuvant RT is administered as either low-dose vaginal cuff or external beam radiation.
Chemotherapy is less effective than RT because endometrial cancers are less responsive to this treatment modality. However, in high-risk, late-stage diseases or unresectable tumors, multi-drug regimens are recommended. The NCCN (2019) guidelines endorse adjuvant chemotherapy for type II disease to reduce the risk of extra-uterine spread. Different drug combinations can be used for advanced diseases, such as cisplatin/doxorubicin and carboplatin/paclitaxel. The carboplatin/paclitaxel combination therapy improves survival by 40-62% and is well tolerated compared to other medications (NCCN, 2019). Single-drug chemotherapy can also be administered to treat endometrial cancer. Drugs such as paclitaxel, doxorubicin, and docetaxel can be prescribed to manage this disease.
Hormonal therapy is another treatment option for uterine cancer, stage I tumors for which noninvasive treatment is indicated. Available agents aim to enhance the expression of estradiol and progesterone receptors (Malpica et al., 2019). Among them is progestin-based therapy, which is indicated for metastatic endometrial cancer. Other hormonal options include LH-releasing agonists and tamoxifen indicated for patients requiring fertility-preserving treatment (Malpica et al., 2019). Novel therapies also exist for managing endometrial cancer at any disease stage. Immunotherapeutic agents are being tested as inhibitors of molecular processes involved in tumor development. Examples include phosphoinositide 3-kinase and metformin, which are being explored in clinical trials to determine efficacy and safety.
Metastasis and Prognosis
Localized or more distant metastasis is associated with type II endometrial cancer. The regional metastatic disease affects the pelvic lymph nodes, cervix, ovaries, and fallopian tubes (Passarello et al., 2019). The lymphatic pathway is the primary mechanism of distant metastasis. Lung metastases, as revealed through x-ray imaging, are evidence of unresectable disease. Uterine cancer prognosis is based on the carcinoma stage and histology (Denschlag & Ulrich, 2018). Type I endometrial tumors are generally associated with better prognoses than type II diseases. The two categories of cancer can be differentiated based on the histologic type. The survival rate is high for patients diagnosed with early-stage disease.
Generally, type I tumors involve a good prognosis compared to type II endometrial carcinomas. They include well-differentiated, low-grade adenocarcinomas that are localized in the uterus during diagnosis. In contrast, type II disease is high-grade and poorly-differentiated tumors that are usually aggressive and metastatic (Denschlag & Ulrich, 2018). They present at a late stage; hence, has a poor prognosis and a five-year survival rate, especially among high-risk older women.
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