I Endometrial Cancer

Epidemiology and Risk Factors

In the development of endometrial cancer, age is the most important risk factor. This is a disease predominantly seen in the postmenopausal female, with a median age at diagnosis of 60 years.³ Other risk factors that have been associated in developing endometrial cancer are long-term exposure to unopposed estrogens, residence in North America and Europe, metabolic syndrome (obesity, diabetes), years of menstruation, nulliparity, history of breast cancer, long-term use of tamoxifen, hereditary nonpolyposis colorectal cancer (HNPCC) family syndrome, hormone-replacement therapy with less than 12 to 14 days of progestagens, and first-degree relative with endometrial cancer.⁴

African American women tend to be diagnosed with higher stage, grade, and risk histologies than non-Hispanic white women.⁵ Although some cases of endometrial cancer have a hereditary basis, the vast majority are sporadic. HNPCC, Lynch’s syndrome, is an autosomal dominant cancer presenting with early-onset colon, rectal, ovary, small bowel, ureter/renal pelvis, and endometrial cancers. Two to 5% of endometrial cancers are associated with the Lynch syndrome.⁶ The gynecologic cancer (endometrial or ovarian) presents earlier than colon cancer in about half of the patients with Lynch’s syndrome.^4,6,,7

Anatomy and Pathology

Two types of endometrial cancer have been described and are associated with the degree of exposure to estrogen levels. Type 1 (low-grade) endometrial cancers are the most common (~80-85%), are associated with long-standing estrogen exposure, occur in younger women, and develop in a background of endometrial hyperplasia. The endometrioid type of endometrial carcinoma accounts for approximately 80% of all endometrial carcinomas. These neoplasms tend to be well differentiated, have minimal myometrial invasion, and have a favorable prognosis.

Type 2 tumors (~10%), are high-grade lesions, are associated with endometrial atrophy, occur in older females, and are at high risk of relapse and metastases. The histologic pattern is that of a poorly differentiated or nonendometrioid carcinoma. The serous and clear cell types belong in this type 2 tumors, with deeper myometrial and vascular invasion frequently present.

On immunohistochemical staining, PTEN mutations are common in type 1 tumors and uncommon in serous tumors. TP53 mutations are not common in type 1 tumors but are common in serous carcinoma.⁴ Other histologic types of endometrial carcinomas include mucinous, mixed, squamous cell, transitional cell, and undifferentiated.⁴ Women taking tamoxifen for the treatment of breast cancer are at an increased risk of developing endometrial cancer; however, the risk-benefit ratio favors the use of tamoxifen. Newer aromatase inhibitors are now available and are being used instead of tamoxifen.

Clinical Presentation

Abnormal uterine bleeding is the classic symptom for endometrial carcinoma. This is more so in postmenopausal women and in those with high risk factors. Occasionally, a female undergoes a pelvic sonogram and is found to have a thickened endometrium or has an abnormal Papanicolaou (Pap) smear. Abdominal distention, pain, and pressure may be presenting symptoms indicating intraperitoneal spread and may mimic that of ovarian cancer.

An office endometrial biopsy (EMB) is more commonly used to sample the endometrium. Other diagnostic procedures include a dilatation and curettage (D&C) or hysteroscopy but are less commonly used.

Patterns of Tumor Spread

Endometrial cancer can spread in many different patterns. The initial spread is to the myometrium and the depth of invasion is part of the Federation of Gynecology and Obstetrics (FIGO) staging system for this tumor. Lymphatic and vascular invasion leads to spread of tumor into lymph nodes. Intraperitoneal and vascular spread is associated with a higher percentage of positive pelvic and para-aortic adenopathy. The location of the tumor within the uterus also tends to have a differential risk for adenopathy, with more nodal involvement seen in those tumors located in the lower uterine segment.

Type 1 tumors primarily spread to pelvic lymph nodes. More positive lymph nodes are seen around the obturator nerve than the external or common iliac vessels. Infrarenal para-aortic adenopathy is seen when there are positive pelvic lymph nodes, adnexal metastases, and serosal infiltration. Type 2 tumors have a higher incidence of lymphatic involvement and extrauterine spread.⁴ The adnexa and cervix can also be invaded by endometrial carcinoma.

Staging Evaluation

Surgery is used to stage endometrial cancer. The most recent FIGO staging is also used to manage these patients. Stage I is endometrial carcinoma confined to the corpus uteri, whereas stage II involves the corpus uteri and the cervix but has not extended outside of the uterus. Stage III endometrial carcinoma extends outside of the uterus but is confined to the true pelvis. In stage IV, endometrial cancer involves the bladder or bowel mucosa or has metastasized to distant sites. These stages are divided into further subgroups (Table 24-1 and Figure 24-1).⁸

Table 24-1 AJCC Tumor-Node-Metastases (TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems for Endometrial Cancer

* Either G1, G2, or G3.

† Note: FIGO no longer includes Stage 0 (Tis).

‡ Endocervical glandular involvement only should be considered as Stage I and no longer as Stage II.

# Positive cytology has to be reported separately without changing the stage.

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (For complete information and data supporting the staging tables, visit ww.springer.com.) Reprinted from Pecorelli S, Denny L, Ngan H, et al. Revised FIGO staging for carcinoma of the vulva, cervix and endometrium. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet. 2009;105:103-104. Copyright 2009, with permission from International Federation of Gynecology and Obstetrics.

Figure 24-1 Staging of uterine cancer.

Imaging Evaluation

Primary Tumor

Various imaging modalities (Figures 24-2 to 24-6) can be used to help the attending physician evaluate the patient with endometrial cancer preoperatively, postoperatively, and during surveillance visits.

Figure 24-2 A 69-year-old woman with postmenopausal bleeding and right hip pain. A, Transvaginal ultrasound (sagittal and transverse) shows a heterogeneous solid, slightly hypoechoic, intrauterine mass. B, Transvaginal ultrasound, sagittal view, shows intratumoral blood flow. C, Contrast-enhanced axial computed tomography (CT) scan shows a poorly defined intrauterine mass (arrows). D, Axial CT scan shows a pathology-proven destructive lytic metastatic lesion (arrow) in the right ileum, accounting for her pain.

Figure 24-3 An 80-year-old woman with postmenopausal bleeding. Contrast-enhanced axial CT scan shows an intrauterine mass (arrowheads) extending into the cervix. An incidental paraumbilical hernia (arrows) is present.

Figure 24-4 A 51-year-old woman with postmenopausal bleeding. A, Axial T1-weighted magnetic resonance imaging (MRI) study with an isointense uterus without a definable mass. B, Axial T2-weighted MRI study shows an antegrade uterus with a heterogeneous mass of increased signal extending into the cervix. C, Sagittal T2-weighted MRI study shows an intrauterine mass of slightly increased signal with focal loss of the junctional zone posteriorly. D, Axial fat-suppressed, dynamic, T2-weighted MRI study shows an intrauterine mass of lower signal than the myometrium.

Figure 24-5 A 62-year-old woman with postmenopausal bleeding. A, Contrast-enhanced CT scan shows an intrauterine mass (arrow) extending from the miduterine segment to the cervix. B, Sagittal T2-weighted MRI study showing an intrauterine mass extending from the miduterine segment to the cervix. C, Sagittal fat-suppressed, dynamic, T2-weighted MRI study shows an intrauterine mass of decreased signal extending into the cervix.

Figure 24-6 A 61-year-old woman with vaginal bleeding being evaluated for recurrence. A fungating mass at apex of vaginal cuff was found on clinical examination. A, Positron-emission tomography (PET)/CT scan shows a focal area of increased metabolic activity in the right upper lobe, consistent with metastatic disease. B, CT scan with lung windows shows a mass in the right upper lobe that corresponds to the area of increased metabolic activity. C, PET/CT scan shows a focal area of increased metabolic activity in the vaginal cuff, consistent with recurrent disease. D, Contrast-enhanced CT scan shows a mass (arrows) in the apex of the vaginal cuff. E, PET/CT scan shows a focal area of metabolic activity (arrow) in the recti muscles of the anterior abdominal wall, consistent with a muscular metastatic lesion. F, Contrast-enhanced CT scan shows a mass (arrow) in the recti muscles of the abdominal wall.

Endometrial cancer is staged surgically in those patients who are surgical candidates. The FIGO staging system incorporates the depth of myometrial invasion and the presence or absence of extrauterine spread and is used to clinically manage patients with endometrial cancer.

Ultrasound, especially transvaginal sonography, is noninvasive, is readily available, is less expensive, uses no ionizing radiation, and in some studies, can image the tumor and myometrial invasion, but it can do poorly in evaluating the spread of tumor to adjacent organs.^9,10 Endometrial thickness (double layer) greater than 4 to 5 mm in a postmenopausal woman is considered abnormal and raises a flag when there is postmenopausal bleeding. However, the endometrium in this setting is nonspecific and can be seen in hyperplasia, polyps, and cancer.

Sonohysterography, although more invasive, can help to differentiate endoluminal mural masses from a more uniformly thickened endometrium.

Magnetic resonance imaging (MRI) is the imaging modality of choice to preoperatively evaluate the depth of myometrial invasion, the presence or absence of adenopathy, and adjacent soft tissue invasion. It has a high soft tissue resolution and accuracy (~90%), especially if it is contrast-enhanced.^11,12 However, it is more expensive and, in some locations, is limited in number and availability. This is an ideal imaging modality to help stage a patient who is not a surgical patient.

MRI protocols vary as the number and type of pulse sequences, body orientations, field of view (FOV), matrix and slice thickness, use or lack of use of dynamic imaging, and other factors. Myometrial invasion is best seen with disruption of the junctional zone on T2-weighted images and subendometrial enhancement on dynamic imaging. Adenopathy, cervical and adnexal involvement, and signal change in the bladder wall and rectum can also be seen. In addition, vaginal involvement can be identified. Functional imaging using diffusion-weighted MRI, although not ready for prime time, shows promise and great potential in managing patients with endometrial cancer.^13,14

Computed tomography (CT) of the chest and abdomen is best used to evaluate for extrapelvic metastatic disease and possible hydronephrosis. This imaging tool is more readily available, and with newer multidetector systems, the image quality has improved with faster patient throughput; however, it does utilize radiation. More recently, fluoro-2-deoxy-D-glucose (FDG)–positron-emission tomography (PET) and FDG-PET/CT have been used to stage, assist in radiation therapy planning, and evaluate response to therapy and in surveillance. Higher standard uptake values (SUVs) are seen with deep invasion of the myometrium. It is also useful for identifying nodal involvement, given that it may dictate the radiation port.^15,16 These imaging modalities are of limited use in diagnosing endometrial carcinoma. Molecular imaging shows great promise for future evaluation in the clinical management of patients with endometrial cancer.

Treatment

The standard of care for primary therapy of endometrial cancer is surgery. The surgical procedure includes a hysterectomy, bilateral salpingo-oophorectomy (BSO), and peritoneal cytologic evaluation, the latter via peritoneal fluid that is present at the time of surgery or peritoneal washings. At times, the omentum is sampled if there are suspicious areas.

The decision for a lymph node dissection of the pelvis and para-aortic nodal groups, superior and inferior to the inferior mesenteric artery, is made at the time of surgery and is a controversial issue among different centers and geographic regions. In the United States, when the endometrial carcinoma is confined to the uterus, a limited staging procedure is done in that pelvis and para-aortic lymphadenectomy is performed.¹⁶

Arguments for and against a pelvic and para-aortic lymphadenectomy are described in the literature with thorough lymph node dissection in patients with type 2 and selected patients with type 1 endometrial cancers.^4,17–20

Chemotherapy for locally advanced or metastatic disease endometrial carcinoma usually consists of a protocol based on taxanes, platinum compounds, and anthracyclines used more in combination rather than as single agents. This type of therapy tends to be palliative. In some instances, these are also used in combination with radiation therapy. Hormonal therapy can be used if there are appropriate steroid hormone receptors in the tumor.

Several trials and various treatment options that use cytotoxic and biologic agents are published in the literature.^4,18,21–23

For certain patients, radiation therapy is used to manage their endometrial cancer. The goal of adjuvant radiation therapy is to treat microscopic disease. However, this is controversial worldwide, as is the use of external beam radiation (pelvic radiation, extended field, or whole abdominal radiation) versus vaginal brachytherapy, especially in the high intermediate-risk endometrial carcinomas. Part of the dilemma that leads to controversy is patient selection, experience in grading, and depth of myometrial invasion of these neoplasms by various pathologists.^4,24–27

Surveillance

Following surgery and appropriate staging, the patient is followed closely for the first 2 to 3 years looking for pain, weight loss, and vaginal bleeding, which are the most common symptoms alerting the attending physician to recurrence and/or metastatic disease. The appropriate intervention is then given to the patient, using chemotherapy and/or radiation therapy.

Imaging plays a role in determining the extent of recurrent or metastatic disease, usually by using CT evaluation. MRI and PET/CT are used selectively.

Potential complications arise from the intraoperative surgical procedure and postoperatively such as ileus, fistulas, and wound infection. Toxicity from chemotherapy includes various grades of nausea, vomiting, infection, and also gastrointestinal, renal, hematologic, and neurotoxicity.

Complication from radiation therapy depends on the technique that is used: vaginal brachytherapy versus pelvic or extended field or whole abdominal radiation. Those organs in the radiation fields will sustain damage based on the radiation dose. Gastrointestinal toxicity tends to be the area of concern.

Postoperatively, the patients are seen every 3 months for the first year, every 4 months for the second year, every 6 months for years 3 to 5, and then annually. A pelvic examination is performed at every visit. Also, a Pap test is done every 6 months for the first year and then annually. A chest x-ray is performed annually. Other imaging is ordered as clinically indicated.

New Therapies

The mainstay of therapy for endometrial cancer is surgery followed by radiation therapy and chemotherapy. Advances have been made into the understanding of the molecular biology of endometrial cancer.^21–23,28 These discoveries have clinical and therapeutic implications. Some of the genetic alterations seen with endometrial cancer involve among others the tumor suppressor protein PTEN and associated pathways, microsatellite instability, K-ras mutations, p53 mutations, and HER-2/neu expression. Some of the target therapies have been directed to the mammalian target of rapamycin (mTOR) inhibitors, human epithelial growth factor receptor (EGFR), and angiogenesis inhibition of the vascular endothelial growth factor (VEGF). With time, these target therapies and others to be discovered should lead to better patient care and survival and minimizing postoperative therapeutic complications. A full discussion on these therapies is beyond the scope of this chapter.

Conclusions