Gynecologic Oncology Consult

Complex atypical hyperplasia: When is it appropriate to refer?


Complex atypical hyperplasia (CAH) of the endometrium is considered the precursor for endometrioid endometrial cancer, the most common gynecologic cancer in the United States. This disease is most frequently diagnosed by gynecologists who are evaluating symptoms of abnormal uterine bleeding in premenopausal women or in postmenopausal women who experience new bleeding. Medical therapies, typically progestin-based treatments, can be employed, particularly when fertility preservation is desired or among patients who are poor surgical candidates. However, the most definitive therapy remains surgery with total hysterectomy for two reasons: CAH is associated with a 28% risk for the development of invasive cancer, and occult invasive cancer frequently coexists with CAH.1,2 This raises a question for gynecologists: Given the risk for occult endometrial cancer, should patients be referred to a gynecologic oncologist for their surgery?

What is the risk for cancer?

Dr. Emma C. Rossi is an assistant professor in the division of gynecologic oncology at UNC-Chapel Hill.
Dr. Emma C. Rossi
Approximately 43% of patients with a preoperative diagnosis of CAH will have invasive cancer diagnosed on their hysterectomy specimen.2 In the majority of these cases these are low grade and minimally invasive tumors at low risk for lymph node metastases. However, approximately 12% are associated with deeply invasive, high grade tumors. Lymph node metastases have been observed in approximately 7% of patients with preoperative CAH who were staged at the time of hysterectomy.3

What is the significance of occult malignancy with CAH?

If surgeons are aware of endometrial cancer preoperatively or intraoperatively, decisions can be made about staging, particularly the need for lymphadenectomy. The virtues of staging in endometrial cancer is a controversial and frequently debated topic. No survival (therapeutic) benefit from lymphadenectomy has been observed in prospective trials when the information from staging results is not used to guide adjuvant therapy.4 However, the administration of adjuvant chemotherapy is associated with improved survival for patients with lymph node metastases.5 Therefore, if there is a benefit to staging with lymphadenectomy, it is its ability to identify patients who most need this life-saving systemic therapy.

Not all patients with endometrial cancer are at equal risk for harboring lymph node metastases and the majority may not benefit from lymphadenectomy. Patients with tumors that are deeply invasive, moderate or high grade, larger than 2 cm, or that have lymphovascular space invasion are at higher risk for lymph node metastases. Women with low grade, minimally invasive tumors that are smaller than 2 cm have extremely low risk for metastases.6 These criteria are commonly employed to stratify women at lowest risk and minimize unnecessary lymphadenectomy procedures. It should be noted that all three of these low risk features must be present to convey that negligible risk profile. The finding of a grade 1 invasive tumor alone is not enough to exclude potential lymph node metastases, particularly in the case of large or deeply invasive cancers.

How can the diagnosis be made preoperatively or intraoperatively?

The gold standard for discriminating between CAH and endometrial cancer is definitive surgical pathology. However, if surgeons wait until these results are available, they have lost the opportunity to stage the patient without subjecting them to a second surgery. The preoperative discovery of cancer may be increased by performing diagnostic curettage rather than relying on office endometrial biopsy sampling.7 This is likely due to the increased volume of tissue removed with dilation and curettage, and a reduction in the risk for sampling error. The addition of hysteroscopy to curettage does not improve upon the detection of cancer. Preoperative MRI to evaluate for depth of myometrial invasion has been described in cases of known endometrial cancer; however, its role in discriminating between CAH and invasive cancer is not well studied.

Intraoperative frozen section is commonly employed to evaluate the hysterectomy specimen for cancer in order to triage patients to staging during that same surgery. However, the accuracy of frozen section with definitive pathology is only approximately 50%.8 This means that at least half of women with CAH will have a false negative frozen section result and will have lost the opportunity for staging at the same procedure. The inaccuracy of frozen section is often overlooked by surgeons who may feel that it is a very straightforward diagnostic procedure. In reality, the characterization of CAH and invasive cancer is technically challenging and relies on multiple sectioning and significant experience in gynecologic pathology.9

Should all patients with CAH be referred and staged?

An alternative to relying on the frozen section process and its inherent inaccuracies would be to routinely stage all women with CAH, knowing that approximately 40% of them have occult cancer, and more than a third of those will have high risk features for lymph node metastases. However, due to the risks associated with lymphadenectomy, particularly lymphedema, most gynecologic oncologists do not routinely stage patients with preoperative CAH with complete lymphadenectomy.

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