Uterine neoplasia

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Chapter 20 Uterine neoplasia

Amy Tang

Benign tumours of the uterus

Uterine polyps

Polyps in the uterine corpus (the commonest site) may be part of a hyperplastic endometrium and present with changes in the menstrual cycle. Presenting symptoms include vaginal discharge and intermenstrual bleeding.

Uterine fibroids (leiomyomas)

These are present in 20%–30% of women and the aetiology is uncertain. Risk factors include nulliparity, family history, African race and hormonal influences, especially oestrogen.

Pathology

• macroscopic: firm, round, whorled masses
• sites: intramural, subserous, submucous, also in cervix and broad ligament
• microscopic: smooth muscle proliferation, fibrous tissue

Degenerative changes

These occur because of poor vascularity, and include:

• hyaline degeneration
• cystic degeneration
• calcification
• necrosis
• red degeneration/necrobiosis
• sarcomatous degeneration, rarely (<0.5%)

Clinical features

• often asymptomatic or variable in presentation; usually shrink after menopause
• presentation: menorrhagia, intermenstrual bleeding, infertility, abdominal swelling, pressure effects on the bladder or on large pelvic veins, which can result in oedema of legs or deep venous thrombosis
• in pregnancy, may grow in size, undergo red degeneration and may obstruct labour

Management

• conservative with small or asymptomatic fibroids
• medical treatment

• progesterone
• gonadotrophin-releasing hormone (GnRH) analogues: cause rapid shrinkage of fibroids in the first 3 months, but they regrow to pretreatment size within 3 months of stopping therapy; reduction in volume is proportional to degree of oestrogen suppression; side effects include menopausal symptoms, pelvic pain from acute necrosis of fibroids, reduced bone density (6% trabecular bone loss in lumbar vertebrae after 6 months, but reversed 6 months after stopping therapy)

• surgery: hysterectomy; hysteroscopic resection, myomectomy with or without pretreatment GnRH analogues

Fibroids in pregnancy

Fibroids become soft because of oedema and grow in size in pregnancy. If pedunculated, the fibroid may undergo torsion. There is an increased risk of red degeneration. This causes pain and a slight rise in temperature. Management of red degeneration of fibroids in pregnancy is conservative (rest, analgesia). Pain will abate in about 10 days.

Effect of fibroids on pregnancy

• uterus is larger than dates; the growth of fibroid occurs mostly in the first trimester
• risk of abortion/miscarriage
• when present at lower parts of the uterus and cervix, fibroids can obstruct the presenting part and cause abnormal lie of the fetus
• risk of postpartum haemorrhage
• caesarean section may be difficult if the fibroid is in the lower uterine segment
• rupture of uterus after myomectomy is rare

Endometrial hyperplasia

Definition. Hyperplasia is an increase in the number of cells in an organ/tissue; it may be pathological or physiologically normal.

Endometrial hyperplasia consists of a variety of changes in endometrial glandular and stromal elements. It is characterised by proliferation of endometrial glands resulting in greater gland-to-stroma ratio than in normal endometrium. These glands vary in size and shape and may show cytological atypia.

World Health Organization classification of endometrial hyperplasia

• glandular/stromal architectural pattern

• simple (cystically dilated glands with occasional outpouching)
• complex (back to back crowding of glands with minimal intervening stroma)

• presence or absence of nuclear atypia

Risk factors

Endometrial hyperplasia is oestrogen-dependent but its precise role is unknown. Conditions such as polycystic ovarian syndrome, unopposed oestrogen therapy, ovarian tumours (oestrogenic or virilising) and obesity are associated with an increased risk of hyperplasia. Other risk factors are infertility, nulliparity and medical conditions (liver disease, hyperthyroid).

Malignant potential

• Cytological atypia is the most useful predictor of the likelihood of cancer progression.
• Simple hyperplasia without atypia: about 1% will progress to cancer; 80% regress after curettage and other treatment.
• Complex hyperplasia without atypia: 3% progress to cancer.
• Simple hyperplasia with atypia: 8% progress to cancer.
• Complex atypical hyperplasia: 29% progress to carcinoma; up to 25% of women have well-differentiated cancers when hysterectomies are done within 1 month of curettage.

Diagnosis and screening

• common presentations: menorrhagia and abnormal bleeding per vagina
• investigations: ultrasound scan to assess thickness of the endometrium; hysteroscopy and endometrial curettage; endometrial sampling; cytological sample from the cervix and/or vagina (sensitivity is low: 35% for atypical hyperplasia, and 20% for adenomatous hyperplasia)

Management

• oral progesterone: by providing a more complete sloughing of the endometrium, reducing the number of oestrogen receptors on endometrial cells and by affecting the metabolism of oestrogen; when using cyclical therapy, the duration of therapy is important (i.e. at least 12 days per month)
• levonorgestrel-releasing intrauterine system (Mirena)
• stop unopposed oestrogen
• surgical treatment: dilatation and curettage; hysterectomy

Guides to treatment

• treatment dependent on the type/grading of hyperplasia, the age of the woman and her desire for future fertility
• simple hyperplasia: dilatation and curettage, hormone therapy, monitoring with yearly endometrial sampling
• complex hyperplasia: if fertility required, treatment with progesterone and induction of ovulation; if fertility not required, or in the older woman, treatment with progesterone or hysterectomy with or without oophorectomy; if conservative management used, an endometrial sample recommended in 3–6 months
• atypical hyperplasia: if fertility required, treatment with progesterone and induction of ovulation; if fertility not required, or in the older woman, treatment with hysterectomy and oophorectomy; if conservative management used, an endometrial sample recommended in 3 months

Cancer of the uterine corpus

This is the leading cause of genital cancer in developed countries, with a 1% lifetime risk.

Epidemiology and risk factors

• 80% postmenopausal (peak incidence at 61 years); <5% aged under 40 years
• obesity: increased conversion of androstenedione to oestrone in fat (this lowers sex hormone-binding globulin and raises free oestrogen—a three-fold increased risk if the woman is up to 25 kg overweight and ten-fold if the woman is >25 kg overweight)
• medical conditions: hypertension, previous pelvic irradiation, immunodeficiency, diabetes (raises risk by two to eight times)
• hereditary non-polyposis colorectal cancer (HNPCC): 40%–45% risk
• abnormal hormonal status: unopposed oestrogen therapy, raised endogenous oestrogen (e.g. obesity, polycystic ovarian syndrome, oestrogen-producing tumours, use of tamoxifen)
• parity: up to 35% of women with endometrial cancer nulliparous, representing a two-fold risk compared with multiparous women; late menopause also a risk factor

Pathology of uterine cancer

• Adenocarcinoma accounts for 60%–80% of endometrial cancers.
• Adenosquamous malignancies occur in 15%.
• Papillary serous carcinomas are aggressive, with early peritoneal spread.
• Clear cell carcinoma is rare and the prognosis is poor.

Mode of spread of uterine cancer

• direct invasion of the myometrium and cervix
• at the time of diagnosis, at least 10% with extension of disease beyond the uterus
• lymphatic spread: para-aortic and pelvic nodes
• haematogenous spread in later stages: lungs, liver, bone

Clinical presentation

• postmenopausal bleeding in 90% of cases
• intermenstrual bleeding, menorrhagia

Diagnosis and investigations

• endometrial sampling
• examination under anaesthesia, hysteroscopy, curettage
• full blood count, electrolytes, blood sugar levels, liver biochemistry
• chest X-ray
• computed tomography (CT) of abdomen and pelvis to assess for metastatic disease
• CA125 can be useful to predict extrauterine disease once diagnosis of uterine cancer is confirmed

FIGO staging for uterine cancer

• stage 1: tumour confined to the body of the uterus

• 1A: tumour limited to endometrium
• 1B: invasion of less than half of the myometrium
• 1C: invasion of greater than or equal to half of the myometrium

• stage 2: tumour extension to the cervix

• 2A: endocervical glandular involvement only
• 2B: cervical stromal invasion

• stage 3: tumour with local spread and/or positive nodes

• 3A: tumour invades serosa and/or adnexa, and/or positive peritoneal cytology
• 3B: vaginal metastasis
• 3C: metastasis to pelvic and/or para-aortic nodes

• stage 4: tumour spread to pelvic viscera and beyond

• 4A: invasion of bladder and/or bowel mucosa
• 4B: distant metastasis, intra-abdominal and/or inguinal nodes

In addition, the stage will include the grade of the tumour (grade 1: well-differentiated; grade 2: moderately differentiated; grade 3: poorly differentiated).

Surgical staging assessment

Myometrial invasion

• Survival rates with endometrial invasion only and superficial myometrium invasion are similar.
• There is reduced survival with deep myometrial invasion.

Adnexal spread

• This is present in 7%–8%, and often microscopic.

Lymph nodes

• Metastases increase with worsening differentiation of the tumour and increasing depth of myometrial invasion.

Survival rates

• The overall 5-year survival of women with uterine cancer is 65%. Survival depends on tumour stage, grade and cell type (the worst being clear-cell).
• Table 20.1 lists survival rates for uterine cancer according to the FIGO stage.

Table 20.1 Survival rates for uterine cancer according to FIGO stage

Stage 5-year survival
1 75%–90%
2 65%–75%
3 30%–40%
4 10%

Management of uterine cancer

Screening and prevention

• Positive cervical smear is found in <50%.
• Aspiration endometrial sampling has up to 96% accuracy.
• Protect endometrium with hormone therapy in conditions of unopposed oestrogens.

Stage 1

• About 75% of patients have stage 1 disease. Survival is better with surgery than radiotherapy alone.
• Standard treatment is total abdominal hysterectomy and bilateral salpingo-oophorectomy and peritoneal washings.
• Intraoperative frozen section to assess tumour grade and myometrial invasion to determine whether lymphadenectomy is required.
• Positive nodes are found in 10% and positive peritoneal cytology in 15%.
• Lymphadenectomy may be used as a prognosticator and treatment modifier (radiotherapy if nodes are positive).
• Incidence of vault recurrence rises with worsening tumour grade and increasing myometrial invasion. Postoperative brachytherapy may reduce vault recurrence from 10% to 3%, but has no effect on overall survival.

Stage 2

• Modified radical hysterectomy, bilateral salpingo-oophorectomy and pelvic and para-aortic lymphadenectomy is associated with better survival when compared with simple hysterectomy.
• Pelvic lymph nodes are positive in up to 20% of cases.
• Postoperative adjuvant radiation is individualised and is given if positive lymph nodes.

Stages 3 and 4

• Treatment must be individualised and may include total abdominal hysterectomy, bilateral salpingo-oophorectomy, debulking of macroscopic tumour, preoperative/postoperative chemotherapy and pelvic irradiation, and hormonal therapy.

Recurrent disease

• About 80% of recurrences occur within 2 years of primary therapy.
• It can be locoregional or distant recurrence.
• Treatment is directed to the site of recurrence.
• Two common sites of vaginal recurrence are apex of vault and lower anterior third of the vagina in the retrourethral position.
• Management includes surgery, irradiation, hormone therapy, chemotherapy or combination.

Hormone therapy and chemotherapy

• high-dose progesterone (gives a better response with well-differentiated carcinoma, as there is a reduction in receptor concentration with worsening histological grade; may be used in the treatment of pulmonary metastasis)
• levonorgestrel-releasing intrauterine system (Mirena): suitable for a patient who is unfit for surgery
• anti-oestrogen
• chemotherapy: carboplatin, paclitaxel, doxorubicin, fluorouracil, cyclophosphamide

Uterine sarcomas

Uterine sarcomas are rare and account for about 3% of all uterine cancers. Sarcomas are mesodermal tumours with an overall 5-year survival rate of 30%.

Classification

Leiomyosarcoma

• It accounts for 50% of uterine sarcomas.
• The mean age at diagnosis is 50 years.
• The risk of malignant change in fibroid is <0.5%.
• Survival is better if it arises in a fibroid.
• It is usually intramural and 60% are solitary.
• Presentation: includes vaginal bleeding/discharge, pain, abdominal mass.
• Diagnosis: 10 or more mitotic figures per 10 high-power fields is associated with a 25% 5-year survival rate.
• There is a 95% 5-year survival rate in those with fewer than 10 mitotic figures per 10 high-power fields.
• Spread of the disease is mainly haematogenous; thus surgical staging is not as important.
• Overall 5-year survival rate is 20%.

Endometrial stromal sarcoma

• It accounts for 15%–25% of uterine sarcomas.
• The mean age of diagnosis is 45 years; only a third of patients are postmenopausal.
• It is divided into low-grade and high-grade categories.
• Low-grade is called endometrial stromal sarcoma. They are relatively indolent and late recurrences may occur. Prolonged survival and even cure is possible even after recurrence. They are responsive to hormonal therapy with progesterone after surgery.
• High-grade is now termed endometrial sarcoma. They are aggressive tumours. Prognosis is poor.

Malignant mixed müllerian tumour

• The mean age at diagnosis is 65 years.
• It is a mixture of sarcoma and carcinoma (thus also termed carcinosarcoma).
• Risk factors include increasing age, hypertension, diabetes, obesity and previous pelvic irradiation.
• Prognosis: metastasise early; overall 5-year survival rate is 25%.

Management of uterine sarcomas

Surgery

• Staging: includes laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy.
• Radical hysterectomy has no significant effect on survival.
• Disseminated disease: value of debulking is uncertain.

Radiotherapy

• Leiomyosarcoma is resistant to radiotherapy.
• In malignant mixed müllerian tumours, radiotherapy reduces pelvic recurrence but may not improve survival rates.

Chemotherapy

• The value of chemotherapy has yet to be proven.

Cancer of the fallopian tubes

Primary cancer of the fallopian tube is rare. It accounts for <0.5% of all gynaecological cancers, and only about 1000 cases have been reported. The mean age at diagnosis is 55 years. The only identified risk factor is an inherited mutation in BRCA1 or BRCA2 gene.

Pathology

• Malignancy is mostly due to secondary disease.
• Most primary carcinomas are adenocarcinoma; very rarely there are sarcomas or choriocarcinomas.

Clinical presentation

• There is a classic triad of pelvic pain, pelvic mass and watery vaginal discharge in 15% of patients.
• It is often asymptomatic, but may present with a mass with ascites.
• The most common symptoms are abnormal vaginal bleeding (30%) and vaginal discharge (20%).

Treatment

• similar to that for epithelial ovarian cancer
• surgery: total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, lymphadenectomy, appendicectomy, peritoneal washings and biopsy
• adjuvant platinum combination chemotherapy
• radiotherapy: may be used in palliative therapy

Five-year survival rate

• overall survival is 56%
• stage 1, 70%; stage 2, 50%; stage 3, 30%; stage 4, 10%

Further reading

Berek J.S., Hacker N.F., editors. Practical gynecologic oncology, 4th edn, Philadelphia: Lippincott Williams & Wilkins, 2005.

Hernandez E. Endometrial adenocarcinoma. Obstetrics and Gynecology Clinics of North America. 2001;28:743-757.

Marsden D.E., Hacker N.F. Optimal management of endometrial hyperplasia. Best Practice and Research Clinical Obstetrics and Gynaecology. 2001;15:393-405.

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