Pathogenesis and Clinical Management of Uterine Serous Carcinoma

Abstract

Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer that has not been well characterized. It accounts for less than 10% of all endometrial cancers and 80% of endometrial cancer-related deaths. Currently, staging surgery together with chemotherapy or radiotherapy, especially vaginal cuff brachytherapy, is the main treatment strategy for USC. Whole-exome sequencing combined with preclinical and clinical studies are verifying a series of effective and clinically accessible inhibitors targeting frequently altered genes, such as HER2 and PI3K3CA, in varying USC patient populations. Some progress has also been made in the immunotherapy field. The PD-1/PD-L1 pathway has been found to be activated in many USC patients, and clinical trials of PD-1 inhibitors in USC are underway. This review updates the progress of research regarding the molecular pathogenesis and putative clinical management of USC. Keywords: endometrial cancer; uterine serous carcinomaPrecis: Uterine serous cancer, although rare, is the most lethal type of uterine cancer. It has distinct molecular features and pathogenic pathways compared with other uterine cancer types Cancers 2020, 12, 686 2 of 21 heterogeneity, grade 3 EEC displays dissimilar features. Although a large number of grade 3 EEC cases show a serous-like phenotype, others display unequivocally endometrioid morphology [6,7]. Type II tumors are typically detected in women 70 years or older and carry a poor prognosis, high recurrence frequency, and much lower 5-year survival rate compared with type I tumors. In addition, type II tumors usually lack estrogen/progesterone receptors and do not respond to hormonal fluctuations [5].Among the type II tumors, uterine serous carcinoma (USC) is the most common subtype. This highly aggressive variant accounts for only 10% of all ECs but 80% of all EC-associated deaths [8,9]. The 5-year tumor-specific survival rate is 74% and 33% for early-and late-stage USC patients, respectively (and 89% and 77% for low-and high-grade EEC) [10]. Unlike type I EC, the risk of metastasis and recurrence of USC does not rely on primary tumor size or grade; this trait contributes to a low overall survival rate of 18% to 27%. Complete surgical staging is performed, comprising total hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection, followed by carboplatin and paclitaxel. In light of poor patient survival and high recurrence rates, the development of targeted therapies specific to USC pathway aberrations would aid in its management. However, conducting studies that focus solely on this rare subtype has been a constant challenge, making it difficult to determine optimal treatment strategies [9].

Additional Value of PET/CT-Based Radiomics to Metabolic Parameters in Diagnosing Lynch Syndrome and Predicting PD1 Expression in Endometrial Carcinoma

“…Treatment with hysterectomy and bilateral salpingo-oophorectomy is the standard of care. Hormone therapy, radiotherapy, and immunotherapy may be used, depending on the individual patient’s wish to preserve her uterus or her potential for fertility ( 2 , 3 ). First discovered in 1895, Lynch syndrome is known to be closely related to colorectal cancer and endometrial cancer, and accounts for 2% to 6% of the latter ( 4 , 5 ).…”

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“…Most type II endometrial carcinomas, especially UPSC, have a complex papillary or glandular architecture, which is similar to serous papillary ovarian carcinomas. In general, densely fibrotic papillae fronds and slit-like spaces are common [1] [ Figure 2,3]. Huge, round, undifferentiated tumor cells with a high number of mitotic figures, increased nuclear-to-cytoplasmic ratios, and prominent nuclear atypia are detached and present in the blank spaces.…”

“…UPSC's aggressive features, resistance to chemotherapy, poor prognosis, and extremely high recurrence rate (50% to 80%) contribute to the increase in endometrial cancer-related deaths every year. Currently, surgery together with chemotherapy and radiotherapy (vaginal cuff brachytherapy or external pelvis radiotherapy) remains the dominant treatment option for UPSC [1].…”

“…Uterine Serous Cancer (USC), although rare, is the most lethal type of uterine cancer. It has distinct molecular features and pathogenetic pathways compared with other uterine cancer types [1]. According to Bokhman's 1983 model, Endometrial Carcinoma (EC) is broadly classified based on histopathologic features into two categories, type I and type II, which differ in incidence, prognosis, epidemiology, molecular pathology, and clinical behavior [2].…”

“…According to Bokhman's 1983 model, Endometrial Carcinoma (EC) is broadly classified based on histopathologic features into two categories, type I and type II, which differ in incidence, prognosis, epidemiology, molecular pathology, and clinical behavior [2]. Type II tumors (nonendometrioid carcinomas), such as serous carcinoma, clear cell carcinoma, carcinosarcoma/malignant-mixed Müllerian tumor, are characterized by poorly differentiated histology and deep migration/ invasion [1]. Among the most common problems encountered in practice is the distinction between primary endometrial and primary endocervical adenocarcinomas, and the determination of the tumor origin when there is synchronous, multifocal involvement of gynecologic tract sites, for example the endometrium and the ovary [3].…”