Uterine cancer is the most common of the gynaecological cancers with almost 2000 women diagnosed yearly in Australia, resulting in over 300 deaths. World wide 190,000 women are diagnosed and almost 50,000 die of the disease(1). Over the last 30 years the age adjusted incidence rate has been increasing, presumably due to our affluent and obese society. There has also been an improvement in overall survival(2).
The disease tends to affect affluent, obese women who are nulliparous or have low parity. Mean age at diagnosis is 61 years. Up to 20% of women are premenopausal and some 5% under the age of 40 years. The majority of women will present with postmenopausal bleeding (PMB), although only 20% of patients with PMB will have endometrial cancer. In premenopausal women, menorrhagia is the most common symptom. Uncommonly patients may be asymptomatic.
Based upon clinical, morphologic and genetic factors there are 2 recognized types of endometrial cancer. Type I the most common, is of endometrioid cell type occurring in a younger obese population and arising from atypical hyperplasia. This tumour is oestrogen related, tends to be of low-grade with an excellent overall prognosis and associated with mutation of the KRAS and CTNNB1 (ß-catenin) oncogenes, methylation of the mismatch repair gene MLH1, and mutation of the PTEN tumour suppressor gene.
Type II are usually non-endometrioid histology, have high grade, tend to occur in older patients and often occurs in the presence of a thin or atrophic endometrium and is not related to oestrogenic stimulation. They are more likely to spread, are more aggressive. They are associated with activation of the ERBB2 (HER2/neu) oncogene and mutation of the TP53 tumour suppressor gene(3).
Whilst most endometrial cancers are sporadic, some 5 to 10% may have a hereditary component and the majority of these are due to Hereditary Non Polyposis Colon Cancer (HNPCC) or Lynch Syndrome (see below). Less commonly endometrial cancer might arise from iatrogenic unopposed oestrogen therapy and rarely Cowden’s Syndrome, an autosomally dominant inherited mutation of PTEN tumour suppressor gene.
Hereditary Non-Polyposis Colon Cancer (HNPCC)
HNPCC is an autosomal dominant inherited cancer syndrome predisposing patients to development of colorectal, endometrial, gastric, upper urinary tract and other cancers. It accounts for about 3% of the colorectal cancers.
Patients with HNPCC have a 40-60% risk of endometrial cancer, up to 20% risk for ovarian cancer and 30-60% for colorectal cancer. Patients have been shown to have a germline mutation in one of several genes involved in DNA mismatch repair (MMR), the most frequent being MSH2 and MLH1. Mutations in other mismatch repair genes (such as MSH6 and PMS2) have been identified, but these occur at lower frequencies.
Immunohistochemistry (IHC) alone can determine retention or loss of MLH1, MSH2, MSH6, and PMS2 protein expression. If loss of one or more of the MMR proteins is identified by IHC, germline testing (i.e., mutation analysis) for the indicated gene(s) should be considered. Therefore, IHC aids in the identification of patients at risk for an inherited colon cancer syndrome due to defective DNA mismatch repair (Lynch syndrome associated-HNPCC) and those who might benefit from subsequent genetic testing.
HNPCC was originally defined by Amsterdam criteria but only 13-36% of patients with molecularly confirmed Lynch-associated colorectal cancer meet these criteria. The Bethesda system has been developed to better identify these individuals. Approximately 9% of women under 50 with endometrioid uterine cancer carry a mutation in a DNA mismatch repair gene, resulting in the Lynch syndrome. For this reason, a family history of bowel/uterine cancer or early onset (<50yrs) or thin women with uterine cancer should arouse suspicion of Lynch syndrome and the tumour should be tested by IHC for the MMR proteins. Referral to a Family Cancer Clinic is recommended where suspicion of Lynch syndrome or other inherited syndromes is present. Genetic counseling and genetic testing may be appropriate.
In 2009 the International Federation of Gynecology and Obstetrics (FIGO) staging system was modified. Stage I is now classified according to depth of myoinvasion with invasion less than or greater than 50% assigned stage IA or IB respectively. Mucosal involvement of the cervix has been removed from stage II and the presence of positive pelvic and paraaortic lymph nodes are sub classified within stage III. The majority of patients will present with tumour confined to the uterine corpus or cervix with about 13% having regional nodal spread(4).
FIGO stage of disease is the most significant variable affecting survival. Other prognostic factors for disease recurrence or survival include tumour grade, histopathology, depth of myometrial invasion and patient age. Other factors, such as tumour size, peritoneal cytology status, hormone receptor status, flow cytometric analysis, and oncogene perturbations may also be important.
The greatest risk for pelvic lymph node metastasis is deep myometrial invasion, whilst the greatest determinant for recurrence in clinical stage I and II endometrial cancer, without metastasis determined by surgical-pathological staging is grade 3 histology(5, 6).
The GOG has quantified the risk of pelvic node metastases according to grade and depth of myoinvasion as shown in the table below. It must be remembered that this data was derived from clinical stage I and II adneocarcinomas (incuding serous, clear cell and indeed likely MMT) with a significant proportion of patients having gross intraperitoneal disease and adnexal involvement, and as such probably represent and overrepresentation of LNM(5).
An alternative way of looking at risk for nodal metastasis intraoperatively is to exclude the cases with obvious extrauterine metastasis (intraperitoneal metastasis, gross breakthrough of the uterine serosa, and gross adnexal metastases). This leaves only grade and invasion as risk parameters. In this schema, low risk (4%) have pelvic node involvement associated with absent myometrial invasion or grade 1 histology with invasion (excluding clear cell and papillary serous cases). Grade 3, outer 33% invasion is high risk (> lo%), and all other cases have a moderate risk (5% to 10%) for pelvic node metastasis(5).
Regarding the aortic nodes, all categories are at low risk (<5%) except the Grade 3, outer 33% group which are high risk. Two groups however, have too few cases to be confidently categorized: the Grade 3, no invasion (zero of nine pelvic or aortic node metastasis) and Grade 1, outer 33% (one of 16 had both pelvic and aortic node metastasis)(5).
The diagnosis is made by histological assessment of curettings. Formerly this was done as a “fractional curettage” in an attempt to define the extent of disease within the uterus. This was inherently inaccurate. Hysteroscopy is now generally performed in the investigation of patients with abnormal bleeding. The advantage of this technique is clear definition of the tumour and particularly for the volume and distribution within the uterus. Disease reaching the cervix or widespread tumour within the cavity are risk factors for nodal metastases. While saline hysteroscopy may cause some washing of cells into the peritoneal cavity, this has not been shown to directly effect outcome. Histological confirmation by an expert Gynaecological Pathologist should occur. Once confirmed, consultation with a Gynaecological Oncologist with review by a Multidisciplinary Team (MDT) should occur. Adjuvant treatment decisions should be tailored to the individual patient according to their risk of vaginal vault, pelvic, para-aortic or distant relapse.
Preoperative imaging may be performed prior to referral to a Gynaecological Oncologist, particularly of the ovaries due to the risk of concurrent ovarian disease. Many would suggest a CT scan, however in most cases this is not associated with detection of pathology and is costly(7).
In its purest sense, the treatment of cancer confined to the uterine corpus is total hysterectomy (with bilateral salpingoophorectomy). This can be achieved by a variety of surgical approaches included abdominal, vaginal, total laparoscopic, laparoscopically assisted and robotic. Surgical staging, as further discussed below is often included in the surgical management to define the extent of disease. This will involve performance of peritoneal washings for cytology, inspecting all peritoneal surfaces, palpation of all intraabdominal quadrants and the pelvic and paraaortic retroperitoneum. Any abnormality is then excised (if feasible to do so) and sent for frozen section analysis. Pelvic lymphadenectomy maybe performed according to physician and patient factors. It has not been shown to improve overall survival or recurrence free survival in women with early endometrial cancer(8).
Incomplete Surgical Staging
Patients may have incomplete or no surgical staging undertaken for a number of reasons, including significant co-morbidities, increased weight and poor pelvic exposure. In addition some patients may have had surgery undertaken by a general gynaecologist unaware of the diagnosis. In these circumstances the decision to offer adjuvant therapy is based on known local hostile uterine factors such as grade, depth of invasion and age.
Low risk patients with grade 1-2 histology and less than 50% myoinvasion are not offered adjuvant therapy.
Intermediate risk patients are at an increased risk of local recurrence and offered vaginal vault brachytherapy(9).
High risk patients with grade 3 tumours and outer third invasion have a substantial risk for lymph node metastasis. Pelvic irradiation therapy should be considered in these situations. The addition of pelvic irradiation while not affecting survival will result in decreased local-regional recurrence(10, 11).
In PORTEC 1 study, patients with stage 1 (FIGO 1988) endometrial carcinoma (grade 1 with deep [>50%] myometrial invasion, grade 2 with any invasion, or grade 3 with superficial [<50%] invasion) were randomized to pelvic radiation therapy or no further therapy. Locoregional recurrence was significantly lower in the radiotherapy group (4%) than in the control group (14%). However the overall survival rates were similar (81% in the radiotherapy and 85% in the no treatment group). 2-year survival after vaginal recurrence was 79%, compared to 21% after pelvic recurrence or distant metastases. Survival after relapse was significantly better for patients in the control group than those in the radiation group. Thus postoperative radiotherapy in stage-1 endometrial carcinoma reduces locoregional recurrence, increases treatment related morbidity, but has no impact on overall survival and is not indicated in patients with stage-1 endometrial carcinoma below 60 years and patients with grade-2 tumours with superficial invasion(10).
The PORTEC 2 study compared the outcome of high-intermediate risk patients with endometrioid carcinoma randomized to either vaginal brachytherapy (VBT) or external beam radiation therapy (EBRT). In this study, features of high-intermediate risk were: (1) age greater than 60 years and stage 1C (FIGO 1988) grade 1 or 2 disease, or stage 1B (FIGO 1988) grade 3 disease; and (2) stage 2A (FIGO 1988) disease, any age (apart from grade 3 with greater than 50% myometrial invasion). Vaginal and locoregional recurrence rates were similar although there was a higher pelvic recurrence rate after VBT but these were often associated with simultaneous distant metastases, and no difference in overall or disease free survival. Importantly toxicity was significantly less with better quality of life in those treated only with VBT.
In the MRC ASTEC and NCIC CTG EN.5 trial of adjuvant EBRT in intermediate and high risk endometrial cancer (defined as stage IAG3, IBG3, IC (FIGO 1988) all grades, papillary serous, clear cell and stage IIA), the authors conclude there is no survival advantage by the addition of EBRT, but there is increased toxicity12. The advantages of rationalizing irradiation therapy are 3-fold. First the morbidity of pelvic irradiation therapy can be spared to a significant number of patients, especially when side effects are exaggerated after surgery. Secondly there is a tremendous cost saving by limiting irradiation therapy to those at high risk of recurrence. Thirdly it is available to treat recurrent disease in the pelvis should it occur. Recent evidence suggests that survival is enhanced after relapse in those patients who did not receive adjuvant radiation therapy after hysterectomy(11).
Surgically Staged Patients
Patients that have been appropriately surgically staged and have endometrioid histology, are assumed to be at low risk of local recurrence if they have grade 1 histology and less than 50% myoinvasion (Stage IA) or grade 2 and no invasion are thus not offered adjuvant therapy.
Vaginal radiation therapy (brachytherapy) may be offered to those patients with high intermediate risk factors that include high grade tumours, deep myoinvasion and cervical or lower uterine segment involvement by tumour(13-18).
There is strong evidence that vault recurrence can be reduced significantly without however an effect on overall survival(19-22). We use high-dose rate (HDR) calculated at the vaginal surface, using a dose of 34 Gy in 4 fractions(23-25).
There are subsets of stage I patients with deep myoinvasion, LVSI and grade 3 histology that may be at an increased risk of systemic relapse and cancer related death. These patients are offered participation in clinical trials looking at the role of chemotherapy in these situations(26).
Our rationale for not offering pelvic irradiation to patients who have had an adequate surgical staging and who are found to have their cancer strictly confined to the corpus is that therapy likely to reduce pelvic recurrence is not likely to affect survival27. The evidence supporting our decision for not offering external beam irradiation to patients with negative nodes relates to a number of prospective studies showing no survival advantage in doing so. The GOG 99 trial showed no difference in survival for patients with intermediate risk of recurrence (i.e. any degree of myoinvasion of any grade and negative nodes i.e. Stage IB, IC, II (occult) (FIGO 1988) treated with pelvic XRT after surgical staging compared to those with no adjuvant treatment.
When the cervix is clinically involved, patients are managed like a primary cervical cancer i.e. if operable radical hysterectomy, lymph node dissection (surgical staging) and postoperative adjuvant treatment based on disease extent. This situation is not commonly encountered however. If the surgical staging is negative no further treatment is needed(28), although vaginal vault brachytherapy may be advocated to reduce the risk of vault recurrence.
A more common situation is encountered after surgery with a standard or type I hysterectomy and cervical invasion found on pathology. The concern is that the parametria have not been resected and is a potential site of relapse (even despite negative nodes). The decision to recommend “central radiation therapy” (i.e. brachytherapy or small field external beam) or pelvic external beam radiation therapy in this situation is dependent upon associated risk factors, including the depth of cervical stromal invasion, grade of tumour, tumour volume and depth of myoinvasion in the uterine corpus.
Stage III and IV
Stage III and IV disease is a heterogeneous group of spread patterns and treatment needs to be individualized based upon disease spread. Surgical treatment involves surgical staging to define the extent of disease along with tumour debulking and THBSO if possible. Resection of macroscopic nodal disease may improve survival(29). The objective of surgery is to achieve local disease control in the pelvis in order to help palliate bleeding, discharge and complications involving the bowel and/or bladder.
For patients with confirmed pelvic nodal disease (IIIC1), surgery followed by pelvic or extended field radiation therapy is a reasonable treatment plan. The role of chemotherapy in this situation remains unclear but is commonly used. GOG 122 comparing whole abdominal radiation (WAR) with chemotherapy (Adriamycin/cisplatin) in patients with stage III or IV (FIGO 1988) disease has confirmed a survival benefit for chemotherapy(30). Despite the findings of GOG 122, an Italian trial did not report any superiority to adjuvant chemotherapy over adjuvant radiotherapy(31). The Italian study of PAC compared to pelvic radiation for stage IC, IIG3 (FIGO 1988) with >50% myoinvasion and stage III (FIGO 1988) showed radiation delayed local recurrence and chemotherapy delayed distant recurrence but neither had affect on PFS or OS(31). A randomised phase III Japanese trial of intermediate and high risk patients (Stage IC-IIIC (FIGO 1988) with > 50% myoinvasion) showed no difference in OS or PFS between those receiving pelvic radiation and those receiving combination chemotherapy (CAP: cyclophosphamide, adriamycin, cisplatin)(32).
If chemotherapy is employed, there is some evidence of the superiority of combination versus single agent therapy as GOG has shown addition of weekly paclitaxel to cisplatin and doxorubicin (TAP) increases PFS and OS in advanced and recurrent corpus cancer(33). It is not unreasonable to substitute carboplatin for cisplatin in view of its more acceptable toxicity profile and ease of administration. Singe agent weekly low dose Taxol is also well tolerated with activity in this setting(34-36).
Extended field irradiation and/or cytotoxic chemotherapy or hormone therapy is warranted in the presence of extra pelvic metastases. Surgical eradication of all macroscopic tumour is of major prognostic importance for all patients with clinical stage III disease.
In patients with advanced (or recurrent disease), high dose progestin therapy is well tolerated and may produce some dramatic responses, and is a logical choice for treatment prior to the initiation of cytotoxic therapy. Progestins however will down regulate their own receptor perhaps limiting their long term usefulness. Alternating with Tamoxifen which helps replenish the progestin receptor may be of benefit(37, 38).
Whole abdominal radiation (WAR) is not routinely employed by our Group. It has been advocated for patients with upper abdominal peritoneal or omental metastases that have been completely excised, or positive cytology and other high risk factors. It has been studied by the GOG for adjuvant treatment of patients with stage III and IV endometrial cancer with a high frequency of severe or life threatening side effects and should only be considered in maximally and completely resected advanced endometrial carcinoma patients(39).
The greatest determinant for recurrence in stage I and II disease is grade 3 histology(6). The majority of recurrences occur within the first 2-3 years post treatment. The most favourable recurrence is the isolated proximal or distal vaginal recurrence. Common sites of extrapelvic metastases are lung (36%), abdomen, aortic and supraclavicular nodes, brain, liver and bone, inguinal node and distal vagina.
Treatment should be individualized depending on site of recurrence and previous treatment. Local recurrence is preferably managed by radiation therapy, surgery or a combination. Debulking gross disease may help local control. Five year survival rates are in the order of 25-50%.
The rationale for routine surveillance after treatment is to detect early treatable and salvageable recurrences. In addition regular surveillance will help identify and manage side effects from either treatment or the disease, provide emotional support to the patient and family that things are going well and to provide information for data base research audits. The timing and pattern of recurrence is dependent upon on many factors including the stage at presentation, the treatment received, the histological cell type, the presence of lymph-vascular space invasion, the depth of myometrial invasion and the presence of lymph node metastases (stage).
Low Risk Patients
Patients at low risk for recurrence are offered alternating surveillance with one of our Clinical Nurse Consultants or Nurse Practitioner. Visits are scheduled every 6 months. At that visit you will discuss with the practitioner how you have been since your last visit and any specific symptoms or concerns you might have. The doctor or nurse will then enquire about specific things such as any bleeding, discharge, bladder or bowel related changes, changes to you overall general health, weight and appetite. A general examination will be performed including feeling for enlarged lymph nodes. This will be followed by a vaginal pelvic examination and sometimes a pap smear of the vaginal vault may be performed. Ultrasounds, X-rays and CT scans are not routinely performed, nor are any blood tests.
Intermediate and High Risk Patients
Patients thought to be of intermediate or high risk for recurrence are seen 3 monthly for 2 years and then 6 monthly to complete 5 years of surveillance. At that visit you will discuss with the doctor how you have been since your last visit and any specific symptoms or concerns you might have. The doctor will then enquire about specific things such as any bleeding, discharge, bladder or bowel related changes, changes to you overall general health, weight and appetite. A general examination will be performed including feeling for enlarged lymph nodes. This will be followed by a vaginal pelvic examination and sometimes a pap smear of the vaginal vault may be performed. Ultrasounds, X-rays and CT scans are not routinely performed, nor are any blood tests. CA125 levels are not routinely performed but may be appropriate in some patients.
The median time for recurrence is 14 months for vaginal recurrence and 19 months for distant disease with 34% of recurrences diagnosed in the first 12 months after treatment, 76% within 3 years and 10% not recurring for more than 5 years after treatment. Approximately one third of patients will have disease detected while asymptomatic(40).
While post treatment follow up guidelines vary between institutions and countries, the general theme is to follow patients at high risk of recurrence closely every 3-4 months for the first year or two, then extend the surveillance interval to 6 monthly to complete 5 years of follow up. Low risk patients undergo less intense surveillance, often in conjunction with the referring gynaecologist. While routine surveillance has not been shown to be either cost effective, nor to significantly prolong the overall survival of all patients41, a strong argument can be made for intense surveillance in the previously non-irradiated patients, to detect vaginal recurrence at the earliest opportunity, given the high salvage rate of such recurrences following radiotherapy(42-49).
Uterine Papillary Serous Carcinomas (UPSC)
Usually present in an advanced stage in older women. More than half of the clinical stage I cases will have deep myoinvasion and 75% manifest LVSI. The problem is that 50% have extrauterine disease at surgery and even with a negative surgical staging, recurrence rates are high. Even tumours without myometrial invasion have significantly higher rates of metastatic disease(50, 51) and hence the recommendation by some for aggressive treatment(51) with 19% lymph node involvement in patients without myometrial invasion(52).
Survival of patients with <25% and >25% UPSC in their histology is similar, suggesting UPSC is biologically dominant in heterogeneous tumours and be managed as UPSC regardless of percentage of UPSC(53).
The optimal treatment remains unsettled. At present we treat such patients with any myoinvasion with combination chemotherapy along the lines of a serous ovarian cancer. Brachytherapy should be considered for surgically staged patients with disease confined to the corpus and with deep myoinvasion and teletherapy (EBRT) for patients with stage IIIC1 or EFRT for stage IIIC2 disease. An updated report from the UPSC Consortium of patients with surgical stage I-II UPSC with any percentage of UPSC in their uterine specimen have a significant risk for extrapelvic recurrence and poor survival and that recurrence risk is significantly reduced by adjuvant treatment with platinum/taxane based chemotherapy +/- radiotherapy. LVSI, myoinvasion and increasing percentage of UPSC do not impact on survival indicating that any element of UPSC in the surgical specimen is the most important prognostic factor when assessing risk. The term “mixed” pathology should be abandoned if serous histology is involved. Primary recurrences of early stage UPSC were almost never salvageable(54). The 5 year survival is 30-50% for stage I disease.
Clear Cell Carcinoma
For patients with disease confined to the uterus, pelvic irradiation therapy is recommended. The role of chemotherapy is less clear and is not recommended for stage I and II disease. Clear cell carcinoma is probably not responsive to progestin or antioestrogen therapy.
Endometrial Cancer Diagnosed After Hysterectomy
This should be avoided by performing curettage on all patients with abnormal bleeding prior to hysterectomy and by inspecting the cavity after performance of a hysterectomy. In those rare occasions where this was not performed 2 options exist. One is immediate reexploration, surgical staging and if ovaries still insitu oophorectomy. The other option is to recommend radiation therapy for high risk uterine features such as deep myoinvasion or high grade tumours. Low grade, superficially invasive tumour may not need further therapy. The risk of subsequent ovarian malignancy should be considered if the ovaries are not removed.
Synchronous Primary Tumours in the Endometrium & Ovary
Patients with synchronous primary tumour of both the uterus and ovary should have their treatment determined on the basis that each represents a primary lesion. This may involve both pelvic irradiation therapy and chemotherapy.
Well Differentiated Carcinomas in Very Young Women
The standard management remains hysterectomy and bilateral salpingoophorectomy and surgical staging to define the extent of disease. In exceptional circumstances, in young women with grade 1 tumours, requesting to maintain their reproductive potential, then a short 3-6 month trial of high dose progestins may be tried, including Mirena(55-57). If a repeat curettage shows no evidence of carcinoma then conservative treatment may continue. If the lesions persist or if childbearing capability is not desired, hysterectomy is the treatment of choice. Consultation with a recognized authority in the field of endometrial pathology is mandatory(58, 59).
Positive Peritoneal Cytology
The significance of positive peritoneal cytology remains controversial. It will not change the FIGO stage, and by itself is probably not an indication for adjuvant therapy. It has now been removed from the FIGO 2009 staging system
Medically Unfit Patient
Those patients that are medically unfit for an abdominal or laparoscopic hysterectomy may be offered a vaginal hysterectomy as a palliative surgical measure. Should this not be feasible they are then offered pelvic irradiation therapy. Selected patients with grade 1 lesions may be offered oral high dose progestin therapy or intrauterine progestin (Mirena).
Oestrogen Replacement Therapy
There is no definitive data on ERT in patients treated for endometrial cancer. It likely does not cause recurrence in patients free of tumour but may hasten recurrence in patients with occult disease. If it can be avoided for the first 2-3 years post treatment, it seems logical to do so. If severe menopausal symptoms occur, the limited data available shows no increased risk of recurrence or death(60).
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