This tumour is almost always an adenocarcinoma; the term adenocarcinoma refers to a cancer which arises from lining cells, this time those that line the uterine cavity. Occasionally there are other types of carcinoma that may arise from the endometrium and sometimes there may be a mix; squamous architecture can co-exist with the adenocarcinoma.
The factors that predispose to endometrial cancer are not well worked out. However, the disease seems commoner in women who have experienced long periods of ‘unopposed’ oestrogen administration (e.g. long term oestrogen administration or granulosa cell tumours of the ovary). Such patients suffer from endometrial hyperplasia (an overgrowth of the uterine lining) and this is a predisposing causative factor for the development of uterine cancer. Pursuing the factor of ‘unopposed’ oestrogen exposure, nulliparous women and those with a long menstrual life (late menopause – after the age of 52) have a 2.5 times higher incidence of the disease. Other factors known to be associated with a higher incidence of the disease include obesity, diabetes mellitus, high blood pressure, endometrial hyperplasia (see above) and a family history of the disease or breast and/or colon cancer. The long term administration of the drug tamoxifen (used in the therapy of breast cancer) is associated with an increased incidence of endometrial cancer via promoting emndometrial hyperplasia; the risk is low circa 1 per 1000cases treated and in most incidences the beneficial effects in terms of breast cancer protection outweigh the risks associated with the drug’s use on the uterine lining.
Incidence of uterine cancer
Uterine cancer is less common than cervical cancer with an incidence in the UK of 13 per 100,000 (3.5% of cancer in women). Established risk factors are nulliparity (no pregnancies), late menopause, obesity and prolonged exposure to oestrogens either as medical therapy or due to an oestrogen excess state. In this last situation, a period of endometrial hyperplasia (overgrowth – but at this stage non-malignant overdevelopment – of the lining of the womb) precedes the development of the cancer. The vast majority of women afflicted by this disease are past the menopause.
Symptoms & diagnosis: Uterine cancer
The most common cause for the patient to present to the doctor is vaginal blood loss. This is an unexpected and worrying symptom for women past the menopause and a symptom that the doctor will always take seriously. In other instances, the patient complains of a vaginal discharge which may or may not be tinged with blood. In pre-menopausal women, the complaint may be of intermenstrual blood loss or discharge and a change to the pattern of the menses.
The doctor will probably order a transvaginal ultrasound, which assesses the thickness of the lining of the womb (from which the cancer of the uterus arises). Other alternative imaging tests include MR (magnetic resonance) scanning. The critical test is the sampling of tissue from the lining wall of the womb and this can be done at the outpatient session by aspiration cytology (through the os – the portal leading through the cervix to the inside of the womb) or more definitively by dilatation and curettage (D+C). In the D+C procedure, the gynaecologist scrapes the lining of the womb out sand sends it for microscopic analysis. Separate sampling of the tissues of the cervical canal will allow the doctor to know if the disease is stage 2 (see Stages).
The best early stage is one where the disease is limited to the endometrium or does not extend to more than half the thickness of the wall of the womb (Stage 1a and 1b respectively). Where the disease extends to more than half the thickness of the wall of the womb (stage 1c) or to the cervix (Stage 2) then the risks of spreading is slightly increased and even more so if the disease invades beyond the wall of the womb or into the vagina, or to local draining lymph nodes (Stage 3). The fourth stage (Stage4) is where the disease has infiltrated other pelvic organs such as the bladder or the rectum or has spread beyond the pelvis.
Treatment & outcomes: Uterine cancer
A total abdominal hysterectomy removal of the womb through an abdominal incision, with or without removal of the ovaries, is the treatment of choice for stage 1 and 2 disease ( Stage 1 vis where the cancer is confined to the womb/uterus – 1a: where the invasion of the musclewall is less than half and 1b: where the invasion is more than half way through the muscle wall fo the womb), Stage 2 is where the cancer has spread to the cervix – the neck of the womb but not further afield) , although a more extensive operation may be chosen for more advanced stage 1b – 2 cases and this may followed by a course of pelvic radiotherapy (external beam radiotherapy over five weeks).
With such therapy, for stage 1 disease, the five year survival rates are 75%, whereas the survival for those women presenting with stage 2 tumours is just under 60 %. In stage 3 disease (where the disease has spread beyond the uterine wall but not outside the pelvis and beyond the ability of the surgeon to obtain a clear margin) then radical pelvic radiotherapy is chosen and a vaginal brachytherapy boost (see cancer of the cervix section for explanation of brachytherapy) may be given if it is deemed that the cervical and high vaginal regions are at especially high risk, given an individual patient’s situation. The five year survival rates for stage 3 cases are considerably less good than those of the first two stages and are around 30% survival at five years.
Chemotherapy has a role in the treatment of the more advanced cases and the two primary chemotherapy agents are paclitaxel and carboplatin. I nmetastatic disease (stage 4 ) chemotherapy is the first line of therapy.
What to do in refractory cases of metastatic disease,after the foregoing therapies have failed?
Some patients with uterine cancer may have the Lynch syndrome and genomic testing for DNA repair faults – mismatch repair deficiency (MMR deficiency) associated with hyper-mutation (and/or testing for microsatellite instability -MSI) and correlated with response to immunotherapy (particularly the PD1/PDL1 ‘check-point’ inhibitors: Pembrolizumab and Nivolumab) – is a genomic analysis that should be investigated as it has therapeutic repercussions. Such genetic mutations should be sought, along with others, by genetic profiling of a new tissue biopsy or, sometimes, if there is adequate release of cell-free DNA fragments (cfDNA) into the blood, via a blood draw. Next Generation Sequencing (NGS) analysis is then performed in a search for ‘driving’ genetic mutations that can be ‘drugged’. For example. Occasionally, uterine cancer can occur in BRCA mutation patients and then there are possibilities for therapy with PARP inhibitors. KRAS, PTEN and HER2 mutations have been found by NGS in uterine cancers and sometimes there are therapeutic implications: for HER2 amplification then drugs such as Trastuzumab can be considered. Everolimus – an mTOR inhibitor can be active against the mutations of the PI3K/PTEN/AKT/Mammalian target for rapamycin pathway. There are good reasons to explore genomic mutations in refractory cases of metastatic uterine cancer.
Immunotherapy remains an alternative option if there is evidence (vide supra) of hyper-mutation.
Dr. P. N. Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics). Tel: +44-207-631-1632
Outcomes of uterine cancer
The good news is that the majority of patients presenting with a uterine cancer that has not spread far afield are cured by the above methods.
Recurrence is problematic. Depending upon prior therapy and the nature of the recurrence, patients may be treated with curative or palliative intent. Treatment options for locally recurrent disease include radiotherapy, surgery, hormone therapy, and chemotherapy.
Surgical management is best reserved for the rare woman who has an isolated vaginal recurrence in a previously irradiated field and who is a good surgical candidate (both medically and surgically). In other cases of recurrence, cure is less likely.
Palliative radiotherapy may be recommended to ease discomfort where the relapse is in the pelvis and the patient has not had previous radiotherapy. For relapses outside the pelvis or those patients presenting with stage 4 of the disease, then occasionally, progestogen therapy (e.g. medroxyprogesterone) may give some worthwhile remissions and will be prescribed in most cases at least for a trial period. However, nowadays, the genomic profiling and assessment of the usefulness of immunotherapy should be done at this time (vide supra) as t here may be more promising options.
Interestingly, some (around 10%) of patients presenting with stage 4 of the disease live five years and with the increasing options provided by genomic profiling, hopefully that % will increase.
Screening for uterine cancer
For patients with Lynch syndrome and possibly BRCA mutations – paerhaps BRCA1, Gynaecological – usually ultrasound – screening is advised.
For others, apart from the annual transvaginal ultrasound scans performed on patients with an oestrogen excess state or those taking agents which cause the overdevelopment of the lining of the womb (e.g. tamoxifen – although it is conterversial as to whether these should be screened), there is no screening programme for this cancer nor would it be cost effective in health economic terms.