Approach

Most women with endometrial cancer present with postmenopausal vaginal bleeding (PVB).[23]

Patients are initially investigated with a pelvic (transvaginal) ultrasound. If there are suspicious findings on ultrasound, such as endometrial thickening or intrauterine mass, patients are referred for biopsy and/or dilation and curettage (D&C) for histologic evaluation and diagnosis.[102]

If a diagnosis is established, the patient is referred to a gynecologic oncologist or a general gynecologist with experience in endometrial cancer surgery. Appropriate referral should be made as soon as possible.[103][Figure caption and citation for the preceding image starts]: Histologic subtype: endometrioid endometrial adenocarcinoma, the commonest subtype; diagnosed on dilation and curettage in a patient presenting with postmenopausal bleeding (photomicrograph, hematoxylin and eosin stain)Courtesy of Professor Robert H. Young, Department of Pathology, Massachusetts General Hospital [Citation ends].com.bmj.content.model.Caption@66401e3c

Clinical history

The history should include determination of risk factors for endometrial cancer, including family history of cancer.

Genetic risk evaluation, including counseling and germline testing, is recommended for women with a blood relative with a known Lynch syndrome pathogenic variant or with a personal or strong family history of a Lynch syndrome-related cancer (e.g., endometrial cancer, colorectal cancer, and/or ovarian cancer).[81][104][105]​​​

Other risk factors strongly associated with endometrial cancer include being overweight/obese, age >50 years, diabetes mellitus, tamoxifen use, unopposed endogenous estrogen (e.g., anovulation), unopposed exogenous estrogen (e.g., estrogen-only hormone replacement therapy [HRT]), polycystic ovary syndrome, and radiation therapy.[104][105]

Direct questions should be asked about vaginal bleeding to establish that no other obvious cause could be responsible for PVB (e.g., intercourse, HRT, urinary source) and that the symptom is unlikely to be due to another genital tract malignancy, such as cervical cancer.

Patients should be asked about symptoms of abdominal or inguinal mass, abdominal distension, persistent pain (especially in the abdomen or pelvic region), fatigue, diarrhea, nausea or vomiting, persistent cough, shortness of breath, swelling, or weight loss, and new-onset neurologic symptoms. These symptoms may suggest extrauterine disease/metastases. The vagina, ovaries, and lungs are the most common metastatic sites.[9]

Premenopausal women

In premenopausal women who develop endometrial cancer, the main complaint is abnormal menstruation or abnormal vaginal bleeding, which may range from simple menorrhagia to a completely disorganized bleeding pattern. For this reason, premenopausal women with abnormal menstruation or vaginal bleeding often have an endometrial biopsy to rule out endometrial cancer, especially if they are ages >35 years. One systematic review found that the risk of endometrial cancer in premenopausal women with abnormal uterine bleeding was 0.33%.[106]

Physical exam

Physical examination is often challenging because of the prevalence of obesity in patients with endometrial cancer. A gynecologic examination bed may facilitate the pelvic examination.

A bimanual examination gives an idea of uterine size, may detect the presence of a uterine mass or fixed uterus, and also evaluates for adnexal mass. The vulva, vagina, and cervix need to be thoroughly inspected using a speculum to rule out other gynecologic causes for the presenting symptoms.[107]

Enlarged lymph nodes may be a sign of metastatic spread; however, nodal metastases are typically not diagnosed until surgery.

Investigations

Women presenting with PVB have a 5% to 10% risk of endometrial cancer; therefore, prompt evaluation with pelvic (transvaginal) ultrasound is warranted.[9][23][108][109]

Ultrasound

Pelvic (transvaginal) ultrasound can evaluate the endometrial thickness and uterine size and exclude a structural abnormality such as a polyp.[110] Women with PVB with suspicious findings on ultrasound, such as a thickened endometrial stripe (>4 mm) or vascular mass, should undergo further investigation with biopsy and/or D&C for histologic confirmation of endometrial cancer.[109] ​Be aware that ultrasound assessment of endometrial thickness may be less reliable for triage of black patients.[111][112]​​

Saline infusion sonohysterography (an ultrasound procedure) can provide detailed imaging of the endometrium if routine pelvic ultrasound is inconclusive; however, it is not routinely used.[109] It involves the transcervical injection of sterile fluid (e.g., normal saline) into the uterine cavity during real-time ultrasound scanning of the endometrium, which provides more detailed imaging than routine pelvic ultrasound.[113]

Biopsy

Office-based biopsy using an endometrial suction catheter (pipelle endometrial suction curette) is often the initial diagnostic step given its high sensitivity, low cost, and ready availability.[74][114][115] The diagnostic accuracy of office-based biopsy can be improved by office hysteroscopy, if available.

If office-based biopsy is not technically feasible or cannot be tolerated by the patient, hysteroscopy and D&C under anesthesia is mandatory.[Figure caption and citation for the preceding image starts]: Histologic subtype: endometrioid endometrial adenocarcinoma, the commonest subtype; diagnosed on dilation and curettage in a patient presenting with postmenopausal bleeding (photomicrograph, hematoxylin and eosin stain)Courtesy of Professor Robert H. Young, Department of Pathology, Massachusetts General Hospital [Citation ends].com.bmj.content.model.Caption@543bf0bd

Tumor molecular analysis

For women with endometrial cancer, guidelines recommend immunohistochemistry analysis for mismatch-repair (MMR) status and/or testing for microsatellite instability (MSI) status for all tumors. Further genetic evaluation should be carried out if the tumor is MMR deficient or MSI-high.[83]​​[84]​

Immunohistochemistry can be carried out at initial biopsy or D&C, or on the final hysterectomy specimen. Further molecular profiling includes immunohistochemistry for p53 mutations and sequencing for POLE mutations.[21][83][116]​​​[117][118]​​​ Molecular analysis may be prognostic and guide treatment.[119]

Tumor mutational burden (TMB) testing with a validated assay may be considered, especially for advanced or recurrent disease. Estrogen receptor and progesterone receptor testing should be carried out for stage III and IV, and recurrent tumors. HER2 immunohistochemistry testing is recommended for advanced and recurrent serous carcinoma or carcinosarcoma, and for all p53-abnormal tumors. NTRK gene fusion testing may be considered for metastatic or recurrent disease.[83]

Genetic evaluation

Genetic evaluation (with genetic counseling and germline testing) should be offered to patients with MMR-deficient or MSI-high tumors, and to those diagnosed at age <50 years and/or with a strong family history of endometrial or colorectal cancer, regardless of MMR/MSI status (if not done already).[83]​

Germline testing for a specific pathogenic variant can be carried out, if known; tailored multigene panel testing is recommended if the variant is unknown, based on personal and family history.[81][120]​ Lynch syndrome genes (MSH2, MLH1, MSH6, PMS2, EPCAM) are generally recommended in multigene panels for patients with endometrial cancer, with further genes added accordingly.[120] Results may inform prognosis and risk-reduction strategies for related cancers, and may highlight risk among family members

Cervical cytology

While a cervical cytology (liquid-based cytology or Pap smear) is primarily used to screen for cervical dysplasia, in approximately 50% of cases it can identify abnormalities higher up in the genital tract and may be obtained initially.[121][122]​​ 

Uncommonly, women with undiagnosed endometrial cancer are found to have atypical glandular cells of uncertain significance on routine cervical cytology, which should prompt immediate evaluation with endometrial sampling.[26][27][121]

Cervical cytology is not a screening test for endometrial cancer.

Imaging studies for suspected extrauterine disease

Occasionally, the patient presentation may suggest the presence of extrauterine disease, and additional imaging (such as computed tomography [CT] of the chest, abdomen, and pelvis, or pelvic magnetic resonance imaging [MRI]) may help in management planning.[123][124]

MRI has a limited role in preoperative assessment but may inform decision making in a patient who wants to pursue conservative management to maintain fertility, or to assess the feasibility of hysterectomy when there is suspicion that the cancer has invaded adjacent structures.[83][124][125]

CT, MRI, or positron emission tomography (PET)/CT may be of value in the assessment of women with endometrial cancer who are not surgical candidates. These investigations can be used in the initial evaluation of disease; to monitor disease response to pharmacotherapy; and for surveillance, especially if recurrence is suspected.

Postoperative imaging

PET/CT may be helpful postoperatively to evaluate for gross residual disease, or in the posttreatment setting in differentiating recurrent or persistent tumor from fibrosis resulting from surgery, radiation therapy, or chemotherapy.[126][127][128][129] However, it is costly and only sensitive for metastases.

Surgical staging

The International Federation of Gynecology and Obstetrics (FIGO) replaced clinical staging of endometrial cancer with surgical staging because clinical staging carries a large margin of error with regard to the true extent of disease.[8][9][130][131]

Following staging surgery, surgical histopathology is performed to:[132][133]

  • Determine the extent of local and distant tumor spread

  • Confirm tumor grade and histology

  • Assess for the presence of prognostic factors such as depth of myometrial invasion, lymphovascular space invasion, blood vessel microdensity, and cervical involvement.

Ancillary tests

A complete blood count early in the clinical work-up can evaluate for anemia and leukocytosis. Preoperative anemia and leukocytosis correlate with poor survival outcomes.[134][135]

If a diagnosis of endometrial cancer is made, liver function tests can be used to screen for liver or bone metastases, and a chest x-ray for lung metastases. Chest x-ray has a low sensitivity for early lung metastases and may be substituted by chest CT.[136][137]

Renal function tests (blood urea nitrogen and creatinine) screen for obstructive uropathy.

CA-125 is a marker for serous or clear cell pathology, but is not often performed unless advanced disease is suspected.

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