Biopsy histomorphometry predicts uterine myoinvasion by endometrial carcinoma: a Gynecologic Oncology Group study

Abstract

A barrier to nonsurgical management of premalignant endometrial disease is the need to perform hysterectomy to exclude concurrent myoinvasive endometrioid adenocarcinoma. Occult adenocarcinoma rates for premalignant disease diagnosed by biopsy or curettage are approximately 40%. We applied the histomorphometric 4-class rule ("4C," which measures epithelial abundance, thickness, and nuclear variation) to diagnostic biopsies to predict myoinvasive cancer outcomes at hysterectomy. Women with endometrial biopsies or curettages having a community diagnosis of atypical endometrial hyperplasia were enrolled in a clinical trial in which subsequent hysterectomy was scored for endometrial adenocarcinoma, and 4C rule ability to predict cancer outcomes was measured. Qualifying biopsies were stratified into high- and low-risk histomorphometric subgroups. Two-hundred thirty-three women had biopsies suited to morphometry and scorable hysterectomy outcomes, of which 46% contained adenocarcinoma. Assignment to a high-risk category by the 4C rule was highly sensitive in predicting any (71%) or deeply (92%) myoinvasive adenocarcinoma at hysterectomy, and assignment to a low-risk group had a high negative predictive value for absence of any (90%) or deeply (99%) myoinvasive disease. Volume percentage epithelium was associated with myoinvasive cancer outcomes above a threshold of 50% (P < .001), and a measure of nuclear pleomorphism was significantly increased (P = .004) in deeply myoinvasive cancers. Formal histomorphometry of endometrial biopsies using the 4C rule has been validated as a means to identify a subset of women with premalignant disease who are unlikely to have concurrent myoinvasive adenocarcinoma and who may qualify for alternative nonsurgical therapies.

Figure 1. Biopsy Morphometry Predicts Hysterectomy Cancer Outcome

The distribution of enrollment biopsy cancer likelihood (Y axis, Cancer likelihood, percent) is shown for each hysterectomy cancer outcome group (X axis: no cancer, non (myo)invasive cancer, superficial (inner half) and deep (outer half) myoinvasive cancers). Scattergram shows, by outcome group, distribution of cancer likelihood's calculated for each enrollment biopsy using the 4-class rule (likelihood of membership in LGA or HGA groups). Cancer likelihood on biopsy increases with all cancer outcomes, most strongly with deep myoinvasive cancers.

Figure 2. Epithelial Density and Nuclear Pleomorphism In a Biopsy Correlate with Hysterectomy Cancer Outcomes

Morphometric variables of Volume Percent Epithelium (VPE, left) and standard deviation of nuclear axis (SDDN, Panel A) as measured in enrollment biopsies are plotted for each hysterectomy outcome group (x axis). As the area of neoplastic epithelium exceeds combined luminal and stromal area (VPE>50%, dashed line, left panel) the likelihood of finding carcinoma in the hysterectomy increases. Acquisition of nuclear pleomorphism (high values of SDDN, Panel B) is most pronounced in deeply myoinvasive carcinoma outcomes.

Figure 3. Examples of 4C Rule hyperplasias and adenocarcinoma

4C Rule morphometric rule reclassification of eight community "atypical endometrial hyperplasias" as low grade hyperplasia (LGH, Panels A–B), high grade hyperplasia (HGH, Panels C–D), low grade adenocarcinoma (LGA, Panels E–F), or high grade adenocarcinoma (HGA, Panels G–H). In general, higher proportion of epithelium and increased nuclear pleomorphism elevate the 4C rule assignment to worse categories. The low grade adenocarcinoma category contains examples judged subjectively to be either EIN (Panel E, individual glands) or well differentiated adenocarcinoma (Panel F, mazelike glands). High grade adenocarcinomas have very little remaining stroma, and pleomorphic tumor nuclei (Panels G–H). Patients with samples shown in Panels E, F, and G were found to have deeply myoinvasive disease at hysterectomy.