Causes of cervical neoplasia

In virtually all cases of cancer of cervix, there is evidence that the tumour is associated with infection with the human papilloma virus (HPV), particularly types 16 and 18. The human papilloma virus produces proteins that bind to the products of two important tumour suppressor genes, p53 and Rb1.

Risk factors associated with cervical cancer are those that promote sexually transmitted disease. These are particularly the age of first intercourse and number of sexual partners. There is a lower incidence of cervical carcinoma in women using barrier methods of contraception. Male behaviour is also important. Partners of men in certain occupations, such as seamen, deep-sea fishermen and long distance lorry drivers, have a higher incidence of cervical cancer. So do those partners of men whose previous partners have developed cervix cancer. Smoking and immunosuppression are also associated with cervical cancer. Cervical neoplasia is more common in women who are HIV positive.

Pathology of cervical cancer

Viral infection of the cervix may lead to premalignant change which is called dysplasia. This can be detected in exfoliated cells removed during a cervical smear. Cervical dysplasia is graded mild, moderate or severe. The terms CIN1, CIN2 and CIN3 are histological terms used to describe increasing degrees of dysplasia, mild, moderate and severe in biopsy material. In some women, there is a progression from mild to severe dysplasia and then invasive cancer. This often takes many years to develop and can be detected during cervical screening. Treatment of premalignant disease is highly effective. Patients with moderate or severe dysplasia are offered ablative treatment using large loop excision, laser vaporization or cryotherapy. However, in most cases, dysplasia is self-limiting. Even the most severe form of dysplasia, CIN3 (previously called carcinoma in situ), will only progress to invasive cancer in between 20 and 40% of women if left untreated. Between 85 and 95% of cases of invasive cancer of cervix are squamous carcinomas. The remainder are adenocarcinoma or adenosquamous tumours. There is some evidence that the incidence of adenocarcinoma is increasing among younger women. Some authorities feel adenocarcinoma of cervix has a worse prognosis than squamous cancer when treated by radiotherapy.

Carcinoma of cervix spreads predominantly by direct invasion and through the lymphatic system. Initially, the tumour spreads into the uterus or vagina and parametrium (the tissues around the uterus). Later, it can infiltrate bladder or rectum. The tumour spreads to the iliac and then para-aortic lymph nodes (Figure 27.4) Blood-borne spread is less common and this may lead to liver, lung and bone metastases.

Figure 27.4 Survival stage 1b operable ca cervix in a randomized trial of 343 patients treated by surgery or radiotherapy.

Symptoms and investigations of cervical cancer

Premalignant changes are usually asymptomatic. The cardinal symptom of invasive cervix cancer is irregular vaginal bleeding. This may be bleeding after intercourse or bleeding in between periods. Sometimes, the women will have a brown vaginal discharge. Pain is usually a symptom of advanced disease and suggests spread to adjacent organs around the cervix. Backache may be associated with para-aortic lymph node spread.

Patients with cervical cancer are staged clinically according to the FIGO staging system (Table 27.2). Accurate staging of cervical cancer is essential so that appropriate treatment can be planned. The cornerstone to staging is an examination under anaesthesia (EUA). The cervix and vagina are inspected and palpated for evidence of tumour. Rectal examination is essential to assess the degree of parametrial spread and to find if the tumour is fixed to the pelvic sidewall. This is usually accompanied by a cystoscopy and, if necessary, a proctoscopy and sigmoidoscopy. Patients usually have a computed tomography (CT) or magnetic resonance imaging (MRI) scan of the abdomen and pelvis looking for nodal spread and urinary obstruction. MRI scanning is a more effective method for imaging the primary tumour, although spiral CT scanning and MRI are probably equally effective in the evaluation of lymph node metastasis.

Table 27.2 FIGO 2009 staging: carcinoma of the cervix uteri

Stage I	The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded)
	Ia	Invasive carcinoma which can be diagnosed only by microscopy. All macroscopically visible lesions, even with superficial invasion, are allotted to Stage Ib carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.0   mm and a horizontal extension of not >7.0   mm. Depth of invasion should not be >5.0   mm taken from the base of the epithelium of the original tissue, superficial or glandular. The involvement of vascular spaces, venous or lymphatic, should not change the stage allotment
	Ia1	Measured stromal invasion of not >3.0   mm in depth and extension of not >7.0   mm
	Ia2	Measured stromal invasion of >3.0   mm and not >5.0   mm with an extension of not >7.0   mm
	Ib	Clinically visible lesions limited to the cervix uteri or preclinical cancers greater than stage 1a
	Ib1	Clinically visible lesions not >4.0   cm
	Ib2 (Figures 27.5 and 27.6)	Clinically visible lesions >4.0   cm
Stage II	Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina
	IIa	No obvious parametrial involvement
	IIa1	Clinically visible lesion ≤4.0   cm in greatest dimension
	IIa2	Clinically visible lesion >4   cm in greatest dimension
	IIb (Figures 27.7 and 27.8)	Obvious parametrial involvement
Stage III	The carcinoma has extended to the pelvic 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 are included, unless they are known to be due to other causes
	IIIa	Tumour involves lower-third of the vagina, with no extension to the pelvic wall
	IIIb (Figures 27.9 and 27.10)	Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney
Stage IV	The carcinoma has extended beyond the true pelvis, or has involved (biopsy-proven) the mucosa of the bladder or rectum. A bullous oedema, as such, does not permit a case to be allotted to stage IV
	IVa (Figure 27.11 and Figure evolve 27.12)	Spread of the growth to adjacent organs
	IVb (Figure 27.13)	Spread to distant organs

Figure 27.5 Manual insertion of a long central tube and ovoids containing cesium.

Figure 27.6 Diagrammatic uterus and vagina, showing intrauterine tube, cross-sections of ovoids in lateral fornices, separated by spacer, and points A and B.

(Reproduced with permission of Arnold from Ralston Paterson, Treatment of Malignant disease, 2nd edn, Edward Arnold, 1943).

Figure 27.7 Impact of 1988 overhaul of UK cervical screening programme on incidence and mortality of cervical cancer in UK.

Figure 27.8 Large cervical tumour in endocervical canal.

Figure 27.9 Cervical tumour (as Figure 27.8) extending into R parametrium.

Figure 27.10 AP simulator radiograph of pelvis (stage IIb ca cervix – as Figures 27.8 and 27.9).

Figure 27.11 Lateral simulator radiograph of pelvis (stage IIb ca cervix as Figures 27.8 and 27.9).

Figure 27.13 A-P view Selectron insertion stage IIb ca cervix (as Figures 27.8 and 27.9).

Treatment

Stage is the most important factor related to outcome. However, tumour size is also an important prognostic feature. It is noteworthy that the survival figures in Table 27.3 relate to patients treated by radical surgery or radiotherapy rather than chemoradiotherapy, as combination treatment has only been given on a wide scale after 1999.

Table 27.3 Carcinoma of the cervix. Patients treated in 1990–92. Survival by FIGO stage (n = 11 945)

Treatment of stage I disease

Stage I tumours are subdivided into stage Ia and stage Ib. They are further subdivided according to tumour size. Stage Ia cases are those that are treated by less than radical means. The prognosis is excellent for stage Ia1 patients and the problem is to avoid overtreatment. A cone biopsy or simple hysterectomy offers many of these patients a virtual 100% change of cure. The outlook is almost as good for stage Ia2 patients. The optimum management of this group has not been clearly defined. The management options vary from cone biopsy to simple or modified radical hysterectomy.

Stage Ib is divided into patients with tumours confined to the cervix and uterus less (stage Ib1) or greater than 4   cm (stage Ib2). Patients with stage Ib1 tumour may be treated by radical hysterectomy. Usually, such patients are relatively slim, fit and often premenopausal. In a radical hysterectomy (a Werthheim’s hysterectomy), the ureter is mobilized to allow wide excision of the uterus and cervix with removal of the cardinal ligaments and a wide cuff of vagina. The pelvic lymph nodes are also usually removed.

Stage Ib2 patients are usually treated by radiotherapy as these tumours have often spread to pelvic lymph nodes. If treated by surgery such patients usually require postoperative radiotherapy.

The only large randomized trial of radiotherapy and surgery in operable cervical cancer showed equally good results for both modalities (Figure 27.14). The number of serious complications was higher in the surgical arm. However, complications of surgery are usually easier to rectify than the complications of radiotherapy.

Figure 27.14 Lateral view Selectron insertion stage IIb ca cervix (as Figures 27.8 and 27.9).

Treatment of stage II–IVa

A few patients with stage IIa disease with early involvement of the vaginal vault are suitable for treatment by radical hysterectomy. Most are treated by radiotherapy which remains the mainstay of treatment of patients with stages IIb– IVa.

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