- Email: [email protected]
Endometrial cancer
Review
Endometrial cancer
often seen on a background of atypical hyperplasia, a precursor lesion. Approximately 40% of atypical hyperplasia is upgraded to invasive endometrial cancer following hysterectomy. Serous, clear cell, squamous and undifferentiated carcinomas are less common and are more aggressive malignancies. Serous carcinomas arise on a background of endometrial atrophy, and a precursor lesion for serous endometrial carcinoma, endometrial intraepithelial carcinoma, has recently been identified. Other types of endometrial cancer are less common. These include, among others, clear cell carcinoma, carcinosarcoma (previously known as malignant mixed müllerian tumour) and endometrial stromal sarcoma, which arises from stromal elements of the endometrium. Endometrial tumours spread by direct extension to the cervix, vagina and, via the fallopian tubes, to the ovaries and peritoneal cavity. Myometrial invasion is common (Figure 1) and may lead to serosal and parametrial involvement. Lymphatic spread occurs to the external iliac, internal iliac and obturator regions of the pelvis and to the para-aortic nodes from the upper part of the uterus. Haematogenous spread results in lung metastases. Non-endometrioid tumours behave in a more malignant fashion, and extrauterine disease may be present even where the uterine disease shows no or minimal myometrial invasion. Patterns of recurrence also suggest a tendency to early systemic metastasis. Pathological grading of disease and accurate classification of histological subtype on diagnostic endometrial biopsy are important in planning appropriate investigations and subsequent treatment, especially where the risk of systemic disease is high.
Cathrine Holland
Abstract The incidence of endometrial cancer is increasing. The overall 5-year survival rate is high, reflecting early presentation in most cases, but outcomes for advanced disease remain poor. Surgery for low-risk disease may be undertaken by general gynaecologists, but all patients require specialist multidisciplinary input. The cornerstone of treatment remains surgery, and laparoscopic surgery is emerging as a means of reducing morbidity. Systematic lymphadenectomy in all cases is unjustified, and adjuvant radiotherapy is now given only to selected patients at high risk of recurrence. Chemotherapy is increasingly used in high-risk and advanced disease, although the optimum drug combination is unclear. Future developments are likely to include the emergence of molecularly targeted therapies as an addition to existing treatments and the possibility of fertility-sparing hormonal treatments in selected patients.
Keywords adjuvant radiotherapy; chemotherapy; endometrial cancer; laparoscopic surgery; lymphadenectomy; management
Aetiology Introduction
In recent years, significant differences have been identified at a genetic level between different histological types, and endometrial cancers may now be broadly classified into two main categories based upon these differences. Type 1 or endometrioid cancers frequently arise on a background of atypical hyperplasia and have
Uterine cancers are the most common gynaecological malignancies. In the UK, the incidence is slightly lower than that for ovarian cancer, with approximately 4500 new cases occurring each year. Most arise in the endometrium, and the majority are diagnosed in women aged over 50 years. The most common presentation is postmenopausal bleeding, although 20–25% of women are premenopausal at diagnosis and approximately 5% of women are diagnosed below 40 years of age. Most women present with disease confined to the uterus, and many of these women have an excellent prognosis. This has led to a false perception that endometrial cancer is not as serious as other cancers. However, some histological subtypes are associated with a poor prognosis, and 5-year survival rates for advanced disease are low. Although some endometrial cancers may be treated by designated gynaecologists in cancer units, all cases must have the benefit of multidisciplinary input before treatment, to identify those requiring management at the regional cancer centre.
Pathology Over 80% of primary endometrial cancers are endometrioid adenocarcinomas. These arise from the glandular epithelium and are Figure 1 International Federation of Gynecology and Obstetrics G3 stage 1C endometrioid endometrial adenocarcinoma. Histopathology revealed more than 50% myometrial invasion with tumour measured 1 mm from the serosal surface. Adjuvant radiotherapy was given after surgery.
Cathrine Holland PhD MRCOG is Senior Clinical Lecturer/Honorary Consultant Gynaecological Oncologist, Academic Unit of Obstetrics and Gynaecology, Division of Human Development, Saint Mary’s Hospital, Manchester, UK.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 17:11
318
© 2007 Elsevier Ltd. All rights reserved.
Review
an association with obesity, nulliparity, insulin resistance and an oestrogenic environment. Type 2 tumours comprise serous and other non-endometrioid histology, for example clear cell carcinoma. Type 2 tumours are not associated with the risk factors for type 1 cancers, often occurring in elderly, thin women. Ongoing translational research seeks to exploit molecular differences between these cancers for therapeutic benefit.
Outpatient endometrial biopsy correctly diagnoses cancer in over 80% of women (Figure 2) and can be preceded by outpatient hysteroscopy if necessary, for example where endometrial polyp(s) are suspected on ultrasound. Hysteroscopy is useful in the evaluation of women with bleeding while taking tamoxifen. The typical subendometrial cystic changes seen with tamoxifen use frequently result in false-positive ultrasound findings. This makes ultrasound less useful in this setting. As tamoxifen is associated with a significant increase in endometrial polyps as well as hyperplasia and cancer, hysteroscopy can provide prompt reassurance and provide a diagnosis, particularly where an endometrial sample is scanty. Serum tumour markers are not recommended for diagnosing endometrial cancer. Although serum Ca125 may be elevated in women with advanced endometrial cancer, it is neither sensitive nor specific enough to be useful in the initial diagnosis or for staging disease.
Hereditary endometrial cancer Hereditary endometrial cancer accounts for less than 5% of all endometrial cancer and is one of the extracolonic cancers caused by hereditary non-polyposis colon cancer (HNPCC) syndrome. This autosomal dominant inherited disorder is caused by germline mutations in DNA mismatch repair genes, leading to faulty DNA repair mechanisms and consequently an increased risk of malignant transformation. Women with confirmed HNPCC have a 40–60% lifetime risk of developing endometrial cancer. Although the value of endometrial surveillance with endometrial imaging and biopsy is unproven, this option is offered to women who wish to retain their uterus. Prophylactic hysterectomy and bilateral salpingo-oophorectomy is recommended for those who have completed their family. Although the proportion of women with HNPCC-associated endometrial cancer is small, recognition of these individuals is important as half of all affected women will develop endometrial cancer as their index cancer. Identifying these women enables them and their extended family to undergo genetic counselling, genetic testing and screening or prophylactic surgery for bowel cancer. Different criteria have been developed to identify individuals at risk. Our current policy is to refer women who are diagnosed with endometrial cancer below the age of 45. In addition, women are also referred if they have had another HNPCCassociated cancer or have a significant family history.
Investigations Once a diagnosis of endometrial cancer has been made, a blood count, renal biochemistry and liver function tests are performed, and further imaging is undertaken to identify metastatic disease and aid treatment decisions. A chest X-ray is carried out to identify lung metastases. Increasingly, magnetic resonance imaging (MRI) is used in the preoperative imaging of women with endometrial cancer to assess the depth of myometrial invasion. Depth of invasion is closely related to the risk of lymph node involvement and may be used to aid decisions for selective lymphadenectomy. MRI is more sensitive than transvaginal ultrasound and computed tomography
Diagnosis Approximately 90% of women diagnosed with endometrial cancer present with postmenopausal bleeding. Up to 10% of women with this symptom will be diagnosed with endometrial cancer, so referral for investigation is mandatory. Initial assessment should take place in rapid-access clinics where a relevant history can be taken to identify risk factors and co-morbidities, and a pelvic examination can exclude vulval and cervical lesions. The recommended initial investigation is a transvaginal ultrasound scan for measurement of endometrial thickness and identification of ovarian masses. A thin endometrium in the postmenopausal woman has a high negative predictive value for endometrial cancer and is reassuring. Approximately 40–50% of women can be reassured having had a normal ultrasound scan, thus avoiding a large number of invasive procedures. Women with a thickened endometrium require further assessment. The threshold endometrial thickness for further intervention varies slightly between authors. The most commonly used threshold for further intervention is an endometrial thickness of over 5 mm. Any further investigations required can be safely performed in the outpatient setting in approximately 80% of women. This is particularly important in women with postmenopausal bleeding as many have significant co-morbidities including cardiovascular disease, diabetes and obesity.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 17:11
A Pipelle endometrial sampler is one of several sampling devices used to obtain endometrial biopsies. The sampler is advanced through the cervix to reach the uterine fundus. Markings on the barrel at 1 cm intervals allow confirmation that the cavity has been entered and give a measurement of uterine length. The plunger is withdrawn to the proximal end of the barrel, and the sampler is drawn backwards and forwards with a rotating motion to draw endometrial tissue into the barrel. Figure 2
319
© 2007 Elsevier Ltd. All rights reserved.
Review
(CT) scanning for the assessment of depth of invasion and can identify cervical involvement (Figure 3). Other investigations, such as cystoscopy, may be indicated if locally advanced disease is suspected. CT may be helpful in assessment of the upper abdomen if intra-abdominal metastases are suspected. Positron emission tomography (PET) using fluorine-18-fluoro2-deoxy-D-glucose (FDG) is emerging as a potentially useful imaging modality in the management of gynaecological tumours.
Experience of FDG-PET in endometrial cancer is currently limited and is unlikely to contribute significantly to preoperative management. However, initial reports suggest that FDG-PET may be clinically useful in evaluating potential disease recurrence, with negative results correlating with a disease-free course.
Treatment of early disease Surgical management Despite the use of preoperative imaging as an aid to treatment planning, the staging of endometrial cancer remains surgicopathological, relying both on a surgical assessment of intra-abdominal disease and in most cases, where disease is confined to the uterine corpus, on depth of myometrial invasion. Low-risk endometrioid tumours with less than 50% myometrial invasion on preoperative MRI scanning are associated with lymph node metastases in fewer than 5% of cases. These women are suitable for surgery with extrafascial hysterectomy and bilateral salpingo-oophorectomy undertaken by a general gynaecologist. The Improving outcomes guidance document published by the National Health Service Executive recommends that all other women with high-grade disease, highly malignant histology, deep myometrial invasion or lymphadenopathy on preoperative imaging, should be managed by gynaecological oncologists as part of a multidisciplinary team. Where the preoperative imaging suggests cervical stromal involvement (stage 2b), gynaecological oncologists often advocate a modified radical hysterectomy in order to ensure removal of the tumour with adequate surgical margins. Although this treatment is extrapolated from the experience of radical hysterectomy for cervical cancer, research evidence confirming a benefit for radical hysterectomy in stage 2 endometrial cancers is lacking. The role of lymphadenectomy There has been considerable debate concerning the surgical staging of endometrial cancer. It is generally accepted that, as a minimum, total hysterectomy with bilateral salpingo-oophorectomy, peritoneal cytology and inspection of the upper abdominal organs and peritoneal surfaces should be performed. The International Federation of Gynecology and Obstetrics (FIGO) staging system is used in the UK (Table 1). Although systematic lymphadenectomy informs FIGO staging, the effect of lymphadenectomy on outcome and its role in directing adjuvant treatment is controversial. In the USA, systematic lymphadenectomy is widely practised compared with the UK and some Northern European countries where the approach to lymphadenectomy is more selective. In the UK, the Medical Research Council ASTEC trial randomised women undergoing surgery for clinical stage 1 endometrial cancer to systematic pelvic lymphadenectomy or no lymphadenectomy. The results from ASTEC showed no therapeutic benefit in the women receiving lymphadenectomy. Therefore it appears that systematic lymphadenectomy in all women with clinical stage 1 disease is not justified. Lymphadenectomy, however, may be indicated in selected cases if the result would inform the need for adjuvant treatment. This too is an area of controversy, and practice differs widely between cancer centres. Although gynaecological oncologists may perform lymphadenectomy for deeply invasive
Preoperative magnetic resonance imaging of endometrial cancer. Both a (a) saggital T2- and (b) coronal T2-weighted images suggest protrusion of tumour into the cervix. Final histopathology confirmed stage 2a disease. Figure 3
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 17:11
320
© 2007 Elsevier Ltd. All rights reserved.
Review
Compared with the open or laparoscopic approach, vaginal hysterectomy alone for endometrial cancer is inadequate for staging as ovarian metastases cannot be detected Bilateral salpingooophorectomy can be undertaken vaginally but does not allow an assessment of the upper abdomen and peritoneal surfaces. Vaginal hysterectomy is therefore not considered adequate for staging and treatment. Despite these limitations, vaginal hysterectomy alone under regional anaesthesia may have a place in the management of exceptional cases of women who have co-morbidities that preclude a general anaesthetic.
International Federation of Gynecology and Obstetrics (FIGO) staging for endometrial cancer FIGO Stage
Features
I Ia Ib Ic
Tumour confined to the corpus uteri Tumour confined to the endometrium Myometrial invasion <50% Myometrial invasion >50%
II IIa IIb
Cervical involvement Endocervical glandular involvement only Cervical stromal invasion but not extending beyond the uterus
III IIIa
Extension beyond myometrium Carcinoma involves serosa of uterus or adnexae, or positive ascites, or positive peritoneal washings Vaginal involvement, either direct or metastatic Para-aortic or pelvic node involvement
IIIb IIIc IV IVa IVb
Radiotherapy Primary radical radiotherapy may be used when the patient cannot undergo surgery for medical reasons. Intracavitary radiotherapy combined with external beam treatment can achieve cure rates of approximately 70% in stage 1 disease. However, surgery to remove the central uterine tumour should be undertaken if at all possible. Radiotherapy is more usually given as adjuvant treatment after surgery in women at high risk of disease recurrence. A prospective randomised trial of 715 women showed that postoperative radiotherapy in stage 1 endometrial cancer reduced locoregional recurrence from 14% to 10% but had no impact on overall survival. Age greater than 60 years was an independent poor prognostic factor for locoregional recurrence. In the same trial, treatment-related morbidity was significantly increased in the women who received radiotherapy. Therefore current practice in Europe is to select patients for adjuvant radiotherapy based on risk stratification. Patients are determined to be at low, intermediate or high risk of recurrence based on depth of myometrial invasion, tumour grade and age. Radiotherapy is given as external beam therapy to cover the pelvic lymphatics, and vault brachytherapy to prevent central recurrence. Side-effects are common, occurring in 25% of women, and include frequent bowel movements, diarrhoea and frequency of micturition. Severe toxicity occurs in approximately 2% of cases. In women at high risk of distant metastases, adjuvant chemotherapy is sometimes given, although practice varies widely. These women generally have highly metastatic tumour types such as serous carcinoma or carcinosarcoma. Progestagens given as adjuvant treatment offer no survival benefit in metaanalyses and should not be used in the adjuvant setting.
Further spread Carcinoma involving the mucosa of the bladder or rectum Distant metastases and involvement of other abdominal or inguinal lymph nodes
Table 1
e ndometrial tumours or those with a highly malignant subtype (e.g. carcinosarcoma), many question the justification for this if adjuvant treatment is to be given regardless of nodal status. This is pertinent as many women with endometrial cancer are elderly and have significant co-morbid conditions. Laparoscopic surgery for endometrial cancer Another issue that has generated much debate is the role of laparoscopic surgery for the staging and surgical treatment of endometrial cancer. The traditional surgical approach of abdominal hysterectomy is based on professional consensus rather than evidence from clinical trials. Total laparoscopic hysterectomy and laparoscopically assisted vaginal hysterectomy (both with bilateral salpingo-oophorectomy) are feasible procedures in women with endometrial cancer and can be successfully performed with low complication rates in elderly and obese women. Although lymphadenectomy has no therapeutic benefit in clinical stage 1 disease, both pelvic and para-aortic lymphadenectomy and omental sampling can be safely and adequately performed if necessary for the management of high-grade disease. In retrospective series, recurrence rates are similar whether women are treated with a laparoscopic approach or an open approach; however, treatment-related morbidity appears to be lower when laparoscopic techniques are employed. Prospective randomised trials are currently underway to determine efficacy of staging, complication rates and survival in women treated laparoscopically compared with those treated with laparotomy.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 17:11
Hormone replacement therapy after treatment for endometrial cancer Premenopausal women treated for endometrial cancer will experience menopausal symptoms, which may cause distress and impair quality of life. There is currently no evidence that hormone replacement therapy (HRT) with oestrogen alone has an adverse impact on survival in women who have had radical treatment for early disease. Therefore women experiencing significant symptoms may be prescribed HRT after receiving appropriate information about risks and benefits. HRT should, however, be avoided in women with more advanced disease or metastatic disease.
Treatment of advanced disease Where possible, it is preferable to remove the uterine tumour with surgery prior to radiotherapy; however, women with clinical stage 3 disease involving the vagina at presentation are usually 321
© 2007 Elsevier Ltd. All rights reserved.
Review
treated with primary radiotherapy. Where stage 3 disease is diagnosed following surgery, adjuvant external beam radiotherapy to the pelvis and vaginal vault brachytherapy are indicated to prevent local recurrence. Those with clinically involved para-aortic nodes or positive peritoneal cytology may also receive adjuvant chemotherapy as extended field radiotherapy covering the paraaortic regions may be poorly tolerated by these women, who frequently have significant co-morbidities. Treatment for stage 4 disease is usually palliative and can be treated with combination therapy. For example, chemotherapy may be given to treat systemic disease, and external beam radiotherapy can be used, if necessary, to palliate vaginal bleeding.
Five-year survival by International Federation of Gynecology and Obstetrics (FIGO) stage Stage
Approx. 5-year survival (%)
I II III IV
85 75 45 25
Table 2
approximately 70%. Other pelvic recurrences are usually treated with radiotherapy. Distant metastasis can be treated with chemotherapy, as discussed above, or high-dose progestagens. Radiotherapy can also be used with good effect to treat isolated bony metastases, which can cause pain and disability.
Chemotherapy in advanced disease The chemotherapeutic agents commonly used in endometrial cancer are platinum-based drugs, for example cisplatin, and the anthracycline doxorubicin. However, the optimal chemotherapeutic regime is unclear and many clinicians use a combination of carboplatin and a taxane (paclitaxel) or single-agent carboplatin, based on experience of these drugs in the treatment of ovarian cancer. A recent meta-analysis of six randomised controlled trials concluded that more intensive regimens improved diseasefree survival and achieved a modest improvement in overall survival in advanced, recurrent and metastatic endometrial cancer. In addition, regimens containing doxorubicin or paclitaxel in combination with cisplatin improved overall survival. Recruitment to trials of intensive multiagent chemotherapy has been limited by toxicity, especially severe myelosuppression and gastrointestinal toxicity. Doxorubicin also carries a risk of cardiac toxicity, and this is relevant in a group of women in whom cardiovascular disease is common. In addition, the gain in survival using intensive combination schedules is only of the order of 3 months. As many women in this situation have significant co-morbidity, these risks and benefits require careful consideration when planning treatment.
Follow-up Most endometrial cancer recurrences occur within the first 3 years after treatment. Follow-up is undertaken with the aim of detecting recurrence and identifying side-effects of treatment. A history of symptoms is taken, and clinical examination (including pelvic examination) is usually then performed. Recurrence may be suggested by vaginal bleeding, a new onset of persistent backache, significant weight loss or persistent pressure symptoms. The frequency and duration of follow-up visits varies between hospitals and usually follows guidelines developed locally within each cancer network. The role of the routine follow-up visit in detecting asymptomatic recurrence and improving survival from recurrence is unproven. It is also recognised that, for some women, routine follow-up after a cancer diagnosis may be a stressful experience. The FIGURE trial is a randomised controlled trial that therefore aims to compare patient-initiated follow-up versus traditional routine follow-up in terms of quality-adjusted survival. Women are eligible to enter the trial if they have completed treatment for histologically confirmed endometrial cancer and do not need follow-up in secondary care. These will generally be women at lower risk of recurrence. The trial aims to start recruitment in February 2007.
Hormonal/systemic endocrine treatment Systemic endocrine hormonal treatment with high-dose oral progestagens is useful for palliation in advanced disease and/ or when the patient is unfit for other types of treatment. Good symptomatic relief can be achieved and tumour deposits may regress for a time. Unfortunately, high-grade tumours frequently lack progesterone receptors, and treatment with progestagens can itself lead to a downregulation of progesterone receptors. Tamoxifen can increase progesterone receptor content and has been used to enhance responses to progestagens in women with advanced and recurrent disease.
Five-year survival for surgical stage 1 endometrial cancer by grade and depth of myometrial invasion Survival at 5 years (%)
Recurrent disease Women who experience recurrence after treatment for early endometrial cancer are managed according to the pattern of recurrence and overall fitness. MRI is useful for evaluating suspected pelvic recurrence, whereas CT is preferable for imaging suspected para-aortic recurrence. Chest X-ray will detect lung metastases, although CT is frequently employed for simultaneous assessment of both the abdomen and chest. Vaginal vault recurrence can be successfully salvaged with either surgery or radiotherapy, with 3-year survival rates of
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 17:11
Depth of myometrial invasion (stage)
FIGO grade 1
2
3
No invasion (1a) <50% invasion (1b) >50% invasion (1c)
96 95 81
92 90 70
85 69 42
FIGO, International Federation of Gynecology and Obstetrics.
Table 3
322
© 2007 Elsevier Ltd. All rights reserved.
Review
Obermair A, Manolitsas TP, Leung Y, Hammond IG, McCartney AJ. Total laparoscopic hysterectomy for endometrial cancer: patterns of recurrence and survival. Gynecol Oncol 2004; 92: 789–93. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 1998; 280: 1510–17.
Prognosis The overall prognosis for endometrial cancer is generally good compared with that for other gynaecological tumours and reflects the early presentation of the disease. The 5-year survival rate for all stages is approximately 80% (Table 2). Prognosis in stage 1 disease is approximately 85% and, within stage 1, varies dependent on tumour grade and depth of myometrial invasion (Table 3). Five-year survival can be as high as 95% for women with minimal myometrial invasion and grade 1 endometrioid disease. Factors that adversely affect prognosis include the nonendometrioid histological subtype and myometrial vascular space invasion. ◆
Practice points • Endometrial cancer is not one disease but a collection of different cancer subtypes with differing behaviours and prognoses • Surgery is the cornerstone of treatment for most women with endometrial cancer • Laparoscopic surgery for endometrial cancer can reduce surgical morbidity, although evidence that long-term survival is equivalent to that of open surgery is awaited • Systematic lymphadenectomy has no therapeutic benefit in clinical stage 1 disease • Adjuvant radiotherapy significantly reduces rates of locoregional recurrence but does not improve survival • Systemic progestagens are effective in the palliation of advanced and recurrent disease but are of no value as adjuvant treatment after surgery • Intensive combination chemotherapy currently provides only a small gain in survival of 3 months • Multidisciplinary input is required in planning appropriate primary and adjuvant treatments
Further reading Creutzberg CL, van Putten WLJ, Koper PCM, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage 1 endometrial carcinoma: multicentre randomised trial. Lancet 2000; 355: 1404–11. Eltabbakh GH, Shamonki MI, Moody JM, Garafano LL. Hysterectomy for obese women with endometrial cancer: laparoscopy or laparotomy? Gynecol Oncol 2000; 78: 329–35. Grigsby PW, Perez CA, Kuten A, et al. Clinical stage 1 endometrial cancer: prognostic factors for local control and distant metastasis and implications of the new FIGO surgical staging system. Int J Radiat Oncol Biol Phys 1992; 22: 905–11. Gupta JK, Chien PF, Voit D, Clark TJ, Khan KS. Ultrasonographic endometrial thickness for diagnosing endometrial pathology in women with post-menopausal bleeding: a meta-analysis. Acta Obstet Gynecol Scand 2002; 81: 799–816. Humber CE, Tierney JF, Symonds RP, et al. Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration. Ann Oncol 2007; 18(3): 409–20. NHS Executive. National Cancer Guidance Steering Group. Guidance on commissioning cancer services; Improving outcomes guidance in gynaecological cancers 1999.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 17:11
Research directions • The accuracy of sentinel lymph node dissection in surgical staging • Conservative management with progestagens for fertility conservation • Direct comparison of systemic hormonal treatments and chemotherapy in advanced disease • Efficacy of molecularly targeted (biological) therapy
323
© 2007 Elsevier Ltd. All rights reserved.
Endometrial cancer
often seen on a background of atypical hyperplasia, a precursor lesion. Approximately 40% of atypical hyperplasia is upgraded to invasive endometrial cancer following hysterectomy. Serous, clear cell, squamous and undifferentiated carcinomas are less common and are more aggressive malignancies. Serous carcinomas arise on a background of endometrial atrophy, and a precursor lesion for serous endometrial carcinoma, endometrial intraepithelial carcinoma, has recently been identified. Other types of endometrial cancer are less common. These include, among others, clear cell carcinoma, carcinosarcoma (previously known as malignant mixed müllerian tumour) and endometrial stromal sarcoma, which arises from stromal elements of the endometrium. Endometrial tumours spread by direct extension to the cervix, vagina and, via the fallopian tubes, to the ovaries and peritoneal cavity. Myometrial invasion is common (Figure 1) and may lead to serosal and parametrial involvement. Lymphatic spread occurs to the external iliac, internal iliac and obturator regions of the pelvis and to the para-aortic nodes from the upper part of the uterus. Haematogenous spread results in lung metastases. Non-endometrioid tumours behave in a more malignant fashion, and extrauterine disease may be present even where the uterine disease shows no or minimal myometrial invasion. Patterns of recurrence also suggest a tendency to early systemic metastasis. Pathological grading of disease and accurate classification of histological subtype on diagnostic endometrial biopsy are important in planning appropriate investigations and subsequent treatment, especially where the risk of systemic disease is high.
Cathrine Holland
Abstract The incidence of endometrial cancer is increasing. The overall 5-year survival rate is high, reflecting early presentation in most cases, but outcomes for advanced disease remain poor. Surgery for low-risk disease may be undertaken by general gynaecologists, but all patients require specialist multidisciplinary input. The cornerstone of treatment remains surgery, and laparoscopic surgery is emerging as a means of reducing morbidity. Systematic lymphadenectomy in all cases is unjustified, and adjuvant radiotherapy is now given only to selected patients at high risk of recurrence. Chemotherapy is increasingly used in high-risk and advanced disease, although the optimum drug combination is unclear. Future developments are likely to include the emergence of molecularly targeted therapies as an addition to existing treatments and the possibility of fertility-sparing hormonal treatments in selected patients.
Keywords adjuvant radiotherapy; chemotherapy; endometrial cancer; laparoscopic surgery; lymphadenectomy; management
Aetiology Introduction
In recent years, significant differences have been identified at a genetic level between different histological types, and endometrial cancers may now be broadly classified into two main categories based upon these differences. Type 1 or endometrioid cancers frequently arise on a background of atypical hyperplasia and have
Uterine cancers are the most common gynaecological malignancies. In the UK, the incidence is slightly lower than that for ovarian cancer, with approximately 4500 new cases occurring each year. Most arise in the endometrium, and the majority are diagnosed in women aged over 50 years. The most common presentation is postmenopausal bleeding, although 20–25% of women are premenopausal at diagnosis and approximately 5% of women are diagnosed below 40 years of age. Most women present with disease confined to the uterus, and many of these women have an excellent prognosis. This has led to a false perception that endometrial cancer is not as serious as other cancers. However, some histological subtypes are associated with a poor prognosis, and 5-year survival rates for advanced disease are low. Although some endometrial cancers may be treated by designated gynaecologists in cancer units, all cases must have the benefit of multidisciplinary input before treatment, to identify those requiring management at the regional cancer centre.
Pathology Over 80% of primary endometrial cancers are endometrioid adenocarcinomas. These arise from the glandular epithelium and are Figure 1 International Federation of Gynecology and Obstetrics G3 stage 1C endometrioid endometrial adenocarcinoma. Histopathology revealed more than 50% myometrial invasion with tumour measured 1 mm from the serosal surface. Adjuvant radiotherapy was given after surgery.
Cathrine Holland PhD MRCOG is Senior Clinical Lecturer/Honorary Consultant Gynaecological Oncologist, Academic Unit of Obstetrics and Gynaecology, Division of Human Development, Saint Mary’s Hospital, Manchester, UK.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 17:11
318
© 2007 Elsevier Ltd. All rights reserved.
Review
an association with obesity, nulliparity, insulin resistance and an oestrogenic environment. Type 2 tumours comprise serous and other non-endometrioid histology, for example clear cell carcinoma. Type 2 tumours are not associated with the risk factors for type 1 cancers, often occurring in elderly, thin women. Ongoing translational research seeks to exploit molecular differences between these cancers for therapeutic benefit.
Outpatient endometrial biopsy correctly diagnoses cancer in over 80% of women (Figure 2) and can be preceded by outpatient hysteroscopy if necessary, for example where endometrial polyp(s) are suspected on ultrasound. Hysteroscopy is useful in the evaluation of women with bleeding while taking tamoxifen. The typical subendometrial cystic changes seen with tamoxifen use frequently result in false-positive ultrasound findings. This makes ultrasound less useful in this setting. As tamoxifen is associated with a significant increase in endometrial polyps as well as hyperplasia and cancer, hysteroscopy can provide prompt reassurance and provide a diagnosis, particularly where an endometrial sample is scanty. Serum tumour markers are not recommended for diagnosing endometrial cancer. Although serum Ca125 may be elevated in women with advanced endometrial cancer, it is neither sensitive nor specific enough to be useful in the initial diagnosis or for staging disease.
Hereditary endometrial cancer Hereditary endometrial cancer accounts for less than 5% of all endometrial cancer and is one of the extracolonic cancers caused by hereditary non-polyposis colon cancer (HNPCC) syndrome. This autosomal dominant inherited disorder is caused by germline mutations in DNA mismatch repair genes, leading to faulty DNA repair mechanisms and consequently an increased risk of malignant transformation. Women with confirmed HNPCC have a 40–60% lifetime risk of developing endometrial cancer. Although the value of endometrial surveillance with endometrial imaging and biopsy is unproven, this option is offered to women who wish to retain their uterus. Prophylactic hysterectomy and bilateral salpingo-oophorectomy is recommended for those who have completed their family. Although the proportion of women with HNPCC-associated endometrial cancer is small, recognition of these individuals is important as half of all affected women will develop endometrial cancer as their index cancer. Identifying these women enables them and their extended family to undergo genetic counselling, genetic testing and screening or prophylactic surgery for bowel cancer. Different criteria have been developed to identify individuals at risk. Our current policy is to refer women who are diagnosed with endometrial cancer below the age of 45. In addition, women are also referred if they have had another HNPCCassociated cancer or have a significant family history.
Investigations Once a diagnosis of endometrial cancer has been made, a blood count, renal biochemistry and liver function tests are performed, and further imaging is undertaken to identify metastatic disease and aid treatment decisions. A chest X-ray is carried out to identify lung metastases. Increasingly, magnetic resonance imaging (MRI) is used in the preoperative imaging of women with endometrial cancer to assess the depth of myometrial invasion. Depth of invasion is closely related to the risk of lymph node involvement and may be used to aid decisions for selective lymphadenectomy. MRI is more sensitive than transvaginal ultrasound and computed tomography
Diagnosis Approximately 90% of women diagnosed with endometrial cancer present with postmenopausal bleeding. Up to 10% of women with this symptom will be diagnosed with endometrial cancer, so referral for investigation is mandatory. Initial assessment should take place in rapid-access clinics where a relevant history can be taken to identify risk factors and co-morbidities, and a pelvic examination can exclude vulval and cervical lesions. The recommended initial investigation is a transvaginal ultrasound scan for measurement of endometrial thickness and identification of ovarian masses. A thin endometrium in the postmenopausal woman has a high negative predictive value for endometrial cancer and is reassuring. Approximately 40–50% of women can be reassured having had a normal ultrasound scan, thus avoiding a large number of invasive procedures. Women with a thickened endometrium require further assessment. The threshold endometrial thickness for further intervention varies slightly between authors. The most commonly used threshold for further intervention is an endometrial thickness of over 5 mm. Any further investigations required can be safely performed in the outpatient setting in approximately 80% of women. This is particularly important in women with postmenopausal bleeding as many have significant co-morbidities including cardiovascular disease, diabetes and obesity.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 17:11
A Pipelle endometrial sampler is one of several sampling devices used to obtain endometrial biopsies. The sampler is advanced through the cervix to reach the uterine fundus. Markings on the barrel at 1 cm intervals allow confirmation that the cavity has been entered and give a measurement of uterine length. The plunger is withdrawn to the proximal end of the barrel, and the sampler is drawn backwards and forwards with a rotating motion to draw endometrial tissue into the barrel. Figure 2
319
© 2007 Elsevier Ltd. All rights reserved.
Review
(CT) scanning for the assessment of depth of invasion and can identify cervical involvement (Figure 3). Other investigations, such as cystoscopy, may be indicated if locally advanced disease is suspected. CT may be helpful in assessment of the upper abdomen if intra-abdominal metastases are suspected. Positron emission tomography (PET) using fluorine-18-fluoro2-deoxy-D-glucose (FDG) is emerging as a potentially useful imaging modality in the management of gynaecological tumours.
Experience of FDG-PET in endometrial cancer is currently limited and is unlikely to contribute significantly to preoperative management. However, initial reports suggest that FDG-PET may be clinically useful in evaluating potential disease recurrence, with negative results correlating with a disease-free course.
Treatment of early disease Surgical management Despite the use of preoperative imaging as an aid to treatment planning, the staging of endometrial cancer remains surgicopathological, relying both on a surgical assessment of intra-abdominal disease and in most cases, where disease is confined to the uterine corpus, on depth of myometrial invasion. Low-risk endometrioid tumours with less than 50% myometrial invasion on preoperative MRI scanning are associated with lymph node metastases in fewer than 5% of cases. These women are suitable for surgery with extrafascial hysterectomy and bilateral salpingo-oophorectomy undertaken by a general gynaecologist. The Improving outcomes guidance document published by the National Health Service Executive recommends that all other women with high-grade disease, highly malignant histology, deep myometrial invasion or lymphadenopathy on preoperative imaging, should be managed by gynaecological oncologists as part of a multidisciplinary team. Where the preoperative imaging suggests cervical stromal involvement (stage 2b), gynaecological oncologists often advocate a modified radical hysterectomy in order to ensure removal of the tumour with adequate surgical margins. Although this treatment is extrapolated from the experience of radical hysterectomy for cervical cancer, research evidence confirming a benefit for radical hysterectomy in stage 2 endometrial cancers is lacking. The role of lymphadenectomy There has been considerable debate concerning the surgical staging of endometrial cancer. It is generally accepted that, as a minimum, total hysterectomy with bilateral salpingo-oophorectomy, peritoneal cytology and inspection of the upper abdominal organs and peritoneal surfaces should be performed. The International Federation of Gynecology and Obstetrics (FIGO) staging system is used in the UK (Table 1). Although systematic lymphadenectomy informs FIGO staging, the effect of lymphadenectomy on outcome and its role in directing adjuvant treatment is controversial. In the USA, systematic lymphadenectomy is widely practised compared with the UK and some Northern European countries where the approach to lymphadenectomy is more selective. In the UK, the Medical Research Council ASTEC trial randomised women undergoing surgery for clinical stage 1 endometrial cancer to systematic pelvic lymphadenectomy or no lymphadenectomy. The results from ASTEC showed no therapeutic benefit in the women receiving lymphadenectomy. Therefore it appears that systematic lymphadenectomy in all women with clinical stage 1 disease is not justified. Lymphadenectomy, however, may be indicated in selected cases if the result would inform the need for adjuvant treatment. This too is an area of controversy, and practice differs widely between cancer centres. Although gynaecological oncologists may perform lymphadenectomy for deeply invasive
Preoperative magnetic resonance imaging of endometrial cancer. Both a (a) saggital T2- and (b) coronal T2-weighted images suggest protrusion of tumour into the cervix. Final histopathology confirmed stage 2a disease. Figure 3
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 17:11
320
© 2007 Elsevier Ltd. All rights reserved.
Review
Compared with the open or laparoscopic approach, vaginal hysterectomy alone for endometrial cancer is inadequate for staging as ovarian metastases cannot be detected Bilateral salpingooophorectomy can be undertaken vaginally but does not allow an assessment of the upper abdomen and peritoneal surfaces. Vaginal hysterectomy is therefore not considered adequate for staging and treatment. Despite these limitations, vaginal hysterectomy alone under regional anaesthesia may have a place in the management of exceptional cases of women who have co-morbidities that preclude a general anaesthetic.
International Federation of Gynecology and Obstetrics (FIGO) staging for endometrial cancer FIGO Stage
Features
I Ia Ib Ic
Tumour confined to the corpus uteri Tumour confined to the endometrium Myometrial invasion <50% Myometrial invasion >50%
II IIa IIb
Cervical involvement Endocervical glandular involvement only Cervical stromal invasion but not extending beyond the uterus
III IIIa
Extension beyond myometrium Carcinoma involves serosa of uterus or adnexae, or positive ascites, or positive peritoneal washings Vaginal involvement, either direct or metastatic Para-aortic or pelvic node involvement
IIIb IIIc IV IVa IVb
Radiotherapy Primary radical radiotherapy may be used when the patient cannot undergo surgery for medical reasons. Intracavitary radiotherapy combined with external beam treatment can achieve cure rates of approximately 70% in stage 1 disease. However, surgery to remove the central uterine tumour should be undertaken if at all possible. Radiotherapy is more usually given as adjuvant treatment after surgery in women at high risk of disease recurrence. A prospective randomised trial of 715 women showed that postoperative radiotherapy in stage 1 endometrial cancer reduced locoregional recurrence from 14% to 10% but had no impact on overall survival. Age greater than 60 years was an independent poor prognostic factor for locoregional recurrence. In the same trial, treatment-related morbidity was significantly increased in the women who received radiotherapy. Therefore current practice in Europe is to select patients for adjuvant radiotherapy based on risk stratification. Patients are determined to be at low, intermediate or high risk of recurrence based on depth of myometrial invasion, tumour grade and age. Radiotherapy is given as external beam therapy to cover the pelvic lymphatics, and vault brachytherapy to prevent central recurrence. Side-effects are common, occurring in 25% of women, and include frequent bowel movements, diarrhoea and frequency of micturition. Severe toxicity occurs in approximately 2% of cases. In women at high risk of distant metastases, adjuvant chemotherapy is sometimes given, although practice varies widely. These women generally have highly metastatic tumour types such as serous carcinoma or carcinosarcoma. Progestagens given as adjuvant treatment offer no survival benefit in metaanalyses and should not be used in the adjuvant setting.
Further spread Carcinoma involving the mucosa of the bladder or rectum Distant metastases and involvement of other abdominal or inguinal lymph nodes
Table 1
e ndometrial tumours or those with a highly malignant subtype (e.g. carcinosarcoma), many question the justification for this if adjuvant treatment is to be given regardless of nodal status. This is pertinent as many women with endometrial cancer are elderly and have significant co-morbid conditions. Laparoscopic surgery for endometrial cancer Another issue that has generated much debate is the role of laparoscopic surgery for the staging and surgical treatment of endometrial cancer. The traditional surgical approach of abdominal hysterectomy is based on professional consensus rather than evidence from clinical trials. Total laparoscopic hysterectomy and laparoscopically assisted vaginal hysterectomy (both with bilateral salpingo-oophorectomy) are feasible procedures in women with endometrial cancer and can be successfully performed with low complication rates in elderly and obese women. Although lymphadenectomy has no therapeutic benefit in clinical stage 1 disease, both pelvic and para-aortic lymphadenectomy and omental sampling can be safely and adequately performed if necessary for the management of high-grade disease. In retrospective series, recurrence rates are similar whether women are treated with a laparoscopic approach or an open approach; however, treatment-related morbidity appears to be lower when laparoscopic techniques are employed. Prospective randomised trials are currently underway to determine efficacy of staging, complication rates and survival in women treated laparoscopically compared with those treated with laparotomy.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 17:11
Hormone replacement therapy after treatment for endometrial cancer Premenopausal women treated for endometrial cancer will experience menopausal symptoms, which may cause distress and impair quality of life. There is currently no evidence that hormone replacement therapy (HRT) with oestrogen alone has an adverse impact on survival in women who have had radical treatment for early disease. Therefore women experiencing significant symptoms may be prescribed HRT after receiving appropriate information about risks and benefits. HRT should, however, be avoided in women with more advanced disease or metastatic disease.
Treatment of advanced disease Where possible, it is preferable to remove the uterine tumour with surgery prior to radiotherapy; however, women with clinical stage 3 disease involving the vagina at presentation are usually 321
© 2007 Elsevier Ltd. All rights reserved.
Review
treated with primary radiotherapy. Where stage 3 disease is diagnosed following surgery, adjuvant external beam radiotherapy to the pelvis and vaginal vault brachytherapy are indicated to prevent local recurrence. Those with clinically involved para-aortic nodes or positive peritoneal cytology may also receive adjuvant chemotherapy as extended field radiotherapy covering the paraaortic regions may be poorly tolerated by these women, who frequently have significant co-morbidities. Treatment for stage 4 disease is usually palliative and can be treated with combination therapy. For example, chemotherapy may be given to treat systemic disease, and external beam radiotherapy can be used, if necessary, to palliate vaginal bleeding.
Five-year survival by International Federation of Gynecology and Obstetrics (FIGO) stage Stage
Approx. 5-year survival (%)
I II III IV
85 75 45 25
Table 2
approximately 70%. Other pelvic recurrences are usually treated with radiotherapy. Distant metastasis can be treated with chemotherapy, as discussed above, or high-dose progestagens. Radiotherapy can also be used with good effect to treat isolated bony metastases, which can cause pain and disability.
Chemotherapy in advanced disease The chemotherapeutic agents commonly used in endometrial cancer are platinum-based drugs, for example cisplatin, and the anthracycline doxorubicin. However, the optimal chemotherapeutic regime is unclear and many clinicians use a combination of carboplatin and a taxane (paclitaxel) or single-agent carboplatin, based on experience of these drugs in the treatment of ovarian cancer. A recent meta-analysis of six randomised controlled trials concluded that more intensive regimens improved diseasefree survival and achieved a modest improvement in overall survival in advanced, recurrent and metastatic endometrial cancer. In addition, regimens containing doxorubicin or paclitaxel in combination with cisplatin improved overall survival. Recruitment to trials of intensive multiagent chemotherapy has been limited by toxicity, especially severe myelosuppression and gastrointestinal toxicity. Doxorubicin also carries a risk of cardiac toxicity, and this is relevant in a group of women in whom cardiovascular disease is common. In addition, the gain in survival using intensive combination schedules is only of the order of 3 months. As many women in this situation have significant co-morbidity, these risks and benefits require careful consideration when planning treatment.
Follow-up Most endometrial cancer recurrences occur within the first 3 years after treatment. Follow-up is undertaken with the aim of detecting recurrence and identifying side-effects of treatment. A history of symptoms is taken, and clinical examination (including pelvic examination) is usually then performed. Recurrence may be suggested by vaginal bleeding, a new onset of persistent backache, significant weight loss or persistent pressure symptoms. The frequency and duration of follow-up visits varies between hospitals and usually follows guidelines developed locally within each cancer network. The role of the routine follow-up visit in detecting asymptomatic recurrence and improving survival from recurrence is unproven. It is also recognised that, for some women, routine follow-up after a cancer diagnosis may be a stressful experience. The FIGURE trial is a randomised controlled trial that therefore aims to compare patient-initiated follow-up versus traditional routine follow-up in terms of quality-adjusted survival. Women are eligible to enter the trial if they have completed treatment for histologically confirmed endometrial cancer and do not need follow-up in secondary care. These will generally be women at lower risk of recurrence. The trial aims to start recruitment in February 2007.
Hormonal/systemic endocrine treatment Systemic endocrine hormonal treatment with high-dose oral progestagens is useful for palliation in advanced disease and/ or when the patient is unfit for other types of treatment. Good symptomatic relief can be achieved and tumour deposits may regress for a time. Unfortunately, high-grade tumours frequently lack progesterone receptors, and treatment with progestagens can itself lead to a downregulation of progesterone receptors. Tamoxifen can increase progesterone receptor content and has been used to enhance responses to progestagens in women with advanced and recurrent disease.
Five-year survival for surgical stage 1 endometrial cancer by grade and depth of myometrial invasion Survival at 5 years (%)
Recurrent disease Women who experience recurrence after treatment for early endometrial cancer are managed according to the pattern of recurrence and overall fitness. MRI is useful for evaluating suspected pelvic recurrence, whereas CT is preferable for imaging suspected para-aortic recurrence. Chest X-ray will detect lung metastases, although CT is frequently employed for simultaneous assessment of both the abdomen and chest. Vaginal vault recurrence can be successfully salvaged with either surgery or radiotherapy, with 3-year survival rates of
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 17:11
Depth of myometrial invasion (stage)
FIGO grade 1
2
3
No invasion (1a) <50% invasion (1b) >50% invasion (1c)
96 95 81
92 90 70
85 69 42
FIGO, International Federation of Gynecology and Obstetrics.
Table 3
322
© 2007 Elsevier Ltd. All rights reserved.
Review
Obermair A, Manolitsas TP, Leung Y, Hammond IG, McCartney AJ. Total laparoscopic hysterectomy for endometrial cancer: patterns of recurrence and survival. Gynecol Oncol 2004; 92: 789–93. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 1998; 280: 1510–17.
Prognosis The overall prognosis for endometrial cancer is generally good compared with that for other gynaecological tumours and reflects the early presentation of the disease. The 5-year survival rate for all stages is approximately 80% (Table 2). Prognosis in stage 1 disease is approximately 85% and, within stage 1, varies dependent on tumour grade and depth of myometrial invasion (Table 3). Five-year survival can be as high as 95% for women with minimal myometrial invasion and grade 1 endometrioid disease. Factors that adversely affect prognosis include the nonendometrioid histological subtype and myometrial vascular space invasion. ◆
Practice points • Endometrial cancer is not one disease but a collection of different cancer subtypes with differing behaviours and prognoses • Surgery is the cornerstone of treatment for most women with endometrial cancer • Laparoscopic surgery for endometrial cancer can reduce surgical morbidity, although evidence that long-term survival is equivalent to that of open surgery is awaited • Systematic lymphadenectomy has no therapeutic benefit in clinical stage 1 disease • Adjuvant radiotherapy significantly reduces rates of locoregional recurrence but does not improve survival • Systemic progestagens are effective in the palliation of advanced and recurrent disease but are of no value as adjuvant treatment after surgery • Intensive combination chemotherapy currently provides only a small gain in survival of 3 months • Multidisciplinary input is required in planning appropriate primary and adjuvant treatments
Further reading Creutzberg CL, van Putten WLJ, Koper PCM, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage 1 endometrial carcinoma: multicentre randomised trial. Lancet 2000; 355: 1404–11. Eltabbakh GH, Shamonki MI, Moody JM, Garafano LL. Hysterectomy for obese women with endometrial cancer: laparoscopy or laparotomy? Gynecol Oncol 2000; 78: 329–35. Grigsby PW, Perez CA, Kuten A, et al. Clinical stage 1 endometrial cancer: prognostic factors for local control and distant metastasis and implications of the new FIGO surgical staging system. Int J Radiat Oncol Biol Phys 1992; 22: 905–11. Gupta JK, Chien PF, Voit D, Clark TJ, Khan KS. Ultrasonographic endometrial thickness for diagnosing endometrial pathology in women with post-menopausal bleeding: a meta-analysis. Acta Obstet Gynecol Scand 2002; 81: 799–816. Humber CE, Tierney JF, Symonds RP, et al. Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration. Ann Oncol 2007; 18(3): 409–20. NHS Executive. National Cancer Guidance Steering Group. Guidance on commissioning cancer services; Improving outcomes guidance in gynaecological cancers 1999.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 17:11
Research directions • The accuracy of sentinel lymph node dissection in surgical staging • Conservative management with progestagens for fertility conservation • Direct comparison of systemic hormonal treatments and chemotherapy in advanced disease • Efficacy of molecularly targeted (biological) therapy
323
© 2007 Elsevier Ltd. All rights reserved.