Cervical neoplasia

Published on 09/03/2015 by admin

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Chapter 19 Cervical neoplasia

Amy Tang

Role of human papillomavirus

Over 60 different genotypes of human papillomavirus (HPV) have been identified. In some populations, it is present in over 70% of women and may be a vaginal commensal. Other co-factors, such as smoking, may be required to promote the development to cervical intraepithelial neoplasia (CIN).

Link with cervical cancer

• HPV has been identified in benign conditions and cancer.

• Infection with HPV is present in over 90% of preinvasive or invasive cervical neoplasia.

• High-risk HPV subtypes include types 16, 18, 31, 33 and 35.

Management

• Up to 10% of women will have HPV on cervical cytology at some stage.

• If HPV only on cytology, 35%–40% will have CIN on further investigations.

• There is no risk of cancer in patients with HPV without CIN.

• If only HPV is present and this is not treated, 20%–25% progress to CIN in 2 years, which persists in 30%–40% of these patients.

• If treated, the rate of progression is similar to untreated.

• There is no evidence that examining or treating male partners changes the outcome for women.

• There is no evidence that wearing condoms reduces the progression of HPV to CIN.

Cervical cytology

When to perform cervical cytology

The best time is at mid-cycle. In the absence of abnormal bleeding and previous abnormal cervical cytology or treatment, smears should be taken every 2 years. When sexually active, perform the first smear test within 2 years of the first sexual intercourse or from 18–20 years of age, whichever is later. Cease at age 70 years if there have been two normal smears within the past 5 years. In women who have had a hysterectomy and who previously had normal cytology, no further smears are required.

Screening for CIN

Management of abnormal Pap smear

• If LSIL, repeat Pap smear in 12 months; then 24 months if normal result. Otherwise refer for colposcopy

• If possible HSIL or HSIL, refer for colposcopy and biopsy.

Cervical intraepithelial neoplasia (CIN)

Definition. Normally, as cells differentiate and mature they move towards the surface. Abnormalities result in mitotic figures, nuclear pleomorphism, and changes in the nuclear-to-cytoplasmic ratio.

• CIN1: two-thirds or more of the upper epithelium showing good differentiation

• CIN2: maturation/differentiation in the upper half of the epithelium with mitotic figures in the basal half

• CIN3: less than one-third of the upper epithelium showing differentiation

Progression of CIN

• Incidence varies in different studies.

• CIN1 progressing to higher CIN lesions: about 16%–25% in 2–4 years.

• CIN3 to invasive cancer: about 18%–35% in 1–23 years.

Management

Colposcopy

• Aims: identify abnormal area and exclude invasive disease.

• The transformation zone needs to be seen. This is the area between the original and existing squamocolumnar junction. The columnar epithelium undergoes metaplasia as the transformation zone extends. The squamocolumnar junction may recede up the endocervical canal (e.g. in postmenopausal women). The pathological process often occurs in the transformation zone.

• With 3%–5% acetic acid, abnormal epithelium turns acetowhite.

• Schiller’s test: columnar or abnormal squamous epithelium has little or no glycogen and does not stain with iodine.

• Colposcopic changes seen with CIN lesions are punctation (vessels are perpendicular to surface), mosaic (capillaries parallel to surface), and atypical vessels irregular in size, shape and course.

Conservative treatment

Current Australian guidelines recommend that histologically proven low-grade squamous abnormalities can be safely managed by repeat Pap smears at 12 and 24 months. If persistent possible or definite LSIL, annual smears should be continued until at least two are negative.

Ablative treatment

• A colposcopic-directed cervical punch biopsy is needed to confirm the diagnosis of CIN and to exclude invasive cancer before ablative treatment.

• Depth of ablation is up to 10 mm, as almost all lesions are <7 mm in depth.

• Postablation, it takes 4–6 months to replace the transformation zone.

• It should not be carried out if presence of glandular lesion or if entire transformation zone is not visualised.

Excision

• Large-loop excision of the transformation zone (LLETZ) or loop electrical excision procedure (LEEP) has a 96% cure rate.

• Its advantage over ablative treatment is the availability of a histological specimen.

Cone biopsy

Indications. At colposcopy, the lesion is not fully visualised, especially the upper limit; suspected adenocarcinoma in situ; colposcopic examination shows no evidence of dysplasia despite repeated cytology with high-grade dysplasia; or early invasive disease is suspected.

Hysterectomy

• It may be indicated if other gynaecological problems are present.

• Yearly vault smears are required, as there is a risk of vaginal intraepithelial neoplasia.

Cryosurgery

• Freeze for 2–3 minutes to obtain a 4 mm depth.

• About 60% are successful with one treatment.

• It is advisable that women with CIN3 are not treated with cryotherapy.

Pregnancy

• Perform colposcopy by an experienced colposcopist to exclude invasive cancer.

• If CIN, leave treatment until postpartum.

• If invasion is suspected colposcopically, biopsy should be performed.

• Cone biopsy of the cervix is associated with a 5% fetal loss.

Follow-up

• After treatment for HSIL, perform colposcopy and Pap smear at 4–6 months.

• Repeat Pap smear and perform HPV typing at 12 months after treatment and annually thereafter until negative tests on two consecutive occasions.

Cervical intraepithelial glandular neoplasia

Adenocarcinoma in situ (AIS) coexists with CIN in 70% of patients. Up to 15% of CIN is associated with glandular abnormalities. AIS is present in 40%–45% of cervical adenocarcinoma.

Atypical glandular cells of undetermined significance (AGUS) refers to morphological changes in glandular cells beyond those suggestive of a benign reactive process, but insufficient for the diagnosis of AIS. Other terminology under the Australian Modified Bethesda System 2004 includes possible high-grade glandular lesion, endocervical adenocarcinoma in situ and adenocarcinoma.

Cervical cancer

Of cervical malignancies, 85% are squamous cell carcinoma and 15% are adenocarcinoma. The development of cervical cancer is in either the squamous epithelium or endocervix. Most squamous cancers originate in the transformation zone.

Spread of malignancy

• Direct extension: ureteric obstruction can occur if malignancy extends to the pelvic side wall.

• There may be lymphatic spread to the pelvic nodes.

• Haematogenous spread is less common.

Risk factors

• age: mean age at time of diagnosis is 52 years, with two peak frequencies at ages 35–39 years and 60–64 years

• early age of sexual activity

• multiple sexual partners

• smoking

• partner with previous partner with cervical cancer

Investigations and staging of cervical cancer

• full blood count, electrolytes, liver biochemistry, renal function

• radiology: chest X-ray, abdominopelvic computed tomography (CT) scan, magnetic resonance image (MRI) of pelvis

• positron emission tomography (PET) scan can delineate extent of disease more accurately

• staging examination under anaesthesia: vaginal/pelvic and rectal examination; cervical biopsy; cystoscopy; curettage and sigmoidoscopy if indicated

FIGO staging for cervical cancer

This is a clinical staging system. See Table 19.1 for correlation of stage and 5-year survival.

• Stage 1: the carcinoma is strictly confined to the cervix; extension to corpus is disregarded.

• 1A: invasive cancer identified only microscopically

• 1A1: measured invasion of stroma not >3 mm in depth and 7 mm in diameter

• 1A2: measured invasion of stroma >3 mm in depth and not >5 mm in depth and 7 mm in diameter

• 1B: clinical lesions confined to the cervix or preclinical lesions larger than stage 1a

• 1B1: clinical lesions not >4 cm in size

• 1B2: clinical lesions >4 cm in size

• Stage 2: the carcinoma extends beyond the cervix, but has not extended onto the pelvic walls. The carcinoma involves the vagina, but not the lower third.

• 2A: no obvious parametrial involvement

• 2B: obvious parametrial spread

• Stage 3: the carcinoma has extended onto the pelvic side wall. On rectal examination there is no cancer-free space between the tumour and the pelvic wall. The tumour involves the lower third of the vagina. All cases with hydronephrosis or non-functioning kidney.

• 3A: no extension to the pelvic wall but involvement of the lower third of the vagina

• 3B: extension onto the pelvic wall and/or hydronephrosis or non-functioning kidney

• Stage 4: the carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum.

• 4A: spread to adjacent organs

• 4B: spread to distant organs

Table 19.1 Correlation of stage and 5-year survival

Management of cervical cancer

Surgical treatment

• incision: mid-line vertical or Maylard incision

• laparotomy: assessing ascites, liver, kidneys, ureters, nodes, spleen, subdiaphragmatic spaces, paracolic gutters, appendix

• radical surgery: removal of the uterus, cervix, parametrium, upper third of the vagina and pelvic nodes

Radiation therapy

• The limiting factor in getting the maximum dose to the tumour is normal tissue tolerance. Cellular DNA is damaged by a direct action of radiation or indirectly via water free radicals.

• Tumour cells undergo mitotic death and rate of tumour shrinkage is proportional to cell cycle time.

• The typical radical dose is 60 gray; a palliative dose is 30 gray. The total dose is delivered in multiple fractions to allow repair of normal tissues between fractions (e.g. 50 gray may be given in 30 fractions over 6 weeks for pelvic radiotherapy). The chance of eradication of the tumour depends on the dose and number of malignant cells.

Morbidity of pelvic radiotherapy

• About 5% severe morbidity is considered acceptable.

• Acute effects are proctitis, ileitis, diarrhoea, tenesmus, skin reaction (especially skinfolds) and bladder irritability.

• Late effects are chronic proctitis, ileitis with perforation or stricture, fistula or necrosis, lymphoedema, vaginal atrophy and contraction, radiation menopause, femoral head necrosis, induction of malignancy.

• Radiation morbidity may be reduced by field planning, barium contrast and gentle fractionation to allow normal tissue the chance to repair.

Treatment of early-stage cervical cancer

Stage 1A

• Microinvasion <1 mm may be treated with cone biopsy or simple hysterectomy.

• Less than 3 mm invasion may be treated with simple hysterectomy.

• Stage 1a lesions >3 mm invasion require radical hysterectomy and lymphadenectomy, with adjuvant radiotherapy and concurrent chemotherapy if nodes are positive.

Stage 1B

• Identical survival rates obtained if managed primarily by radical hysterectomy/lymphadenectomy or radiotherapy when surgical margins and lymph nodes are clear.

• Radical hysterectomy and pelvic lymphadenectomy are often used to treat stage 1B1 disease.

• Use radiotherapy and concurrent chemotherapy if the woman is unfit for surgery or as adjuvant therapy if the nodes are positive.

• Radical trachelectomy can be an option for a woman who wants to preserve fertility if the tumour is <2 cm.

Stage 2A

• Surgery can be offered to patients with early stage 2A cervical cancer. Otherwise, primary radiation therapy is the standard treatment for more advanced disease.

Advantages of surgery

• In young women, the ovaries may be left if they appear normal, as the risk of ovarian metastasis is <1% in squamous cell carcinoma of the cervix, stage 1.

• The risk of distant metastasis is influenced by primary therapy (i.e. lower risk with surgery than with radiation).

Management of advanced-stage cervical cancer

• Radiation treatment with concurrent chemotherapy is used for stages 2B or greater. Radiation doses are normally quoted from point A (i.e. 2 cm lateral to the centre of the uterus and 2 cm above the lateral fornix).

• Stage 2B and large (>5 cm) stage 1B cancers may be treated with radiation and chemotherapy followed by hysterectomy. Stage 4A may be treated with pelvic exenteration.

Adenocarcinoma of the cervix

• This accounts for 15%–25% of cervical cancer. FIGO prognosis for this condition is poorer than for squamous lesions, due to greater tumour volume.

• Clinical behaviour of the disease is similar to that of squamous cell carcinoma.

• In young women with early-stage disease, the ovaries may be conserved, as <2% metastasises to the ovaries.

Special circumstances

Cervical cancer in pregnancy

• It occurs in about 1 in 1500 pregnancies.

• Vaginal delivery is not advised, as this may disseminate disease through large cervical venous sinuses and dilated lymphatics, cause disease to be transmitted down the vagina or produce haemorrhage.

Small cell cancer

• metastasises early and requires local surgery in conjunction with combination chemotherapy

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