Commentary

Serous EIC as an early form of uterine papillary serous carcinoma: recent progress in understanding its pathogenesis and current opinions regarding pathologic and clinical management

High-grade endometrial carcinoma (HGEC) is a heterogeneous group of tumors with various morphologic, genetic, and clinical characteristics. Morphologically, HGEC includes high-grade endometrioid carcinoma, serous carcinoma, clear cell carcinoma, undifferentiated/dedifferentiated carcinoma, and carcinosarcoma. The morphologic classification has been used for prognostication and treatment decisions. However, patient management based on morphologic classification is limited by suboptimal interobserver reproducibility, variable clinical outcomes observed within the same histotype, and frequent discordant histotyping/grading between biopsy and hysterectomy specimens. Recent studies from The Cancer Genome Atlas (TCGA) Research Network established four distinct molecular subtypes: POLE-ultramutated, microsatellite unstable, copy number high, and copy number low groups. Compared to histotyping, the TCGA molecular classification appears superior in risk stratification. The best prognosis is seen in the POLE-ultramutated group and the worst in copy number high group, while the prognosis in the microsatellite unstable and copy number low groups is in between. The TCGA subtyping is more reproducible and shows a better concordance between endometrial biopsy and resection specimens. It has now become apparent that the molecular classification can supplement histotyping in patient management. This article provides an overview of the pathologic diagnosis/differential diagnosis of HGEC and the TCGA classification of endometrial cancers, with the clinical significance and applications of TCGA classification briefly discussed when appropriate.

Frequently involving an endometrial polyp, minimal uterine serous carcinoma (MUSC) represents the earliest recognizable forms of endometrial serous carcinoma. The aim of this study was to provide a comprehensive morphological and clinical outcome assessment of MUSC involving endometrial polyp. A total of 77 fully staged MUSCs involving endometrial polyp were identified, including 53 MUSCs confined to polyp and 24 nonpolyp confined tumors. Extrauterine disease was found in 17% (9/53) of polyp-confined MUSCs compared to 41.7% (10/24) of nonpolyp confined tumors (p = 0.02). Lymphovascular invasion was observed in 3.8% (2/53) of polyp-confined cases compared to 25% (6/24) of nonpolyp confined cases (p = 0.047). Lymph node metastasis was observed in 11.3% (6/53) of polyp-confined cases, compared to 29.2% (7/24) of nonpolyp confined cases (p = 0.058). Positive pelvic washing cytology was seen in 18.9% (10/53) of polyp-confined versus 37.5% (9/24) of nonpolyp confined tumors (p = 0.078). Overall, 58 of 77 (75.3%) patients had low tumor stage (57 stage I cases and 1 stage II case) and only two patients (3.5%) had a recurrence. In contrast, 19 of 77 (24.7%) patients had advanced stage (stage III or IV) disease and 17 (89.5%) patients had recurrence (p < 0.0001). Only one of 57 low-stage patient (1.7%) versus 11 of 19 high-stage patients (57.8%) died of the tumor (p < 0.0001). Five of 53 (9.4%) patients with polyp-confined MUSC and 7 of 24 (29.2%) patients with nonpolyp confined MUSC died of the disease (p = 0.03). In conclusion, while a small percentage of MUSCs exist without the involvement of an endometrial polyp, a close topographic relationship between MUSC and the endometrial polyp is confirmed in this largest series, supporting the theory that most if not all MUSCs arise in an EMP. Patients with MUSC without extrauterine spread have an excellent prognosis. Compared to patients with MUSC confined to an endometrial polyp, patients with MUSC extending to the background endometrium have a significantly higher risk for high-stage disease at presentation.

Hormonal field effects (non–atypical endometrial hyperplasia) must be distinguished from true precancerous lesions (endometrioid intraepithelial neoplasia [EIN]) because of their differing management. This chapter also presents mimics of precancerous lesions and includes special presentations of lesions with altered differentiation (metaplasias).

Serous endometrial intraepithelial carcinoma is often associated with extrauterine disease. It is currently unclear where does the extrauterine disease come from. This study addressed this issue. A total of 135 samples from 21 serous endometrial intraepithelial carcinoma patients were studied. Cellular lineage relationships between intrauterine and extrauterine serous carcinomas were determined by TP53-mutation analysis and correlated to the clinicopathologic features. There were three conditions contributing the extrauterine disease: metastasis from serous endometrial intraepithelial carcinoma (n=10) showed identical TP53 mutation between intrauterine lesions and extrauterine disease, cases of adnexal origin (n=5) had discordant TP53 mutations, and the mixed cellular origin cases (n=6) with both identical and discordant mutation status. Patients with extrauterine disease from serous endometrial intraepithelial carcinoma metastasis typically had small tumor masses (<2 cm) in extrauterine sites and without finding of serous tubal intraepithelial carcinoma, while extrauterine disease with adnexal or tubal origin commonly had larger tumor masses in extrauterine sites including ovary and omentum and serous tubal intraepithelial carcinoma. The majority of extrauterine diseases associated with serous endometrial intraepithelial carcinoma are metastasized from the endometrium. Serous endometrial intraepithelial carcinoma is frequently associated with serous cancers of adnexal or tubal origin, indicating that endometrial and adnexal or tubal serous cancers may share similar etiologies. TP53-mutation analysis provides a strong linkage for cellular lineage analysis. Tumor size in extrauterine disease and presence of serous tubal intraepithelial carcinoma or not are useful clinicopathologic features to determine primary cancer site, which helps in clinical management.

Abdominal peritoneal implants are characteristic of uterine serous carcinoma (USC). The presumed mechanism of dissemination is retrograde transit via the fallopian tube. We assessed the impact of tubal ligation (TL) on the metastatic profile and survival of USC patients.

Patient risk factors, process-of-care variables, and disease-specific parameters were annotated. Categorical variables were compared using the χ² test. Overall survival (OS) was estimated via the Kaplan–Meier method.

Among 211 USC patients, fallopian tube status was documented in 142 patients; 35 had a history of TL and 107 did not. When comparing patients with and without TL, positive peritoneal cytology was present, respectively, in 18.8% vs 45.0% (P = .01) and stage IV disease in 14.3% vs 34.6% (P = .02). Using Cox models, age was the sole significant determinant of OS in stage I/II USC. By contrast, age, lymphovascular space involvement, positive cytology, and TL independently and adversely affected survival in stage III/IV USC. Adjusting for these factors in a multivariable model, the association between TL and OS among patients with advanced disease yielded a hazard ratio of 8.61 (95% CI, 3.08–24.03; P < .001). The prevalence of lymphatic metastasis and nodal tumor burden was significantly greater in patients who underwent ligation.

Patients with TL had significantly lower rates of positive cytology and stage IV disease than patients without TL. The lymphatic system appeared to be the dominant mode of spread after TL and was associated with a paradoxic worsening of OS, perhaps reflecting a delay in diagnosis.