Endometrial Cancer

Endometrial cancer (EC) is a malignancy that arises from the endometrium. Different histotypes are described:  epithelial malignant tumours (endometrioid, mucinous, serous, clear cell, mixed, and undifferentiated cancer) and mixed epithelial -mesenchymal malignant tumors (carcinosarcoma and Malignant Mixed Müllerian Tumour, (MMMT)).

Endometrial cancer is the most common malignancy of the female genital tract (1) with a lifetime risk of 2-3%. The median age at diagnosis is 60-65 years and the most commonly associated risk-factor is obesity. Indeed, overweight (BMI> 25 kg/m²) and obese (BMI >30 kg/m²) women show a 2- 3-fold increased risk of EC (2). Other risk-factors are: increasing age, long reproductive period, Polycystic Ovarian Syndrome (PCOS), long-term exposure to unopposed estrogens, Tamoxifen, and Tibolone (3, 4). Physical exercise and sun exposure may have a preventive effect (5).

The most common symptom is abnormal uterine bleeding, which is present in 90% of women. Other possible symptoms are abdominal pain, which may be either due to the hemato/pyometra that occurs in women with cervical stenosis, or more rarely to the local tumor overgrowth, and abdominal distension due to the abdominal spread of disease.

Prognosis depends on: age of the patient, tumor grade, histological type and size, depth of myometrial invasion, cervical stromal invasion and lymph node status. (6)^. Approximately 80% of cases are diagnosed at stage I (7), with a 5-year survival rate of 90% for stage I, of 78% for stage II, of 62% for stage III and of 21% for stage IV (8).

EC originates most frequently in the corpus (Figure 1a), but it may also arise in the lower uterine segment (Figure 1b). At macroscopy, tumors typically appear as polyps that fill the endometrial cavity, but in rare cases they can be entirely endophytic. Invasion of the myometrium can be usually identified at macroscopic examination, but when the invasion is minimal, it cannot be appreciated. There are no distinctive gross appearances to enable differentiation between the different histological types, thus immunohistochemistry may help in the differentiation.  Tumors may have an exophytic, or invasive growth pattern (Figure 1a). Necrosis and haemorrhage may be seen.

The most frequent histological type is the endometrioid tumor (80-85% of the all ECs) and 50% of them are of grade 1, 35% of grade 2 and 15% of grade 3. (Figure 2 a-b). Endometroid tumors can also show a mucinous differentiation (Figure 2c). The FIGO Grading system is based on the growth pattern of cancer, on the relative proportions of glandular versus solid components, and on the number of atypia. The solid component is less than 5% in Grade 1 tumors, 6-50% in Grade 2, and more than 50% in Grade 3. A particular growth pattern-  MELF (Microcystic, Elongated structures or Fragmented solid cells) - has been recognized in some cases of endometrioid endometrial cancer (Figure 3)(9). The MELF pattern is associated with a 2 to 3-fold increased risk of adverse prognosis and advanced disease (10).

The histological features of non-endometroid tumors are shown in Figure 4a- and they include papillary serous type carcinoma (10% of all ECs), clear cell carcinoma, and carcinosarcoma. The serous type carcinoma is composed of high-grade anaplastic cells with complex papillary, glandular or solid growth patterns. It is a highly aggressive tumor resembling the ovarian serous carcinoma. The clear cell carcinoma comprises ~ 5% of ECs; it consists of clear cells with a tubular or solid growth pattern. The carcinosarcoma, also called Malignant Mixed Müllerian Tumor (MMMT), is characterized by high-grade malignant stromal and epithelial components arranged in a biphasic pattern. These tumors are often large, soft, friable with signs of necrosis and hemorrhage (11).  

The ultrasound features of endometrial cancer have been described by the IETA (International Endometrial Tumor Analysis) group (Figure 5a-b)(7, 12). The authors found a correspondence between the vessel pattern at ultrasound and the tumor growth pattern at histology: i.e. tumors with an exophytic growth pattern presented more often with a focal vessel pattern at ultrasound (single or multiple focal vessels), whereas tumors with an infiltrative growth pattern presented more often with a multifocal vessel pattern at ultrasound (13) (Figure 6). Moreover, different ultrasound features characterizing either low risk endometrial carcinomas or high risk endometrial carcinomas were recognized. Women with high risk tumours presented more frequently with thickened endometrium, irregular endometrial-myometrial junction, non-uniform endometrial echogenicity, rich vascularization and multiple-multifocal vessels, compared to patients with low risk endometrial cancers (7)  (Figure 7-9).

Sonographic characteristics of non-endometrioid tumors (clear-cell carcinoma, serous carcinoma, mixed-cell carcinoma and carcinosarcoma) are presented in Figure 10. Carcinosarcomas and clear cell carcinomas appear as large (median endometrial thickness (ET), 39 mm and 28 mm, respectively), irregular, well vascularized tumors, with multiple-multifocal vessels. Serous carcinomas have a median endometrial thickness of 18 mm. Mixed-cell carcinomas have a median endometrial thickness of 20 mm and are highly irregular and well vascularized tumors (Epstein UOG 2018).

When assessing EC extension, the key points are: to determine the extent of myometrial invasion (less or more than 50%), to evaluate the presence or absence of cervical stromal invasion, to assess serosal infiltration, parametrial infiltration, tumor spread beyond uterus and adnexa and lymph node status (LN)  (7,14).

Typical cases of high and low-risk cancers are shown in the videoclips (Figure 11 and 12).

It may be difficult to differentiate benign endometrial pathology, such as hyperplasia or polyp, from EC when endometrial thickness is less than 15mm (15). Endometrial stromal nodule (benign) or endometrial stromal sarcoma may also resemble EC when found in the endometrial cavity. Cervical adenocarcinoma arising in the cervical canal may be difficult to differentiate from an endometrial cancer arising in the lower uterine segment. Uncommonly, other extragenital primary tumors (most commonly from breast cancer, gastric cancer and pancreatic cancer) may metastasize to the endometrium or to the uterine body (Figure 13) (16).

^{​​​​​​1.         Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90.}

^{2.         Calle EE, Thun MJ. Obesity and cancer. Oncogene. 2004;23(38):6365-78.}

^{3.         Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I. Endometrial cancer. Lancet. 2005;366(9484):491-505.}

^{4.         Beral V, Bull D, Reeves G. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2005;365(9470):1543-51.}

^{5.         Epstein E, Lindqvist PG, Geppert B, Olsson H. A population-based cohort study on sun habits and endometrial cancer. Br J Cancer. 2009;101(3):537-40.}

^{6.         Benedet JL, Bender H, Jones H, 3rd, Ngan HY, Pecorelli S. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet. 2000;70(2):209-62.}

^{7.         Epstein E, Fischerova D, Valentin L, Testa AC, Franchi D, Sladkevicius P, et al. Ultrasound characteristics of endometrial cancer as defined by International Endometrial Tumor Analysis (IETA) consensus nomenclature: prospective multicenter study. Ultrasound Obstet Gynecol. 2018;51(6):818-28.}

^{8.         Creasman WT, Odicino F, Maisonneuve P, Quinn MA, Beller U, Benedet JL, et al. Carcinoma of the corpus uteri. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006;95 Suppl 1:S105-43.}

^{9.         Stewart CJ, Brennan BA, Leung YC, Little L. MELF pattern invasion in endometrial carcinoma: association with low grade, myoinvasive endometrioid tumours, focal mucinous differentiation and vascular invasion. Pathology. 2009;41(5):454-9.}

^{10.       Eriksson LSE, Nastic D, Fruhauf F, Fischerova D, Nemejcova K, Bono F, et al. Clinical and Ultrasound Characteristics of the Microcystic Elongated and Fragmented (MELF) Pattern in Endometrial Cancer According to the International Endometrial Tumor Analysis (IETA) criteria. Int J Gynecol Cancer. 2019;29(1):119-25.}

^{11.       Kurman R, editor. Blaustein´s Pathology of the Female Genital Tract. 4th ed. New York: Springer Verlag; 1995.}

^{12.       Leone FP, Timmerman D, Bourne T, Valentin L, Epstein E, Goldstein SR, et al. Terms, definitions and measurements to describe the sonographic features of the endometrium and intrauterine lesions: a consensus opinion from the International Endometrial Tumor Analysis (IETA) group. Ultrasound Obstet Gynecol. 2010;35(1):103-12.}

^{13.       Epstein E, Van Holsbeke C, Mascilini F, Masback A, Kannisto P, Ameye L, et al. Gray-scale and color Doppler ultrasound characteristics of endometrial cancer in relation to stage, grade and tumor size. Ultrasound Obstet Gynecol. 2011;38(5):586-93.}

^{14.       Fischerova D, Cibula D. Ultrasound in gynecological cancer: is it time for re-evaluation of its uses? Curr Oncol Rep. 2015;17(6):28.}

^{15.       Epstein E, Valentin L. Gray-scale ultrasound morphology in the presence or absence of intrauterine fluid and vascularity as assessed by color Doppler for discrimination between benign and malignant endometrium in women with postmenopausal bleeding. Ultrasound Obstet Gynecol. 2006;28(1):89-95.}

^{16.       Kumar NB, Hart WR. Metastases to the uterine corpus from extragenital cancers. A clinicopathologic study of 63 cases. Cancer. 1982;50(10):2163-9.}

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