Carcinoma Of The Cervix

CARCINOMA OF THE CERVIX Carcinoma of the cervix is the commonest form of female genital cancer seen worldwide and it is the second commonest cancer in women, it is very nearly as common as breast cancer. In Europe and America, the incidence has fallen considerably due to the screening procedures adopted in the 2nd half of the last century.

AETIOLOGY AND EPIDEMIOLOGICAL FACTORS 1.

AGE: Invasive cancer has 2 distinct peaks of incidence due to rising rate in younger cohorts. These age of peak incidence have been identified at about 35years and 50-55years. There is reduced incidence after 55years. CIN occurs in much lower age group.

2.

RACE: Commoner among Africans than in caucasians. It may show familial tendencies.

3.

SOCIO-ECONOMIC

STATUS:

Low

socio-economic

status

is

associated with increased incidence of the disease. 4.

SEXUAL HISTORY:

(a) Low risk of the dx. among women of fanatical religions group – viz. Nuns, Amish, Jews and Muslims. The dx is rare among virgins. (b) High risk behaviour is associated with the following:

1

(i) Early coitache – before 20th birthday – 50% excess of cases. (ii) Early marriage (iii)Multiple childbirths (High parity). (iv)Frequent change of partners (Promiscuity and prostitution) – multiple sexual partners. No correlation between the no. of sexual acts and cervical neoplasia among women with two or less lifetime partners. (c) Male factors:

2.7 fold increased risk of developing cervical

neoplasia for a woman whose husband had previously married a woman with cervical carcinoma. Recent evidence refutes association of penile cancer and cervical cancer. A history of 15 or more partners is associated with a 7.8% increased risk of the current female partner developing cervical neoplasia (Buckley et al 1981). Several immunosuppressive agents are present in human seminal plasma. These may influence the development of cervical neoplasia by reducing the local immune response to viral infections or to cells transformed by other agents. 5. INFECTIONS: Cervical infection with the following viruses have been implicated.

2

- Human papilloma virus (HPV) types 16, 18 and 33, while types 6, 11,31, 35, 42 and 50 is associated with condylomata acuminata, low-grade CIN and only rarely in invasive tumours. - Herpes simplex hominis type II has a possible link but this has not been proven by large population study. - Human immunodeficiency virus or other causes of immunodeficiency status. 6. SMOKING: There is a strong epidemiological link between smoking and the dx. Smoking reduces the number of Langerhan’s cell present in the cervical epithelium which plays a role in local immune surveillance. - A 12.7 fold greater risk of developing carcinoma-in-situ has been found after 12years of smoking. Products of cigarette smoking – cotine and nicotine are found in higher concentrations in cervical mucus than in serum from women with CIN. Another product Nitrosamines, a chemical carcinogen has also been linked with – related cancers of the cervix. 7. CONTRACEPTION: oral contraceptive increases the risk of cancer of the cervix while diaphragm decreases the risk. PATHOLOGY The main histological types are: (i)

SQUAMOUS CELL CARCINOMA – 90-95% of all invasive Ca. 3

(a)

Large cell keratinizing.

(b)

Large cell non-keratinizing.

(c)

Small cell non-keratinizinng.

(d)

Verrucous:

a

rare

variant

of

keratinizing

squamous

carcinoma. Slow growing, progressive local invasion occurs but it rarely metastasizes to the lymphatic system. The relatively low mitotic rate in these tumours renders them rather resistant to radiotherapy. The choice of treatment therefore is surgery. (ii)

ADENOCARCINOMAS – Account for the rest (5-10%): malignant

tumours of glandular origin. Glandular type which is typically endocervical (a)

Clear cell

(b)

Adenoid cystic (basaloid cylindroma)

(c)

Adenoma malignum or minimal Deviation. Adenocarcinoma – carcinoma in which the glandular pattern is well differentiated and there is virtually no atypia of the epithelial cells.

(iii)

(d)

Endometrioid

(e)

Mucinous cells

(f)

Papillary patterns

Mixed (a)

Adeno-squamous 4

(b)

Glassy cell

There are two main types of growth (clinical cervical cancer).

1. Predominantly exophytic, growing out from the surface often as a papillary or polypoid excrescence (cauliflower or fungating growth).

2. Endophytic, infiltrating the surrounding structures. Ulceration and excavation is frequent. Clinical classification - grade or degree of differentiation may be more important. SPREAD 1.

DIRECT EXTENSION: Local spread involves the body of the uterus, upper vagina, bladder, rectum, broad ligament and the uterosacral and cardinal ligaments.

2.

LYMPHATIC SPREAD: The spread is along the line of the following nodal groups – paracervical nodes; obturator nodes; External iliac nodes; Internal iliac nodes; common iliac nodes; sacral nodes and Para-aortic nodes.

3.

HAEMATOGENOUS SPREAD: may occur, usually with poorly differentiated tumours and the higher stages. Most common sites are the lungs, liver and bones.

5

COMPLICATIONS 1.

Pyometra as a result of endocervical obstruction.

2.

Vesico-vaginal fistula may occur in advanced cases.

3.

Recto-vaginal fistula is rare.

4.

Ureteric

obstruction

with

hydroureter,

hydronephrosis

and

pyonephrosis. 5.

uraemia

6.

haemorrhage

7.

cachexia

CAUSES OF DEATH 1.

Hemorrhage

- usually painless

2.

Uraemia

- rendered unconscious and dies later.

3.

Cachexia

- associated with recurrent hemorrhage.

CLINICAL FEATURES The dx is either symptomatic or asymptomatic. Asymptomatic:

discovered accidentally through screening procedure usually at family planning clinics.

Symptomatic: (a).

Symptoms arise when the cervix ulcerates.

6

• Bleeding: irregular intermenstrual bleeding and recur in contact including post-coital bleeding. • Vaginal discharge: which may be purulent and malodorous due to secondary infection. (b) In advanced cases systemic effects are seen (i)

Cachexia

(ii)

Micturition symptoms: dysuria, increased frequency, haematuria and incontinence due to V.V.F.

(iii)

Intestinal symptoms: tenesmus and rectal bleeding.

(iv)

Pain: low backache – deep pelvic ache – sciatica; ureteric colic.

(v)

Pedal oedema.

PHYSICAL SIGNS 

Should include careful examination of the supraclavicular and vaginal lymph nodes and palpation of the abdomen for enlarged liver and kidneys.



Early cases may be seen as erosion in chronic cervicitis.



Cervical lesion seen in speculum examination may be ulcerated or furgating.

7



Bimanual examination may reveal a hard, friable, irregular, enlarged cervix which becomes fixed as the tumour spreads into the parametra.



Rectovaginal examination to assess parametrial and posterior spread.

INVESTIGATIONS (PRE-RX EVALUATION) FBC, serum E/U/Cr, serum calcium and uric acid, LFT, IVU, CXR and ECG (all those with stage 1b disease or worse, should have a CXR and IVU to exclude distant metastasis, and complete the staging process by looking for obstructive uropathy). Group and cross match 4 units of blood. A smear (Pap) may be taken from the cervix for cytology and a punch biopsy performed if there is an obvious lesion (smear or superficial biopsy may be negative in the presence of invasive disease).

EXAMINATION UNDER ANAESTHESIA Ideally this should be done jointly by the gynaecologist and radiotherapist. Rectovaginal examination is repeated to stage the tumour clinically. If there is suspicion of rectal spread proctoscopy and sigmoidoscopy are performed. 8

Cystoscopy is also performed if the dx appears locally advanced. Histological confirmation of the diagnosis is essential often parts of the exophytic tumour detach easily from the cervix, but if an adequate sample cannot be obtained in this way a wedge or cone biopsy should be obtained with a scalpel rather than using a small punch biopsy. Length of the uterine cavity is measured and Curettings taken from the endocervix and the endometrical cavity.

OTHER INVESTIGATIONS:

but do not alter the FIGO staging.

(i)

helps in planning radiotherapy and may be

Lymphangiography:

used in monitoring the completeness of lymphadenectomy. (ii) & (iii)

CT and Abdomino-pelvic USS – may be used to estimate size

and extent of the primary tumour and to detect nodal dx. Neither is sufficiently accurate to merit use. (iv)

MRI: best imaging method; especially when an endovaginal receives coil is used. -

Although it gives reliable information about the primary tumour, MRI is unable to identify small deposits in lymph nodes.

PROGNOSTIC FACTORS 9

1.

CLINICAL FACTORS (a)

Age: in young patients the dx tends to be less aggressive as it is usually grossly differentiated.

(b)

Stage: This is related to distant spread.

(c)

Tumour: Size or volume.

(d)

Gross Tumour Configuration: Exophytic, endophytic in barrel-shaped form.

2.

HISTOPATHOLOGY (a)

Tumour grade: does not affect clinical staging.

(b)

Lymph or vascular space involvement.

(c)

Depth of tumour invasion.

(d)

Regional node metastases. Stage 1A1 0-0.5% Stage 1A2 – 1-2% Stage 1B – 12-20% Stage 2B – 16-36% Stage 3 > 35% Stage 4> 50%

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STAGING OF CARCINOMA OF THE CERVIX UTERI (FIGO 1995)

STAGE Stage 0 Stage 1

DEFINITION Carcinoma is Situ, intraepithelial carcinoma Cervical carcinoma confined to the cervix extension to the corpus

,,1A

should be disregarded. Invasive Ca. diagnosed microscopically only. All gross lesions even with superficial invasion is regarded as 1B. Invasion is limited to measured stromal invasion with maximum

,, 1A1

depth of 5mm and maximum width 7mm. Minimally microscopically evident stromal invasion. Measured stromal invasion with maximum depth of 3mm and

,, 1A2

maximum width of 7mm. Measured stromal invasion with depth from 3-5mm and maximum

,, 1B

width of 7mm. Clinical lesions confined to the cervix or preclinical lesions greater

,, 1B1 ,, 1B2 Stage II

than stage 1A. Clinical lesions less than or equal to 4cm in size. Obvious lesions greater than 4cm in size. Cx Ca. invades beyond the uterus but not to the pelvic sidewall or

,, IIA ,, IIB

to the lower third of vagina. No obvious parametrical invasion (upper 2/3rd of **** be involved). Obvious parametrical invasion.

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Stage III

Extends to the pelvic wall or involves the lower third of the vagina

IIIA

or causes hydronephrosis or non-functioning kidney. Tumour extends to the lower third of the vagina but not the pelvic

IIIB

sidewall. Tumour extends to the pelvic sidewall or causes hydrophrosis in

Stage IV

non-functioning kidney. Carcinoma extends beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum. A bullons oedema

,, IVA ,, IVB

as such does not permit the growth to be attached to stage IV. Spread of the growth to adjacent organs rectum and bladder. Spread of the growth to distant organs.

TREATMENT (a)

Primary Surgery

(b)

Primary Radiotherapy

(c)

A combination of radiotherapy and surgery does not increase survival but it may reduce the incidence of therapy failure.

(d)

Adjust Chemotherapy

The treatment by stages is as follows: 1.

Stage 1A1:  Cervical conisation

 Hysterectomy: vaginal or abdominal.

12

2.

Stage 1A2: Extended (Class II) abdominal hysterectomy with bilateral pelvic node dissection.

3.

Stage1B1 and IIA: Extended (Class III) abdominal hysterectomy with bilateral pelvic lymphadenectomy. A high-risk patient may have pelvic radiation in addition to surgery.

4.

Barrel shaped lesions: Full external and intracavitary pelvic radiation followed after 6weeks by para-aortic node biopsy.

5.

Stage 1B2, 2B, 3A, 3B, 4A and 4B. Full extended and intracavitary pelvic irradiation is given except when there is fistular formation.

HYSTERECTOMY FOR MALIGNANT DISEASE The hysterectomies done for cervical cancer is divided into 5 different classes according to Pivers – Rutledge classification (Pivers 1974). 1.

Class 1: simple radical hysterectomy also termed extra-fascial hysterectomy The entire uterus (corpus and cervix) is removed without including paracervical tissues. The main indication is for the Rx microinvasive cervical carcinoma with stromal invasion of < 3mm and no evidence of lymph-vascular space involvement (stage 1A1).

2.

Class II:

This is termed modified radical hysterectomy or Te

Linde’s hysterectomy. The operation removes more paracervical 13

tissues as well as pelvic and para-aortic lymphadenectomy – medial half of both cardinal and uterosacral ligaments are removed with the uterus, as well as a portion of the vagina, the uterine artery is ligated just medial to the ureter, allowing preservation of the blood supply that the ureters receives from the proximal uterine artery. The main indication is stage 1A2 carcinoma of the cervix – microinvasive cancer with depth of invasion > 3mm but < 5mm, with areas of lymph-vascular space involvement. 3.

Class III: Wertheim’s

This is extended radical hysterectomy or meigs – operation

–

it

involves

pelvic

and

para-aortic

lymphadenectomy, total abdominal hysterectomy, bilateral salpingooophorectomy (BSO not done for young patients), removal of the upper third to half of vagina, ligation of the uterine arteries at their origin at the anterior division of the internal iliac artery and wide excision of the paracervical and paravaginal tissues – the uterosacral and cardinal ligaments are transected from sacrum and pelvic side wall respectively. This is usually done for stages 1B1 or 2A disease. The superior vesical artery is preserved to maintain blood supply to the distal ureter. This is the commonest mode of surgery for operable carcinoma of the cervix. 4.

Class IV and V:

These are ultra-radical hysterectomy. 14

 Class IV – the ureters are completely dissected from their beds and the superior vesical arteries are transected.

 Class V – involves resection of the distal ureter or portion of the bladder or both. With re-implantation of the ureter into the bladder or urinary diversion to an ileal bladder. The ultraradical TAH is done for small central recurrence after radiotherapy. OTHERS:

 Radical trachylectomy removes the Cervix and paracervical tissues but conserves the uterus for future fertility.

 pelvic exenteration – could be anterior or posterior. Bowel preparation: by giving mild aperients and small enema to ensure that the pelvis is not filled with distended loops of bowel – clean the bowel of faecal matter. This help to make the patients first few post-operative days more comfortable. - Cross-match 4 units of blood: may be needed. - Prophylactic antibiotics:single dose – reduces risk infection. - Mini-heparin prophylasix for those at risk of DVT eg. obese and elderly – 5,000 i.u tid. - Some patients may benefit from pre-operative physiotherapy particularly smokers.

15

- Epidural anaesthetic is a valuable adjunct to the G.A; reducing blood loss and causing some constriction of the bowel, which thus occupies less of the operative field. It also enhances post-operative analgesia.

COMPLICATIONS OF SURGERY 1. Anaesthetic complications 2. Local –Bleeding – intra-operative and post-operative. - Damage to the bladder, ureters, rectum and blood vessels. 3. Bladder injury:

4.

5.

(i)

Fistula

(ii)

Neurogenic dysfunction

Ureters: (i)

Hydro-ureter

(ii)

Hydro-nephrosis which may resolve in 6weeks.

(iii)

Stenosis

(iv)

Fistula

(v)

Sheath damage.

Retroperitoneal space: (a)

Haematoma

(b)

Lymphocyst formation

(c)

Infection 16

(d)

Thrombosis – DVT Q pulminary evaluation

(e)

neurogenic damage and neuropathies – femoral, obturator, perennial sciatic

(f)

Rectum – partial denervation with acute or chromic rectal dystunction.

POST OPERATIVE CARE

-

Monitor vital signs (i.e. Temp, blood press, pulse and resp

rate). -

I.V fluids for 1-2 days

-

Anaelgesics – Pethidire 100 – 150mg 4hourly

-

Antibiotic course

-

urinary catheter drainage for 10–14 days, or retain till bladder sensation occurs. Culture urine when catheter is removed.

-

Urinary output should exceed 30 ml/hr

Follow-up

17

-

To evaluate results, provide reassurance and to give symptomatic relief to those whose treatment has failed.

-

Pt is seen 2 months after discharge, then monthly visits for 1-2 year and then 3-4 months visits for 3rd and 4th years. Thereafter visits could be for every 6 -12months

-

At each visit do general examination, including looking out for nodes, do speculum exam also take pap smear from region of vault for cytology.

-

Central recurrence after radiothereapy is treaded by pelvic exenteration (a)

Anterior exenteration – removal of the urinary bladder with diversion of the urine through an ileal loop or a continent pouch.

(b)

posterior exenteration – removal of the rectum, with a colostomy.

(c)

Total exanteration – both (a) and (b) urines treated

As for anterior and separate colostomy is done. A wet colostomy is avoided

RADIOTHERAPY

18

-

Involves application of cesium – 137 to treat the local dx (brachytherapy) and the application of external beam radiation (teletherapy) in the pelvic sidewall. This is necessary because of the rapid fall off of the radiation energy with distance (the inverse square law).

-

Two important points are considered on radiation therapy. Point A is 2cm lateral to the external cervical os and 2cm above the lateral fornices. This point is considered to lie in the paracervical region, a landmark for where the uterine artery crosses over the ureter

Point B- is 5cm lateral to the cervical canal and 2cm above the internal cervical Os. It represents the location of the obturator nodes on the lateral pelvic wall. Doses of irradiation to point B is roughly about one third of the dose to point A. owing to the rapid fall of irradiation with intracavitary insertions. Teletherapy is normally given first, especially in large tumours and the apparatus used is the linear accelerator and occasionally cobalt.

19

In Brachytherapy – In Manchester system, 6600 - 7600cGy were prescribed to point A in two treatments, each lasting 70 hrs, 4-7 days apart. If it is to be used alone a dose of 800cgy is given to point A in 3 insertions with an interval of I week b/w each insertion.

Following External Beam Therapy (EBT) a dose of 2000-2500cgry is given to point A as a single insertion. For EBT the dose to the rectum should not exceed 6000 cGy

Complications: -

Radiation dermatitis

-

Entero – colitis with mucoid diarrhoea

-

Radiation menopanse

-

Vaginal stenosis – with difficulty such as dysparennia and

apareunia -

Urinary fistulae

-

Faecal fistulae

-

Intestinal obstruction

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ADVANTAGES OF PRIMARY SURGICAL Rx OVER PRIMARY RADIATION Rx

-

It is possible to conserve the ovaries in young patients.

-

Psychologically the pt knows that the whole disease has been removed so he feels satisfied, unlike with radiotherapy where he feel that the dx was only burnt or roasted.

-

Infection is not a contraindication for surgery, but it is for radiotherapy

-

After surgery the tumour is available for histological examination and prognostication, follow-up examination is also easier.

-

If there is recurrence after surgery radiotherapy could be used

-

The vagina maintains its capacity for coitus after surgery post radiation fistula formation and other complications of radiation

are not experienced with surgery.

CHEMOTHERAPY

21

-

Surgery

is

the

only

modalities

that

can

cure

but

chemotherapy can cause tumour regression. -

Single agents that have significant response are Cisplatin, Bleomycin and methotrexate

-

can be combined and cisplatin combinations appear to have the best response.

-

Conbination of neoadjuvant chemotherapy and radiotherapy has not resulted on improved survival, but combination of chemotherapy with surgery has given some encouraging results but no randomized trials yet.

CARCINOMA OF THE CERVICAL STUMP -

EBT should be used to obtain maximum satisfactory dose, a medium caesium tube should be inserted, if not possible the EBT dose should be increased.

CARCINOMA AFTER SIMPLE HYSTERECTOMY

-

The mx and prognosis depended on the stage of dx before operation.

22

-

Radical

hysterectomy,

lymphadenectomy

or

upper

vaginectomy

alternatively

pelvic

and

pelvic

irradiation

–

4500CGY in 5 weeks CARCINOMA OF THE CERVIX DURING PREGNANCY -

Mx will depend on the stage of carcinoma of the cervix at diagnosis, the gestational age and the wishes and beliefs of the patient and her partner

-

When fetal survival is desired delivery should be delayed until the fetus is mature rather than just potentially viable.

-

The prognosis of the disease does not seem to be affected adversely by the pregnancy in women with early stage dx (Vender venge et al 1995)

HAEMORRHAGE -

Bed rest and vaginal packing may arrest the haemorrhage

-

If not successful – intracavitary 2000cGy to point A

RECURRENCE AFTER RADIOTHERAPY

-

Should be assessed jointly with a gynaecological oncologist

to ensure that the possibility of surgical salvage is not overlooked. 23