Endometrial Adenocarcinoma

Description

Endometrial adenocarcinoma is a malignancy that originates from the endometrial glands, the cells lining the uterus. As the most common gynaecologic cancer in developed countries, it can be categorised into two main types: Type I (endometrioid, mucinous and villoglandular) and Type II (serous and clear cell).

Subtypes

Endometrial adenocarcinoma is broadly divided into two types, each with its specific subtypes:

Type I

Type I cancers (most common) are linked to excess oestrogen exposure and typically carry a favourable prognosis.

• Endometrioid adenocarcinoma: The most common subtype of endometrial cancers (around 75-80%) and is typically associated with unopposed oestrogen stimulation. The histology reveals glandular, tubular, or villous architecture resembling the normal endometrial glands.
• Mucinous adenocarcinoma: A subset of endometrioid adenocarcinoma with columnar cells rich in intracytoplasmic mucin. It comprises a small percentage of endometrial cancers.
• Villoglandular adenocarcinoma: Another variant of endometrioid adenocarcinoma, distinguished by the presence of elongated, slender papillae with a fibrovascular core. These cancers are typically well-differentiated and carry a favourable prognosis.

Type II

Type II cancers are often linked to p53 mutations (not oestrogen) and typically develop in atrophic endometrium with a more aggressive course.

• Serous adenocarcinoma: This type accounts for approximately 10% of endometrial cancers and is not related to oestrogen stimulation. It is typically high-grade with a papillary pattern and is known for its aggressive behaviour and poor prognosis.
• Clear cell adenocarcinoma: This is a rare and aggressive variant of endometrial adenocarcinoma, characterised by clear or hobnail cells and a tubulocystic, solid, or papillary pattern. Clear cell cancers are typically high-grade and associated with a poorer prognosis.

Pathogenesis

Type 1 endometrial adenocarcinoma often emerges from a background of endometrial hyperplasia, a precancerous condition characterised by an uncontrolled proliferation of endometrial cells driven primarily by continuous exposure to oestrogens unopposed by progesterone. This endocrine imbalance could be a consequence of polycystic ovary syndrome, obesity, nulliparity, or oestrogen-secreting tumours. Type 1 spreads by direct myometrial invasion with eventual extension to periuterine structures.

In contrast, Type II endometrial adenocarcinomas, which include serous and clear cell subtypes, are less commonly associated with oestrogenic stimulation and often arise in atrophic endometrium. They frequently harbour TP53 mutations and are associated with a more aggressive clinical course. This oncogene encodes the protein p53, which is crucial for cell cycle regulation and apoptosis. Mutations in TP53 can result in unchecked cell proliferation and survival, ultimately leading to carcinogenesis. These tumours represent a distinct pathogenetic entity, which underscores the heterogeneity of endometrial cancer. Type 2 demonstrates transtubal spread to the peritoneum and lymphatics.

Epidemiology, Risk Factors & Associations

Endometrial adenocarcinoma is the most common gynaecologic malignancy in developed countries, with a peak incidence in the sixth decade of life.

Risk factors and associations can be broadly divided into those that increase exposure to oestrogen, thus predominantly associated with Type I tumours, and those linked to specific genetic alterations, which are more commonly seen in Type II tumours.

Type I

• Usually seen in women between 55 to 65 years old
• Obesity (overweight and obesity are associated with up to 50% of cases; for every 5 kg/m2 increase in body mass index (BMI), the risk of endometrial cancer increases by 60%)
• Nulliparity (nulliparous women have a two- to three-fold increased risk)
• Early menarche or late menopause (prolonged exposure to oestrogen)
• Oestrogen replacement therapy without a progestogen (increases risk two- to three-fold)
• Tamoxifen (increases risk two- to three-fold due to its oestrogenic effects on the endometrium)
• Polycystic ovary syndrome (associated with chronic anovulation and thus unopposed oestrogen)
• Lynch syndrome a.k.a. hereditary non-polyposis colon cancer (HNPCC) (5-10% of endometrial cancers – Estimated lifetime risk of endometrial cancer similar to their risk of colorectal cancer.

Type II

• Older age (peak incidence is a decade later than Type I), usually between 65 – 75 years old.
• Atrophic endometrium (lack of oestrogenic stimulation)
• TP53 mutations (commonly found in serous and clear cell subtypes)
• Prior pelvic radiation
• Endometrial intraepithelial carcinoma (may be a precursor lesion for serous carcinoma)

Clinical Features

• The most common symptom is postmenopausal bleeding. Other symptoms can include abnormal uterine bleeding, pelvic pain, and, in advanced stages, symptoms related to metastasis.

Complications

• Metastasis typically occurs via direct extension, lymphatic spread (pelvic and para-aortic lymph nodes), and haematogenous spread (commonly to the lungs and liver).

Pathological Features

Histopathology

• Macroscopic: Tumours may appear as polypoid masses or diffusely infiltrative lesions within the endometrium.
• Microscopic: Varies based on subtype, from well-differentiated glandular structures in endometrioid adenocarcinoma to high-grade papillary architecture in serous adenocarcinoma.

Serology

• Elevated levels of cancer antigen 125 (CA-125) may be associated with advanced or recurrent disease.

Biochemistry

• No specific biochemistry findings are associated with endometrial adenocarcinoma.

Radiological Features

General Features

• Endometrial adenocarcinoma usually presents as an irregular thickening of the endometrium.
• Advanced disease can cause distortion of the endometrial cavity and invasion into the myometrium or beyond.

Ultrasound

• Endometrial carcinoma characteristically presents as thickening of the endometrium, but it may also appear as a polypoid mass.
  • Endometrial thickening can also result from benign proliferation, endometrial hyperplasia, or polyps. Knowledge of patients’ menstruation cycle is required.
  • In postmenopausal women, an endometrial thickness greater than 5 mm is considered thickened (>8 mm if the patient is on hormone replacement therapy or tamoxifen)
• Heterogeneous and irregular endometrial thickening, a polypoid mass lesion, an intrauterine fluid collection, and frank myometrial invasion – favour carcinoma rather than hyperplasia.
• Disruption of a subendometrial halo on ultrasound may suggest myometrial involvement.

CT

• Lack of zonal differentiation limits evaluation of depth of myometrial invasion
• Non-contrast: May demonstrate endometrial thickening or a mass.
• Contrast-enhanced: Lesions typically enhance less than the surrounding myometrium.

MRI

• T1:
  • Tumours appear iso- to hypointense relative to the endometrium.
  • Useful for detection of lymphadenopathy
• T2:
  • Iso- to hypointense relative to the endometrium, hypointense to the myometrium, may be heterogenous.
  • If junctional zone (endometrium-myometrium interface) is intact – deep myometrial invasion is excluded
  • If junctional zone is poorly visualised – myometrial invasion must be considered
• T1 C+ (Gadolinium-enhanced):
  • Enhances less avidly than myometrium.
  • Dynamic contrast-enhanced sequences assist with assessing the depth of myometrial invasion and delayed-phase sequences can help assess for cervical stromal invasion.
    • Stage IA: Intact band of subendometrial enhancement
    • Stage IB: Disrupted band of early endometrial enhancement
• T1 Gad+ with FS: Help differentiate tumour from haematometra
• DWI/ADC: Tumours often demonstrate restricted diffusion, indicating high cellularity.

Grading and Staging

Endometrial adenocarcinoma is graded and staged based on the FIGO system. Grading (G1–G3) is based on the degree of glandular differentiation, while staging (I–IV) reflects the extent of disease spread.

Endometrial adenocarcinomas are graded based on the architectural style and the extent of solid tumour growth.

• Grade 1: Less than 5% of the tumour is solid (most of the tumour shows glandular or villoglandular growth)
• Grade 2: Between 6% and 50% of the tumour is solid
• Grade 3: More than 50% of the tumour is solid

The International Federation of Gynecology and Obstetrics (FIGO) 2009 system is used for staging of endometrial cancer:

Stage I: Tumour confined to the corpus uteri

• IA: No or less than half myometrial invasion
• IB: Invasion equal to or more than half of the myometrium

Stage II: Tumour involves the corpus and the cervix, but does not extend outside the uterus

Stage III: Local and/or regional spread of the tumour

• IIIA: Tumour invades the serosa of the corpus uteri and/or adnexa
• IIIB: Vaginal and/or parametrial involvement
• IIIC: Metastases to pelvic and/or para-aortic lymph nodes

Stage IV: Tumour invades the bladder and/or bowel mucosa (IVA), or distant metastases (IVB)

The FIGO system does not account for lymphovascular space invasion, which is an important prognostic factor especially in early-stage disease. Furthermore, the grading and staging of endometrial adenocarcinomas can be further complicated in cases with significant heterogeneity in tumour architecture and in cases of mixed histological types.

Diagnosis

The definitive diagnosis of endometrial adenocarcinoma requires histopathological examination, often obtained via endometrial biopsy or dilation and curettage.

Differential Diagnosis

• Endometrial hyperplasia: Often presents similarly on imaging and clinically but lacks the destructive invasion of malignancy. May be tamoxifen induced (correlate with history of breast cancer) endometrial thickening, with cystic change. Biopsy is required.
• Leiomyoma: A benign smooth muscle tumour of the uterus, typically demonstrating a well-circumscribed mass on imaging, often with characteristic whorled appearance on histology.
• Endometrial Sarcoma: Cannot be differentiated based off imaging, though are usually larger.

Management

Management of endometrial adenocarcinoma depends on the disease stage and patient factors. Initial management is often surgical, with total hysterectomy and bilateral salpingo-oophorectomy. Radiotherapy, chemotherapy, and hormonal therapy may be utilised depending on disease stage and histological subtype.