Endometrial Cancer

Jane M.Hawnaur

BACKGROUND INFORMATION Epidemiology

In the United Kingdom, endometrial carcinoma has an incidence of 4850 new cases per year, compared to 6820 per annum for ovarian cancer and 3240 for cervical cancer. There are approximately 990 deaths per year from uterine cancer in the UK. Endometrial carcinoma is the commonest gynaecological malignancy in the USA, and the American Cancer Society estimates that 39 300 new cases and 6600 deaths will occur in 2002. The disease predominantly affects postmenopausal women, peaking in the decade 55-65 years. The most frequent presenting symptom is abnormal vaginal bleeding or discharge. Asymptomatic tumours may be detected by cervical smear or as an incidental finding during pelvic ultrasound. Women at high risk include those with the hereditary nonpolyposis colorectal cancer (HNPCC) gene who usually develop endometrial cancer before the age of 50 years. Women on long-term treatment with Tamoxifen for breast cancer also have an increased risk of developing endometrial malignancy. Other predisposing factors include chronic exposure to unopposed oestrogens, either extrinsic or as a result of obesity or ovarian malfunction, for example in polycystic ovarian disease. There is also an association between endometrial cancer and diabetes mellitus.

Histopathology

The majority of endometrial carcinomas arise within glandular epithelium and are adenocarcinomas of endometrioid type (75%). The less common papillary serous, adenosquamous and clear cell types are associated with a worse prognosis. Tumours are graded from Grade 1 (well differentiated) to Grade 3 (poorly differentiated). Rare tumours of stromal origin include endometrial sarcoma, mixed Mullerian tumour and leiomyosarcoma.

Patterns of tumour spread

Endometrial carcinoma arising in glandular epithelium commonly grows as a polypoidal mass, ulceration of which results in bleeding. Direct invasion into the myometrium may initially occur at the stalk of a polypoid tumour, eventually extending more widely and deeply into the myometrium. Tumour may eventually reach the serosa of the uterus and thence into the peritoneal cavity and adjacent organs. Tumour may spread down the cervical canal, with the potential for invasion of cervical glandular epithelium and stroma. Cervical stromal invasion may also occur directly from myometrial tumour invasion extending below the isthmus of the uterine corpus into the cervix. Extension of tumour at the uterine cornua into the Fallopian tubes provides another route of spread to the adnexal structures and peritoneal cavity. Peritoneal metastases can also occur as a result of lymphovascular or trans-myometrial spread from endometrial carcinoma. Lymphovascular space invasion is associated with lymph node metastasis. The endometrium and myometrium of the upper corpus and fundus of the uterus drain via lymphatics in the infundibulo-pelvic ligament to the common iliac and para-aortic lymph nodes. The mid and lower corpus and the uterine cervix drain to parametrial, paracervical and obturator lymph nodes, and thence along the external iliac, internal iliac, common iliac and para-aortic/para-caval lymph node chains. Fallopian tube or ovarian tumour can also metastasise directly to para-aortic lymph nodes. Tumours extending via the cervix to the lower vagina can metastasise to the inguinal lymph nodes. Inguinal nodes may also be involved via spread along the round ligament from adnexal or pelvic sidewall tumour involvement. Distant haematogenous metastasis can occur to lungs, liver or bones, but is unusual at presentation.

Staging

The TNM staging classification and its equivalent FIGO staging is given in Table 5.1. Carcinoma of the endometrium is commonly staged in the UK using the International Federation of Obstetrics and Gynaecology (FIGO) staging classification (1994), which is surgicopathological.

Prognostic indicators

The mortality rate in the UK for endometrial carcinoma is 3 per 100000 women per year. In the USA, the average mortality rate is slightly higher at approximately 4 per 100000 women. It is particularly high in American black women (7 per 100000). Although 5 -year survival in endometrial carcinoma is better than that for other gynaecological cancers, this is because most (75%) present with FIGO Stage I disease. The patient's prognosis depends on the histological type and grade of tumour, and the patient's fitness for surgery, as well as tumour stage (see Table 5.1). The probability of lymph node metastases is closely related to histological grade and the depth of myometrial invasion. Survival rates at 5 years vary from 80% for Stage 1 to 5% for Stage IV, i.e. similar to that for cervical carcinoma. Poor prognostic indicators include papillary serous, clear cell or undifferentiated

Table 5.1. Clinical staging of carcinoma of the endometrium: correlation of TNM (2002) and FIGO classifications (FIGO 1994)

TNH Classification

FIGO Stage

Description of tumour extent

Tis

0

Carcinoma in situ, intraepithelial neoplasm

T1

I

Tumour confined to the uterine corpus.

T1a

IA

Tumour confined to the endometrium

T1b

IB

Invasion into the inner half of the myometrium

T1c

IC

Invasion into the outer half of the myometrium

T2

II

Invasion of the cervix. Does not extend beyond uterus

T2a

IIA

Endocervical glands only involved. No stromal invasion

T2b

IIB

Invasion of cervical stroma

T3

III

Extra-uterine spread +/- positive peritoneal cytology

T3a

IIIA

Invasion of the uterine serosa, or adnexae

T3b

IIIB

Vaginal invasion or metastasis

T4

IVA

Invasion of bladder and/or bowel mucosa

N0

No regional lymph node metastasis

N1

IIIC

Regional lymph node metastasis to pelvic and/or para-aortic nodes

M0

No distant metastasis

M1

IVB

Distant metastases, including inguinal lymph node metastases

histological type, and high grade (poorly differentiated) tumours of any type. Tumour size, the depth of myometrial invasion, and the proximity of tumour to the serosal surface of the uterus are inter-related adverse factors. Invasion of the cervix, spread to the adnexae, and the presence of lymphovascular space invasion or lymph node metastases also correlate with reduced survival.

Treatment

The choice of treatment for endometrial carcinoma is guided by patient factors and the histological grade/FIGO stage of the tumour. For surgically fit patients with tumours at low risk of extrauterine spread (Grade I-II, FIGO stage IA-IB), total abdominal hysterectomy and bilateral salpingo-oophorectomy is performed. Pelvic and paraaortic lymph nodes are palpated and removed if enlarged, and peritoneal washings are obtained for cytology. For higher risk tumours (Grade 2 or higher, FIGO stage>IB) full pelvic lymph node resection should be considered. In patients with papillary serous type tumours, the peritoneum should be thoroughly inspected and an omentectomy performed, since these tumours behave in a similar way to ovarian carcinoma. Simple hysterectomy may be performed in women with major surgical risk factors and an early stage tumour. Adjuvant radiotherapy is usually given to the vaginal vault if the tumour is any worse prognostically than a Grade I tumour with limited myometrial invasion. Metastatic tumour in pelvic or retroperitoneal lymph nodes is also an indication for adjuvant radiotherapy Disseminated tumour can be treated by hormonal treatment with progestogens, but only about 25% of patients respond and only over the short term. Chemotherapeutic agents such as doxorubicin and cisplatin may also produce a significant tumour response in approximately 25% of patients with advanced disease.

MR IMAGING OF ENDOMETRIAL CANCER

Technique

A standard pelvic imaging protocol is used. One of the T2-weighted sequences should be angled parallel to the short axis of the uterine corpus, to assess depth of tumour invasion into the lateral myometrium. T2-weighted sections through the short axis of the cervix may also be helpful if cervical stromal invasion is suspected. If T2-weighted sequences are not diagnostic for tumour extent, useful tumour-myometrial contrast can be achieved using enhancement with a paramagnetic contrast agent. A dynamic acquisition T1-weighted Gradient Recalled Echo sequence is obtained during bolus intravenous injection of Gadolinium-chelate 0.1 mmolkg-1 body weight. The imaging plane should be the one best demonstrating the endometrial/myometrial interface of tumour.

Current indications

MRI is indicated in patients with endometrial cancer where pre-operative knowledge of the stage of tumour might affect the choice of treatment or the surgical approach used. Examples include patients with clinical or ultrasound evidence of a bulky or fixed uterus, cervical or adnexal abnormality, or peritoneal or extrapelvic disease. In such cases, there is a significant chance of tumour spread beyond the uterine corpus, for which adjuvant or alternative treatment to hysterectomy is indicated. Conversely, MRI may be used to replace full FIGO staging in unfit patients with early stage disease in whom a simple hysterectomy may be adequate for treatment. There is no evidence at present that the results of MRI have a significant impact on clinical outcome in endometrial cancer, but research is ongoing.

Staging accuracy

Published evidence to support the use of MR imaging for staging endometrial cancer has been recently reviewed. MRI is 8090%

accurate for assessing depth of myometrial invasion and the presence of cervical involvement. Post-contrast T1-weighted sequences do not increase staging accuracy over T2-weighted sequences. Dynamic contrast-enhanced techniques may be useful in post-menopausal patients.

Imaging features

Primary tumour

Primary endometrial carcinoma appears on T2-weighted images as a mass or thickening of the endometrium, of intermediate signal compared to the high signal intensity of normal endometrium or intracavitary fluid, and the low signal of myometrium. Integrity of a smooth endometrial/myometrial interface in the presence of histologically proven endometrial carcinoma indicates a Stage la tumour. Myometrial invasion is indicated by replacement of the relatively hypointense myometrium by tumour contiguous with the primary tumour. The normal uterine low signal junctional zone increases the contrast between tumour and inner myometrium, but may not be present in post-menopausal women. The endometrial/myometrial interface should be assessed in at least two planes, with thin sections, and with contrast enhanced T1 -weighted sequences if T2-weighted scans are inconclusive, to look for evidence of myometrial invasion. The relationship of the tumour to the cervix is important prognostically, and should be evaluated carefully on T2-weighted images in the sagittal and transverse oblique planes.

Lymph node metastases

Lymph nodes replaced by tumour metastasis often have a similar signal intensity to the primary tumour (on T2-weighted sequences) whereas reactive lymph node enlargement tends to be of lower signal intensity. The lower the value of short axis diameter used as a cut-off for normality, the higher the sensitivity and the lower the specificity of MRI. Lymph nodes exceeding 5mm in short axis diameter should be examined carefully for other signs of metastasis (e.g. abnormal shape, margins and signal intensity), and the probability of involvement given the stage of the primary tumour (and grade if known) as well as knowledge of the patterns of lymph node spread.

Post treatment

Since hysterectomy is the usual treatment, imaging in the early post treatment period is rarely carried out. MRI can be used to assess tumour response to primary radiotherapy prior to surgery in advanced endometrial cancer. It may be difficult to evaluate changes in viable tumour volume due to associated radiotherapy-induced necrosis, inflammatory reaction and oedema, and MRI can only provide a very crude assessment under these circumstances.

Recurrent tumour

Recurrent endometrial cancer most frequently occurs at the vaginal vault, and is detected by clinical examination. The pelvic sidewall is also a common site for recurrence, and tumour here usually presents with symptoms such as pain or swelling of the ipsilateral leg. There is no evidence that routine surveillance by diagnostic imaging or clinical follow-up improves the outcome by detecting asymptomatic recurrence of endometrial cancer. However diagnostic imaging is indicated to assess salvageability of the patient with a known recurrence by evaluating the extent of local tissue invasion, lymph node metastases and extrapelvic spread.

Pitfalls of MRI

Identification of the primary tumour

• Thickening of the endometrium, without myometrial invasion, may be due to benign disease such as endometrial hyperplasia or polyps, causing false-positive MRI.

• Stage la carcinoma may be of too small a volume or too similar in signal intensity to normal endometrium to visualise on MRI, resulting in a false-negative examination.

Assessment of depth of myometrial invasion

• The integrity of the endometrial / myometrial interface may be difficult to assess in post-menopausal women where the low signal junctional zone is indistinct.

• Concentric stretching and thinning of myometrium by a large tumour makes it difficult to assess the proportion of myometrium infiltrated, i.e., whether less than or more than half of the normal thickness.

• Concomitant benign disease, such as fibroids or adenomyosis, can result in morphological and signal changes in the myometrium mimicking tumour infiltration.

• Distortion of the endometrial/myometrial interface at the base of the stalk of a polypoid tumour may be difficult to distinguish from infiltration.

Assessment of invasion of the cervix

• It can be difficult to distinguish between tumour prolapsing into the upper cervical canal and early glandular or stromal invasion.

• Glandular and early stromal invasion are difficult to differentiate.

• When there is invasive disease near the isthmus, it can be difficult to determine whether or not myometrial tumour infiltration extends into the cervical stroma.

• Benign disease, such as tunnel clusters of glands, or even normal mucosa, can be mistaken for tumour.

Assessment of lymph nodes

• Microscopic or very small macroscopic tumour deposits in lymph nodes may be occult on MRI.

• Reactive lymph node enlargement can cause false-positive calls on MRI.

• Metastatic lymph nodes may be indistinguishable from adnexal structures/bowel loops/peritoneal tumour.

• Cystic lymph nodes may be mistaken for fluid-filled bowel/ascites.

Other extra-uterine disease

• The sensitivity of MRI for small peritoneal deposits is low.

FURTHER READING

1. Endometrial Cancer. Diagnosis and pre-treatment staging and Endometrial Cancer. Treatment. (1999) In: Guidance on Commissioning Cancer Services. Improving Outcomes in Gynaecological Cancers. The Research Evidence. NHS Executive. Review of research evidence for current management of endometrial carcinoma.

2. Odieino F, Favalli G, Zigliani L, etal. (2001) Staging of gynecological malignancies. Surgical Clinics of North America 81(4): 753-770. Describes the current staging system for endometrial carcinoma.

3. Making the best use of a Department of Clinical Radiology, 5th Edn (2003). The Royal College of Radiologists. Evidence-based recommendations for diagnostic imaging in uterine tumours- UK.

4. Hricak H, Mendelson E, Bohm-Velez M et al (2000) Endometrial cancer of the uterus. ACR Appropriateness Criteria. Radiology 215 Suppl: 947-953. Evidence-based recommendations for diagnostic imaging in uterine tumours- USA.

5. Kinkel K, Kaji Y, Yu KK, Segal MR, Lu Y, Powell CB and Hricak H. (1999) Radiologic staging in patients with endometrial cancer: a meta-analysis. Radiology 212(3): 711-718. A comparison of imaging techniques for staging endometrial carcinoma.

6. Frei KA and Kinkel K. (2001) Staging endometrial cancer: role of magnetic resonance imaging. J.Magn. Reson. Imaging 13(6): 850-855. Up-to-date review of the topic.

7. Ascher SM, Takahama J and Jha RC. (2001) Staging of gynecologic malignancies. Top. Magn. Reson. Imaging. 12(2): 105-129. Another up-to-date review of the topic.

Uterus Zonal Anatomy
Figure 5.1. Normal uterine zonal anatomy.

Sagittal T2W1 in (a) a pre-menopausal patient and (b) a post-menopausal patient. The zonal anatomy of the uterus is appreciated in the pre-menopausal patient. There is a central high signal intensity stripe (asterisk in (a)), which represents the endometrium and its secretions. The low signal intensity junctional zone (arrowheads) represents the inner portion of the myometrium and blends inferiorly with the fibromuscular stroma of the cervix. The outer myometrium (arrows) is heterogeneous intermediate and high signal intensity. The junction between the uterine corpus and the cervix is marked by waisting of the contour of the uterus (open arrows). Bladder (B). Ascites (A) from an incidental non gynaecological cause. In the post menopausal patient the endometrial stripe is thin and the entire uterus is of low signal intensity with loss of the junctional anatomy.

Signal Intensity
Figure 5.2. T1aN0/stage IA endometrial cancer.

(a) sagittal and (b) transaxial T2W1 tumor (arrowhead) confined to the endometrium with minimal widening of the endometrial cavity, a smooth interface between the endometrium and the inner myometrium (M) and no sign of myometrium invasion. Incidental note is made of an arachnoid cyst (Cy) in the dpinal canal.

Endometrial Cancer Stage Grade Mri
Figure 5.3. T1bN0/Early stage IB endometrial cancer.

(a) Sagittal and (b) transaxial T2W1 of an endometrial tumour (asterisk) which demonstrates irregularity of the endometrial/myometrial interface (arrowheads) indicating myometrial invasion confined to the inner half of the myometrium. Incidental note is made of cervical Nabothian cysts (arrows in (a)).

Arachnpic Cyst
Figure 5.4. T1bN0/Late stage IB endometrial cancer.

(a) Sagittal and (b) oblique transaxialT2W1 showing a large endometrial tumour (T) invading the inner half of the myometrium on its fundal aspect (arrowheads). Note hyperintense compressed myometrium surrounding the endometrial fibroids (F), which has a similar signal intensity to the tumour proper.

Sehnenansatz Hamstring
Figure 5.5. T1cN0/Stage 1C endometrial cancer.

(a) Sagittal and (b) oblique transaxial T2WI showing a large endometrial tumour (T) invading the outer half of the myometrium on its anterior aspect (arrowheads). Note that the intact posterior myometrium is markedly stretched and thinned by the tumour but that the inner myometrial junctional zone retains its low signal intensity (arrows).

Endocervicla Stromal Tumor
Figure 5.6. T2aN0/Stage IIA endocervical cancer.

(a) Sagittal and (b) transaxial T2W1 showing myometrial invasion by an endometrial tumour (T), which is also extending into the cervix without stromal invasion.

Figure 5.7. T2bN0/Stage IIB endometrial cancer.

(a) Sagittal and (b) oblique transaxial T2W1 demonstrating a large endometrial tumour (T) extending down into and distending the endocervical canal. Tumour is invading the cervical stroma anteriorly (arrowheads). Note mural fibroids (F). Bladder (B).

Stroma Cervical Canal

Figure 5.8. T3aN0/Stage IIIA endometrial cancer.

(a) and (b) Sagittal and (c) and (d) oblique transaxial T2W1 demonstrating a large endometrial tumour (T) within the endometrial cavity but not involving the cervix. There are bilateral adnexal masses (M), larger on the left side.the solid portions of which have similar signal intensity to the endometrial tumour. There is a cystic component (Cy) on the left side. Bladder (B).

Anterior Mural Fibroid
Figure 5.9. T3bN0/Stage 1MB endometrial cancer.

(a) and (b) Sagittal and (c) transaxial T2WI demonstrating a large endometrial tumour (T) distending the uterine cavity without evidence of myometrial or cervical invasion.There is a metastasis (M) in the right vagina which demonstrates similar signal intensity to the endometrial tumour proper.

Incidental note is made of an anterior wall uterine fibroid (F).There is small volume pelvic ascites (A). Bladder (B).

Endometrial Cancer Stage Grade Mri
Figure 5.10. T3aNI/Stage IIIC endometrial cancer.

(a) Sagittal and (b) coronal T2W1 showing an endometrial tumour (T) with myometrial invasion to the outer half (arrowheads) but also extension to the cervix with stromal invasion (arrows in (a)), and a tumour nodule on the right adnexa (asterisk in (b)). There is also a metastatic lymph node in the right external iliac chain (N in (b)). The MR stage is therefore T3aNI/IIIC. The patient also has intramural fibroids (F). Bladder (B).

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Responses

  • fatimah
    Does endometrial cancer cause a thickened junctional zone?
    2 years ago

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