Endometrial cancer

Endometrial cancer is one of the most common forms of gynecological cancer. It is more common in North America and most of Europe than in other parts of the world. The majority of cancers are diagnosed in peri- or postmenopausal women between 50 and 65 years of age. Endometrial cancer is highly associated with hormonal factors. Later age at menopause and obesity are associated with increased risk. Historically, unopposed estrogen therapy use (use of estrogen without progestogens) was associated with increased risk but such administration of estrogen is no longer a common practice. Parity and duration of oral contraceptive use are associated with decreased risk for the development of endometrial cancer. Polycystic ovary syndrome and disruption of hormone production bear a higher risk for cancer in women at younger age. Women with breast cancer who used Tamoxifen, a selective estrogen receptor modulator, develop endometrial cancer more often. Approximately 5% of endometrial cancer cases are part of inherited cancer syndromes, as a consequence of mutations in mismatch repair genes (Lynch syndrome), PTEN (Cowden syndrome), and BRCA genes. Such women usually have an earlier onset of the disease and positive family history of uterine, colon, or breast cancer.

Endometrial cancer is rarely asymptomatic and symptoms include abnormal, dysfunctional, or postmenopausal uterine bleeding, pain in the lower abdomen, or symptoms caused by compression of nearby organs by a growing tumor. Diagnosis is often made on biopsy samples obtained through endometrial curettage (surgical procedure of scraping uterine lining through a dilated cervix).

Most of the endometrial cancers, around 90%, are of epithelial origin (endometrial carcinoma), while endometrial stromal sarcoma is less common. The classification of endometrial carcinomas is based on morphology with the addition of molecular features. As such, they can be classified as endometrioid carcinomas, serous carcinomas, clear cell adenocarcinomas, mixed cell adenocarcinomas, and other rare types.

Endometrioid carcinoma represents around 80% of endometrial carcinomas. It is considered estrogen-dependent. Endometrioid carcinoma is the most common form of endometrial cancer in Lynch and Cowden syndrome. Tumor cells resemble proliferative type endometrium but show varying degrees of atypia and loss of nuclear polarity. Typically, cells form tightly packed glands with sharp luminal borders and without intervening stroma. Cribriform, microacinar, papillary, villoglandular, or solid growth patterns are also found. Squamous, morular and mucinous differentiation are often present. A three-tiered histological grading system is based on the percentage of the solid growth pattern in tumor. A precursor lesion of endometrioid carcinoma is well recognized and is called endometrioid intraepithelial neoplasia.

Serous carcinoma accounts for approximately 5 - 10% of endometrial carcinomas. It is more common in postmenopausal women and is considered estrogen independent. It is composed of cells with large atypical nuclei with hyperchromasia and prominent nucleoli, and frequent mitotic figures. Cells show several growth patterns: papillary, with or without appreciable fibrovascular cores, micropapillary pattern, gland-like without sharp luminal borders as seen in endometrioid carcinoma. It is not graded as it is considered a high grade by definition.

Clear cell adenocarcinoma is found in less than 5% of all endometrial carcinomas, more commonly in postmenopausal women. It is rarely found in patients with Lynch syndrome. Clear cell adenocarcinoma is composed of variably pleomorphic cells that may be polygonal, cuboidal, flat or hobnail and have clear or eosinophilic cytoplasm. The cells show papillary, tubulocystic, or solid growth patterns. Diffuse nuclear stratification in the papillary areas or diffuse columnar cell changes exclude the diagnosis of this type.

Diagnosis of endometrial cancer is often based on morphological features. Immunohistochemistry is used in poorly differentiated tumors and for the diagnosis of precursor lesions. Endometrial carcinomas usually have the expression of cytokeratin 7 (KRT7), PAX8, and vimentin (often), and antibodies against hormone receptors (ER, PR), HNF-1B, Napsin A (NAPSA), p16, and p53 are useful for differentiation between types. Loss of PTEN expression confirms the diagnosis of endometrioid intraepithelial neoplasia and excludes reactive proliferations of the endometrium. Immunohistochemical evaluation of microsatellite instability (MSI) with antibodies against MSH2, MSH6, MLH1, and PMS1 is used for the screening of Lynch syndrome. Molecular investigation in endometrial cancer is gaining more importance as it may have prognostic and diagnostic use. Deletion of PTEN gene shown by fluorescent in situ hybridization has the same role as immunohistochemistry but is more sensitive ad specific. Detection of mutations in POLE and TP53 genes has a prognostic impact.

Primary treatment in most cases is surgical with complete removal of the uterus and both ovaries. The treatment with chemo- or radiotherapy is applied after surgery and depends on tumor stage and histologic grade of the tumor. Hormonal therapy is an option in women in reproductive age with low-grade tumors, non-invasive tumors who want to preserve fertility, and it can lead to complete remission. Overall, prognosis depends on tumor stage, histological type, and tumor grade. Patients with localized disease have better 5-year survival (near 95%), while the prognosis is poor in distant diseases with a 5-year survival being only near 18%. Serous carcinoma is regarded as an aggressive subtype. The presence of POLE mutations in high-grade endometrial carcinomas is a favorable prognostic factor despite high-grade histology, unlike TP53 mutations, which bear s poor prognosis.