(24) Cervical Cancer

CERVICAL CANCER AND CIN

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Cancer of the cervix has long been recognized as the commonest malignancy of the female genital tract However, in the last four decades invasive cancers of the cervix showed a significant decline in their occurrence being now nearly as common as endometrial carcinomas. One of the key features of cervical cancer is the slow progression from normal cervical epithelium to precancerous changes (CIN) to invasive cancer. This slow progression through numerous precancerous changes provided the rationale for the preventive and early treatment strategies that have caused the decline of cervical cancer over the past decades.

INCIDENCE: 

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Cervical intraepithelial neoplasia (CIN), may occur at any age, however it is commoner in younger age groups 25 – 45 years. It is usually present several years before the occurrence of preinvasive and invasive disease, and is considered as the premalignant lesion. Pre-invasive carcinoma (carcinoma in situ) occurs mostly between 35-45 years. Invasive carcinoma of the cervix prevails mostly at ages from 40-60 years, with a peak incidence around 50 years, an age incidence which is nearly 10 years earlier than that for endometrial carcinoma.

RISK FACTORS:   

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Early age at the first sexual intercourse. Multiple sexual partners (promiscuous intercourse). Viral sexually transmitted diseases (HPV types 16,18,31 & HSV type 2). Low socioeconomic standards and poor hygiene (chronic irritation). Smoking. (Chemicals in cigarettes may interact with cells in the cervix).

HPV AND CIN: 

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Forms of HPV, a virus whose different types cause skin warts, genital warts, and other abnormal skin and body surface disorders, have been shown to lead to many changes in cervical tissues that may eventually lead to cancer. Because HPV can be transmitted by sexual contact, early sexual contact and having multiple sexual partners have been identified as strong risk factors for the development of cervical lesions that may progress to cancer.

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type of HPV present can affect whether the CIN develops into a cancer or not. Only certain HPV types such as 16,18,31 and 33 seem to be associated with the development of cervical cancers.  In general, CIN is an asymptomatic condition, at least in its milder forms, and is usually diagnosed during screening for cervical cancer by the PAP smear.

There are three grades of CIN: 

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CIN 1 (mild dysplasia): where abnormal cells occupy the basal one third (1/3) of the thickness of the squamous epithelium. These cells have high nucleo-cytoplasmic ratio, and pleomorphic nuclei. Cells of the upper 2/3 show normal stratification and maturation. CIN II (moderate dysplasia): Abnormal dysplastic cells occupy (2/3) of the thickness of squamous epithelium. Cells of the upper (1/3) show normal stratification and maturation CIN III (severe dysplasia – carcinoma in situ): Abnormal dysplastic cells occupy the full thickness of the squamous epithelium, without invasion of the basement membrane. CIN III & in situ carcinoma are commonly grouped as one category.

CIN 1

CIN 2

CIN 3

DIAGNOSIS OF CIN: 1) Cervical smears (Pap smear test):  The smear, or Pap test, is commonly used as a routine test to detect early cell changes (dyskaryosis). This is known as cervical screening and is aimed at women with no symptoms, however it is sometimes used to help diagnose cancer cervix.  Scrapings are made from the ectocervix at the squamo-columnar junction, using a cytobrush, or from ectocervix using an Ayre wooden spatula. The cells is spread on a glass slide fixed by ethyl alcohol and stained by Papanicolau stain.

The Pap smear test result may be either:  Normal: No inflammation, No CIN.  Inflammatory without dysplasia. No CIN  CIN I: mild dysplasia or dyskariosis  CIN II: moderate dysplasia or dyskariosis  CIN III: severe dysplasia (In situ carcinoma) (invasion may be suspected).

Normal Pap Smear

Moderate Dyskariosis

Severe Dyskariosis

 Advantages

of cytological diagnosis include being; easy, cheap, allows early detection of malignancy, before symptoms, with an accuracy exceeding 95%. The test on the other hand needs a well trained cytologist for proper interpretation, and has a small percentage of false positive and false negative results.

2) Colposcopy: 

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A colposcope is like a pair of binoculars with a light that allows binocular inspection of the ectocervix up to the squamocolumnar junction within the transformation zone with magnification of up to 20 times the normal size. If the smear test is abnormal, a colposcopic examination will be useful in visualization of abnormal areas showing abnormal vascularity by use of green filters. If the cervix is swabbed with acetic acid, suspicious areas within the epithelium will appear as white bleached areas requiring close attention (aceto-white areas).

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Biopsies may be taken from these suspicious areas (colposcopically directed biopsy) for histopathologic examination, and hence the diagnosis of CIN is confirmed, and the degree of CIN accurately determined. Abnormal colposcopic findings include: Aceto-white epithelium Abnormal vascularity (punctation, mosaic) Leukoplakia Iodine negative (Schiller +ve) painting with lugol’s iodine result in brownish staining of the normal epithelium

Colposcope

TREATMENT OF CIN: 

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Treatment of CIN depends upon its severity. In general the management is usually conservative requiring no or very limited surgical techniques. CIN I : Treat infection and repeat the smear test after 8 – 12 weeks. CIN II : Destruction or ablation of abnormal cells. CIN III: Excision of a cone of cervical tissue if patient is young. Simple total abdominal hysterectomy, in older patients.

A) Ablative Techniques:  All

these techniques are meant to destroy abnormal epithelium within the cervical tissue. In contrast to excisional methods, no tissue will be available for histologic examination. Hence it is essential to exclude invasive disease by colposcopic directed biopsies before starting such treatment techniques.

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Cryosurgery: Allows destruction of affected epithelium by freezing to a depth of 3-5 mm. It is quick, sufficiently painless and done without general anaesthesia. Diathermy: Under general anaesthesia, destroys tissues to a depth of > 7 mm. CO2 Laser: Results in tissue vaporization to a depth of 7-9 mm. with maximum precision and very minimal trauma.

Cryosurgery

B) Excisional Techniques:  Excisional

techniques have the advantage of both treating the condition and obtaining tissue available for histologic examination, where the original diagnosis may be confirmed, disease free margin established, and invasion of basement membrane excluded.

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Large Loop Electrodiathermy of the Transformation Zone (LLETZ): A thin wire loop is used to excise the transformation zone using a blended diathermy current. It is rapid, cheep, safe, and easy, hence became the most popular technique in most centres. Knife Cone biopsy: Less common nowadays because it is associated with higher incidence of bleeding, infection, cervical stenosis and cervical incompetence in subsequent pregnancies. Laser Cone Biopsy: less commonly used as it is more expensive, needs complicated instruments, done under general anaesthesia, and requires special training and experience.

Knife cone biopsy

 Follow

Up After Treatment: Despite the efficacy of the above mentioned techniques in treating CIN, yet recurrence is still common and follow up by annual Pap smears is recommended for a period of up to 10 years.

INVASIVE CARCINOMA OF THE CERVIX PATHOLOGY: two main histological types  Squamous cell carcinoma: The commonest type; (> 90%) develops from the flat cells, which cover the outer surface of the cervix (ectocervical carcinoma of the portio vaginalis). However it may rarely arise in the endocervix due to previous squamous metaplasia. It is easily and early detected with the Pap smear test.  B) Adenocarcinoma: Less common; (<10%) develops from the glandular epithelium, which lines the cervical canal (endocervical carcinoma), but may rarely arise from the columnar epithelium covering an erosion on the ectocervix, 

 Ectocervical

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carcinomas are almost always of the squamous type, they usually present in one of three common varieties Hypertrophic type (exophytic) Ulcerative type (endophytic) Infiltrative type (nodular)

 Endocervical

carcinomas are mostly adenocarcinomas arising from the columnar epithelium lining the endocervix. It forms a spherical growth distending the cervix and giving it a barrel-shaped appearance.

SPREAD OF CANCER CERVIX: 

Direct spread: From the cervix into adjacent tissues including the corpus uteri. Further spread to the parametrium induces signs and symptoms as chronic pelvic inflammation. Significant spread may result in ureteric obstruction. Spread downwards into the vaginal wall may later involve the bladder and rectum. Backwards spread along the uterosacral ligaments leads to involvement of the sacral plexus causing intractable sciatic pain.

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Lymphatic spread: Usually follows direct spread, but may coincide with it. The primary groups affected include spread from the cervical lymphatics along the paracervical lymph tract, to the external iliac nodes. Occasionally the extension is backwards to the internal iliac group. Secondary groups affected involve drainage into the common iliac and lateral sacral groups. Ultimately the common iliac group drains into the lower lumbar group of the para-aortic lymph nodes.

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Blood stream spread: Least common, usually in late or advanced cases. Metastases may occur to distant organs as to the liver, lungs, brain and bone. Direct implantation: to the peritoneum and vagina is exceedingly rare.

STAGING OF CERVICAL CARCINOMA  The

FIGO staging classification is based on findings on examination under anaesthesia (EUA), intravenous pyelogram (IVP), and cystoscopy.

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Clinical Staging of Cancer Cervix (FIGO classification): Stage 0 : Preinvasive cancer ( Carcinoma in situ or CIN 3 ). Stage I A : Microinvasive cancer (invasion depth < 5.0 mm & width < 7.0 mm) Stage I B : Invasive carcinoma confined to the cervix (depth > 5.0 mm & width > 7.0 mm) Stage II A: Tumour involving upper 1/3 of the vagina. Stage II B: Extension to parametrium (not reaching the lateral pelvic side wall) Stage III A: Tumour extending to lower 1/3 of the vagina Stage III B: Extension to parametrium (reaching the pelvic side wall) Stage IV A: Tumour involving the bladder or rectum (direct spread) Stage IV B: Extrapelvic spread, e.g. liver or lung metastases (blood borne spread)

Staging of Cervical Carcinoma

CLINICAL PRESENTATION OF CANCER CERVIX Clinical Symptoms: 1. Vaginal Bleeding: is the most common presenting complaint It may be either;  Contact bleeding i.e. after coitus or douching (commonest).  Intermenstrual bleeding i.e. metrorrhagia.  Postmenopausal bleeding  Persistent bleeding during pregnancy (rarest) 

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2. Vaginal Discharge: In addition to bleeding, some patients will complain of profuse, offensive, often blood stained vaginal discharge, resistant to conventional treatment. 3. Other Symptoms, such as pain, are uncommon until very late disease. Pain may be associated with infiltration of the parametrium or uterosacral ligaments, pyometra, or sciatic and obturator nerve affection.

Clinical Signs: 

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General examination: In early cases, most patients are in a good general condition and relatively young in age. In advanced stages, chronic blood loss, urinary manifestations and ureteric obstruction may lead to severe anaemia, uraemia and cachexia. Inspection via a speculum vaginal examination: Invasive cancer of the cervix presents as a small nodule or ulcer that bleeds easily on touch. As it advances, it becomes a friable warty mass that may break into a large ulcer. Later on, the mass or ulcer will extend to the vaginal walls obliterating the vaginal fornices.

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Per rectum examination (PR): To evaluate possible parametrial extension.

DIAGNOSTIC PROCEDURES FOR CANCER CERVIX:   

1. The Pap Smear Test 2. Coploscopy 3. Schiller Iodine Test In cases where a Pap smear is positive or suspicious, and in absence of a naked-eye lesion and unavailable colposcopic examination facilities, the Schiller’s iodine test will be helpful to locate abnormal cervical epithelium from which biopsies should be performed. The cervix is painted with Schiller’s iodine solution. Normal squamous epithelium takes a deep brown colour, owing to its rich glycogen content. Abnormal areas of epithelium remain unstained and retain their normal colour

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Cervical Biopsies Histopathologic examination of a specimen of cervical tissue containing the abnormal epithelium is the gold standard for diagnosis of cervical cancer.  Knife Biopsies  Colposcopic Directed Biopsies  Multiple Punch Biopsies

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Cone Biopsy: Removal of a cone shaped piece of the cervix with the apex of the cone including the transformation zone. The procedure is associated with possible excessive bleeding, and may lead to scarring, stenosis and later cervical incompetence. It is indicated in only a few cases: with endocervical extension when the entire extent of the lesion cannot be delineated colposcopically when a repeatedly positive smear is obtained in absence of positive colposcopic findings.

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Fractional Curettage: Some cases of endocervical carcinomas will be diagnosed by obtaining endocervical tissue during a fractional curettage (FC).

PREVENTION:  By

early diagnosis and proper management of premalignant lesions (CIN)

PLANNING FOR TREATMENT: 

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Before starting treatment, staging of the disease should be complete. Staging requires thorough clinical evaluation together with the use of some special procedures including, EUA cystoscopy IVP chest X ray abdominal ultrasonography (U.S.)

Treatment Of Carcinoma In Situ (Stage 0) 

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Cervical Conization: only in young patients with low-grade tumours and wide free surgical margin after excision. The aim is to preserve the uterus for fertility. TAH (Total abdominal hysterectomy): In middle age patients not desirous of fertility. The aim is remove the cancer and preserve ovarian hormonal production. TAH-BSO (TAH + Bilateral salpingo-oophorectomy): In premenopausal or postmenopausal patients Lymphadenectomy is not required as there is no invasion of the basement membrane

Treatment Of Microinvasive Carcinoma (Stage Ia)  Total

abdominal hysterectomy + bilateral salpingo-oophorectomy (TAH-BSO). The patients may be spared a complete lymphadenectomy, or may be offered only selective lymph node sampling, to minimize the extent and morbidity of surgery.

Treatment Of Invasive Cancer  Choice

of treatment, whether surgery, radiotherapy or both, and the extent of each of them is based namely on;  The stage of the disease.  The grade of the tumour.  The age and general condition of the patient.  The availability of well-trained teams for both surgery and radiotherapy.

 Results

of surgery and radiotherapy are comparable in the early stages of the disease, however surgery is more preferred as it allows for complete resection of the tumour and provides a specimen available for ensuring the extent of the disease.

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The prognosis in stage I disease is excellent with 5 year survival rates of 80% - 85% whether surgery or radiotherapy were used. The prognosis in stage II drops sharply to a 5 years survival of 50%. In stages III and IV, 5 years survival may be as low as 25% and 5% respectively. The treatment in these stages is therefore only palliative.

1) SURGERY IN CANCER CERVIX

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Where the disease is confined to the cervix, surgery is usually the first line of treatment (stage IA& IB). In this situation, radiotherapy is as effective as surgery but the side effects are greater, and the morbidity is higher. Wertheim’s hysterectomy (Radical hysterectomy), is the standard surgical procedure for invasive carcinoma of the cervix. It involves a total hysterectomy and bilateral salpingooophorectomy (TAH-BSO) with removal of the paracervical tissue surrounding the cervix and 2-3 cm from the upper vagina. In addition the pelvic lymph nodes are carefully dissected with removal of as many of the nodes as possible. The pelvic nodes include the external iliac, internal iliac, common iliac, obturator and presacral nodes. If a large number of removed nodes are affected, then it is usual to offer the patient adjuvant radiotherapy.

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principal complication seen with surgery is related to some degree of bladder dysfunction due to division of the parasympathetic nerve supply to the bladder that runs within the uterosacral ligaments.

2) RADIOTHERAPY IN CANCER CERVIX:  If

cancer has spread beyond the cervix (stage II & III), it will not be curable by surgery and Radiotherapy becomes the preferred first line of treatment. It may be given alone, or in combination with surgery or chemotherapy

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External beam irradiation: Radical radiotherapy for cervical carcinoma involves the use of linear accelerator to treat the whole pelvis with external beam radiotherapy to shrink the central carcinoma and also to treat possible site of regional metastases. Internal irradiation: Internal sources of irradiation are then placed in the upper vagina and within the cervical canal to provide a very high dose to the central tumour. Two internal applications (tandum & ovoids) are usually inserted within a week after completing the external beam therapy (which usually require five weeks).

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Postoperative radiotherapy: Radiotherapy following surgery is indicated if more than one lymph node is positive, if tumour margins were very close, or if the tumour was bulky and has a high chance of recurrence. Palliative radiotherapy: In advanced cancer cervix (stage III & IV), radiotherapy may be used in palliative settings to reduce vaginal bleeding and discharge and to assist in local control of the central disease.

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Complications of radiotherapy include, diarrhoea that often settles after treatment is finished, radiation induced menopause in premenopausal patients variable degrees of vaginal narrowing and fibrosis, few weeks after treatment is completed. Rarely radiation vesico-vaginal fistulas may occur and are difficult to deal with.

3) CHEMOTHERAPY In Cancer Cervix: 

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Recently studies have shown that the addition of chemotherapy during radiotherapy increases cure rates by approximately 10%. Chemotherapy may also be used in adjuvant settings prior to surgery to reduce the size of the primary tumour. In some cases chemotherapy will be used in adjuvant settings following surgery. Chemotherapeutic drugs include cisplatinum, bleomycin, mitomycin and adriamycin.

CARCINOMA OF THE CERVIX AND PREGNANCY  A)

In early pregnancy: External irradiation may be given. Abortion of a dead foetus will follow and then internal irradiation with caesium can be given. Medical induction of abortion using oral and vaginal tablets of mesoprestol (prostaglandin inhibitor) is also possible. For early lesions radical hysterectomy may be performed.

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In the 2nd and 3rd trimesters: The uterus is evacuated surgically, by hysterotomy or Caesarean section, before caesium can be inserted.  Many surgeons will prefer to treat these cases with Wertheim’s radical hysterectomy at the time of Caesarean section.

CARCINOMA OF THE CERVICAL STUMP After Hysterectomy  The

stump of the cervix left after subtotal hysterectomy is just as prone to the development of carcinoma as when the uterus is present.  The results of treatment of stump carcinoma are much worse than when the uterus is intact.

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Internal irradiation is compromised by the absence of the uterus as a container for intrauterine applicators, while vaginal irradiation may not deliver the sufficient dose without risk of damage to the bladder and rectum. Surgery (radical cervicectomy and lymphadenectomy) is complicated by presence of adhesions and abnormal anatomic relations induced by the previous hysterectomy.

RECURRENT CERVICAL CANCER  A)

Recurrence after primary surgery (more than 6 months); is treated palliatively by external beam irradiation. The aim is to control; bleeding, pain, and infection. Prognosis is poor in all conditions.  B) Recurrence after radiotherapy; Palliative surgery through pelvic exentration may be considered, in order to control pain, bleeding, and infection.

PALLIATIVE THERAPIES 

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Advanced cases of stages III and IV require special care aiming at amelioration of symptoms, control of pain, bleeding and infection. Palliative measures include: Palliative medications for pain relief, as pethidine, morphia palliative surgeries for fistulas, colostomies & ileal bladder Palliative radiotherapy presacral neurectomy and Nerve block procedures

Colposcopic image of an acetowhite lesion

Colposcopic image of an acetowhite lesion

Colposcopic image of an acetowhite lesion with abnormal vessels ( cancer)

Diagram showing mosaicism and punctation suggestive of cancer