Carcinoma of the Uterus

Summary

  • Two variants - Type I (endometroid adenocarcinoma) related to high oestrogen exposure, and Type II (high grade, serous carcinomas) that occur in older women with no known risk factors
  • Commonly present with post-menopausal bleeding
  • Endometrioid adenocarcinomas have well defined glandular structures; higher grade lesions lose this distinction.
  • Papillary serous tumours have a papillary growth pattern microscopically and over 80% have mutations in TP53
  • TNM and FIGO staging is equivalent; most type I tumours are IA (< 50% invasion through myometrium).

Epidemiology

Endometrial carcinoma is the 4th most common tumour in women in Australia. The incidence is increasing as the population becomes more obese and less active.
Endometrial carcinoma falls into two distinct groups:

  • Type I - Endometroid adenocarcinoma, related to high levels of oestrogen exposure, and which is the most common gynaecological malignancy in Western countries. These make up 85% of endometrial carcinomas.
  • Type II - Non-oestrogen related carcinomas, which typically occurs in older women and is unrelated to high oestrogen / low progesterone exposure.

The highest rates of endometrial carcinoma are seen in North America. Australia has an incidence of 11 per 100,000 women per year.

Aetiology

Oestrogen related endometroid adenocarcinoma is related to:

  • Obesity - the strongest risk factor and associated with 40% of endometrial malignancies
  • Oestrogen exposure - obesity contributes to this, as does nulliparity, early menarche and late menopause.
  • Lack of progresterone exposure - Progesterone is a protective factor in the development of the hormonally associated endometrial carcinomas.

Non-oestrogen related endometrial carcinomas have no association with the risk factors for the endometroid adenocarcinomas; their causative factors are poorly understood.

Pathogenesis

Oestrogen related tumours often arise in women with endometroid hyperplasia, usually due to uncontrolled oestrogen exposure (without progesterone). This may be related to a number of medical conditions, including polycystic ovarian syndrome; or alternatively may be due to iatrogenic causes (use of hormone replacement medication or contraception with oestrogen-only medication). Tamoxifen, a partial agonist of the oestrogen receptor, is known to increase the rates of endometrial malignancy in women with breast cancer.

Natural History

Endometroid hyperplasia and atypical hyperplasia have a similar aetiology to oestrogen related endometrial carcinomas; they may be precursor lesions. Loss of PTEN, KRAS and the presence of microsatellite instability can be seen in otherwise normal glandular structures that go on to develop into a malignancy.
Serous endometrial intraepithelial carcinoma is the presumed precursor lesion of serous adenocarcinoma; it may be as aggressive as the invasive type.


Clinical Presentation

Symptoms and Signs

Localised disease may be clinically silent. Patients most commonly present with menorrhagia or post-menopausal bleeding.
Advanced disease causes signs and symptoms related to involved organs.

Bloods

Anaemia is not uncommon as patients may have had a long period of heavy bleeding due to the malignancy. Derangement of other bloods requires further investigation.

Radiology

Transvaginal ultrasound remains the best method of evaluating abnormal vaginal bleeding. The endometrium is visible and a thickness of over 5 mm requires further evaluation in the post-menopausal woman. This finding is sensitive but non-specific, and must be followed up with a dilatation+curettage procedure.
Staging of endometrial cancer is often done with MRI of the pelvis, where it is superior to CT.


Tumour Features

Macroscopic Features

Regardless of histological type, most endometrial cancers have a similar macroscopic appearance. There is usually a single large mass which may be exophytic. Invasion through the myometrium occurs in more advanced disease. Rare macroscopic appearances include diffuse involvement of the entire endometrium; this may be seen with serous subtype.

Microscopic Features and Immunohistochemistry

Most endometrial adenocarcinomas are easily differentiated on their microscopic appearance. Immunohistochemistry is poorly described in the literature.

Endometriod Adenocarcinoma

These tumours are frequently low grade, associated with oestrogen exposure, and present at a less advanced stage. Endometroid adenocarcinomas show a variety of appearances depending on grade. Most are well-differentiated, showing glandular structures without intervening stroma. There is little atypia of cells and extracellular mucin may be present. Areas of squamous differentiation may be present. Higher grade tumours may have bizzare cells present; it is important to ensure that serous or clear cell carcinomas are not present. Higher grade lesions show less defined architecture.

Mucinous Adenocarcinoma

Similar in prognosis to endometroid adenocarcinoma, the distinguishing feature of mucinous adenocarcinoma is the presence of intracellular mucin. Most are low grade.

Serous Adenocarcinoma

Serous adenocarcinoma is one of the instant 'high grade' tumours that may occur in the uterus, and are usually not associated with high oestrogen exposures. The classical microscopic features are a papillary growth pattern, exfoliation of malignant cells and psammoma bodies (round collections of calcium). These lesions often penetrate deeply into (or through) the myometrium; even without significant local invasion there may be peritoneal or other distant spread of this tumour; it is associated with a relatively poor outcome.

Clear Cell Adenocarcinoma

Clear cell carcinoma is another aggressive endometrial carcinoma which is always high grade. Cells with clear cytoplasm are the hallmark on microscopy, often with a papillary architecture. Psammoma bodies are not seen.

Other Microscopic Appearances

Squamous cell, transitional cell and small cell carcinomas are all potential diagnoses in the uterus.

Genetics

This is quite an interesting area as the Type I and II malignancies have a very different genetic profile.

Type I adenocarcinomas are oestrogen related and the most frequent genetic abnormality seen is mutation or loss of PTEN, seen in about half of these malignancies. PTEN is an important pro-apoptotic gene that interacts with the AKT pathway. Other common mutations occur in KRAS and ╬▓-catenin. Microsatellite instability is another common finding. Familial syndromes that affect microsatellite stability (hereditary non-polyposis colon cancer) or PTEN (Cowden syndrome) increase the rate of endometrial malignancies.
Type II adenocarcinomas possess abnormalities in the TP53 gene in over 80% of cases, as opposed to 5-10% of type I carcinomas. This suggests a different pathway in the development of type II adenocarcinoma.


Staging

The TNM staging system for uterine carcinoma mirrors the FIGO staging system.

T Stage FIGO Stage Description
Tis N/A Carcinoma in situ
T1a IA Tumour limited to endometrium or invasion through less than one half of the myometrium
T1b IB Invasion through the outer half, but not through, the myometrium
T2 II Invasion into the cervical stroma
T3a IIIA Involvement of serosa or adnexal structures
T3b IIIB Involvement of vagina or parametrium
T4 IVA Invasion of bladder or bowel
N Stage FIGO Stage Description
N0 N/A No nodal involvement
N1 IIIC1 Involvement of pelvic lymph nodes
N2 IIIC2 Involvement of para-aortic lymph nodes
M Stage FIGO Stage Description
M0 N/A No distant metastases
M1 IVB Distant metastases

The grade of an endometroid or mucinous adenocarcinoma is also included; this excludes small areas of squamous differentiation.

Grade Description
G1 < 5% solid growth pattern
G2 5 - 50% solid growth pattern
G3 > 50% solid growth pattern

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