CANCER OF THE CERVIX - DR NJOROGE WAITHAKA • They bind to and enter into cells, through small breaks.

INTRODUCTION
• Gynecological cancer are very devastating to the
affected patient, her spouse and her immediate family
• The effect is felt in the whole family and her community.
• In our community these diseases have a bigger impact
than other cancers
• Cervical cancer is the most common killer of women in
this country and most developing countries -2nd ww
• World wide 471,000 new cases are reported annually. Of
these 233,000 die of the disease
• The age standardized rate in East Africa is 44.32/100,000
women

• For maintenance of the infection, the virus has to infect

EPIDEMIOLOGY
an epithelial stem cell
• Age standardized rate in Kenya is 36.56/100,000 women
• The replication cycle is in two parts.
or 3000 new cases per year
• Annual deaths are 1524. 1. The viral genome is replicated to a copy number of
• In KNH 207 new cases were seen in 2005 and 500 cases in about 100 and maintained for varying periods of time
at this low copy number within competent
total were treated
replicating cells.
• Squamous cell carcinoma of the cervix represents 90% of
The viral proteins E1 and E2 are essential for this
the cases while10% are adenocarcinoma
basal DNA replication.
2. Once the basal cells are pushed to the suprabasal
ETIOLOGY
compartment, they lose their ability to divide and
• Human Papiloma Virus infection is now believed to be the
instead initiate the terminal differentiation
causative agent
program.
• The eight most common HPV types HPV-16, -18, -45,
• Papillomaviruses replicate in this compartment, and for
-31,-33, -52, -58, and -35,
their release into the environment, take advantage of
• These are responsible for about 90% of all cervical the natural disintegration of the epithelial cells.
cancers worldwide • E6 and E7 interact with the proteins pRB and p53, which
• HPV-Types 16 and 18 are the most commonly involved are central molecules in cell cycle control.
• Squamous Cell Carcinomas attributable to HPV-16 and -18 • Binding of E7 to pRB activates the transcription factor,
was 70% which triggers the expression of proteins necessary for
• while that for Adenocarcinoma was 86%. DNA replication.
• Other predisposing factors are • Unscheduled S-phase would normally lead to apoptosis by
o Early onset of coitus the action of p53
o Multiple sexual partners • E6 protein, which targets p53 for proteolytic degradation
o Multiparity counteracts this effect
o Uncircumcised male partner • As a consequence, the dependence on cell cycle control
o HIV infection is abolished
o Herpes simplex type 2 infection
o Oc use, smoking, vit def, low ses
o Promiscous sexual partners
o malnutrition

PATHOPHYSIOLOGY
• Human papillomavirus particles consist of 8000 base-pair
(bp) long circular DNA molecules wrapped into a protein
shell that is composed of two molecules (L1 and L2).
• The viral genome has the coding capacity for these two
proteins and at least six early proteins (E1, E2, E4–E7)
• These are necessary for the replication of the viral DNA
and for the assembly of newly produced virus particles
within the infected cells.
• The cycle is initiated when infectious particles reach the
basal layer of the epithelium.

Pathology
About 85% of cervical carcinomas are squamous cell
The remainder are composed of various types of
adenocarcinomas, subcolumnar reserve cell carcinomas, and
adenosquamous carcinomas (either double primaries or
collision tumors)
Squamous cell Carcinomas
>classified according to the predominant cell type
• large cell nonkeratinizing, best prognosis (68.3%),
• large cell keratinizing, and
• small cell carcinomas. lowest 5-year survival rate (20%).
>Classification by grade (differentiation)
Well-differentiated (grade I):
• Squamous cells demonstrate well-defined intercellular
bridges and cytoplasmic keratohyalin.
• Epithelial pearls are a common feature of this type of
tumor
• Mitotic figures are not too numerous- fewer than 2
mitoses per high-power field
• Minimal variation in the size and shape of tumor cells.
Moderately differentiated (grade II)
• This is an intermediate group.
• Varieties of all 3 patterns may be found in the same
tumor
• rendering accuracy of tumor grading on the basis of
degree of differentiation somewhat difficult.
• There are infrequent epithelial pearls
• Moderate keratinisation
• Occasional intercellular bridges
• 2-4 mitoses per high-power field
• Moderate variation in size and shape of tumor cells.
Poorly differentiated (grade III)
• Poorly differentiated cancers present nests and cords of
small, deeply stained cells barely resembling mature
squamous epithelium.
• These have scant cytoplasm surrounding hyperchromatic
nuclei and show little tendency to differentiation.
• There are no epithelial pearls,
• slight keratinisation,
• No intercellular bridges,
• More than 4 mitoses per high-power field,
• Often marked variation in size and shape of tumor cells,
• Occasional small, elongated, closely packed tumor cells,
and numerous giant cells.
 The degree of malignancy roughly parallels the grade
 The undifferentiated variety metastasizes earlier but also
responds better initially to radiation therapy.
 Vascular space involvement by tumor cells increases the
likelihood of lymph node involvement and worsens the
prognosis for survival.
 A marked lymphocytic response surrounding tumor cells,
decreases the chance of lymph node spread and is
associated with a somewhat better prognosis.
Adenocarcinoma
• Adenocarcinoma of the cervix is derived from the
glandular elements of the cervix.
• It is composed of tall, columnar secretory cells arranged
in an adenomatous pattern with scant supporting stroma
• The clear cell variety is related to in-utero exposure to
diethylstilbestrol (DES).
• A much less common adenocarcinoma is derived from the
mesonephric (wolffian) duct remnants within the cervix.
• In these, the cells are small, cuboid, and irregular and
the glandular pattern less well defined.
Secondary cancers of the cervix
• Carcinoma of the endometrium involving the cervix by
direct extension from the corpus of the uterus (stage II).
• Sarcomas
• Choriocarcinomas
• Melanomas are encountered rarely in the cervix.
Clinical Staging
• It is important to estimate the extent of the disease not
only as an aid to prognosis but also in order to plan
treatment.
• Clinical staging also affords a means of comparing
methods of therapy
CLINICAL STAGES OF CANCER OF THE CERVIX
Stage I Cancer confined to the cervix
• IA Invasive cancer detectable microscopically only
o IA1 Invasion less than 3 mm and width less than
7 mm
o IA2 Invasion more than 3 mm but less than 5 mm
• IB All others, any visible cancer
o IB1 Cervix less than 4 cm in diameter
o IB2 Cervix greater than 4 cm
Stage II Spread to adjacent structures
• IIA Spread onto the vagina
• IIB Spread laterally toward the pelvic wall
Stage III More extensive but still within the pelvis
• IIIA Extends to the lower vagina
• IIIB Extends onto the pelvic wall, obstructed ureter
Stage IV Distant spread or involvement of a pelvic organ
• IVA Involves the inside of the bladder or rectum
• IVB Distant metastases, i.e. lung, liver or bone
Clinical Findings
Symptoms
• Intermenstrual bleeding
• Bloodstained pv discharge
• Spotting
• frank bleeding
• Post coital bleeding
• Leukorrhea, usually Sanguineous or Purulent, Odorous,
Nonpruritic,
• Involuntary loss of urine or feces through the vagina
• Pelvic pain
• Weight loss,
• Anemia
signs
• Microinvasion or early stromal invasion (stage IA) causes
no symptoms (preclinical carcinoma). However, as the
local disease progresses, physical findings appear.
Infiltrative cancer produces enlargement, irregularity,
and a firm consistency to the cervix and eventually to
the adjacent parametria
• An exophytic growth generally appears as a friable,
bleeding, cauliflower like lesion.
• Ulceration is the primary manifestation of invasive
carcinoma,
• The adjacent vaginal fornices may become a nodular
thickening of the uterosacral and cardinal ligaments with
resultant loss of mobility and fixation of the cervix.
Laboratory Findings
Vaginal smear (Papanicolaou) studies
• Suspect or positive Papanicolaou smear calls for further
investigation
• 6% of cytologic smears are falsely negative
• false-negative smears are more frequent in invasive than
in intraepithelial neoplasm
Special Examinations
1. Biopsy-
• Punch biopsy of any schiller-positive areas or of any
ulcerative, granular, nodular, or papillary lesion will
confirm the diagnosis of invasive carcinoma.
• Four-quadrant biopsies of the cervix
• Scalpel conization of the cervix
2. Colposcopy
• Early invasive carcinoma in a field of cervical
intraepithelial neoplasia should be suspected when the
surface capillaries are markedly irregular, appearing as
commas, corkscrews, and spaghetti-shaped capillaries.
• Directed biopsy of these areas often will show
microscopic evidence of early stromal invasion.
• Frank invasion frequently produces ulceration
• colposcopically shows markedly irregular surface with a
waxy, yellowish surface and numerous bizarre, atypical
blood vessels.
3. Cold cone biopsy
Indications
• Severe dysplasia or carcinoma in situ
• No suspicious areas on the portio vaginalis
This is usually performed in conjunction with a D & C, after
the cone biopsy has been accomplished
Differential Diagnosis
A variety of lesions of the cervix may be confused with
cancer. Histopathologic examination is usually definitive.
• cervical ectopy,
• acute or chronic cervicitis
• condyloma acuminatum
• cervical tuberculosis
• ulceration secondary to sexually transmitted disease
(syphilis, granuloma inguinale, lymphogranuloma
venereum, chancroid)
• abortion of a cervical pregnancy
• metastatic choriocarcinoma
• rare lesions such as those of actinomycosis or
schistosomiasis.
Complications
The complications of cervical cancer, for the most part, are
those related to
• Necrosis of the tumor,
• Infection
• metastatic disease.
There are also problems pertaining to treatment of the
disease (eg, radical surgery or radiotherapy).
Treatment
General Measures:
1. Vaginal, urinary, and pelvic infections should be
eradicated before surgery or irradiation is initiated.
2. Anaemia must be corrected and nutrition improved.
3. The debilitated patient should be kept in the hospital for
supportive therapy during x-ray and radium treatment
4. If exposures are poorly tolerated, discharged patients
should be readmitted.
5. Pain may be controlled with analgesics such as aspirin
with codeine.
6. Give anti-diarrhea (e.g. Lomotil) as necessary for
diarrhea.
7. For urinary frequency and dysuria, give a bladder
sedative mixture.
Surgical Measures
1.Carcinoma in situ –
• Carcinoma in situ is best treated by complete removal of
all of the involved epithelium with an ample margin of
normal epithelium.
• The most effective measure when reproductive function
is no longer important is total hysterectomy.
• This may be accomplished either vaginally or
abdominally, with preservation of the ovaries.
• In younger women who wish to preserve the uterus, a
cone biopsy may be considered therapeutic if the
following safeguards are observed
• Careful pathologic examination of the cone specimen
must reveal an ample margin of normal columnar
epithelium at the apex and squamous epithelium at the
base of the cone.
• The patient must be cooperative and return for frequent
clinical and cytologic follow-up examinations (every 3
months for the first year and then every 6 months for a
total of 5 years).
• Cytologic examinations must remain consistently
negative for severely dysplastic or malignant cells.
• The cervical canal must not become stenosed, thus
invalidating the cytologic sampling.
IN CARCINOMA IN SITU that is localized to the ectocervix
In carefully selected patients who have been subjected to
colposcopic examination and endocervical curettage
• Cryosurgery,
• Laser beam therapy,
• Electrosurgical cauterization (LEEP)
2. Microinvasive carcinoma (STAGE 1a1)
When pathologic examination of a conization specimen
reveals
a. early stromal penetration to a depth of ≤3mm and
width ≤ 7mm
b. no confluence of tumor or vascular space
involvement,
 Treatment is simple or extended hysterectomy
 Conization should be considered therapeutic in very
carefully selected patients who strongly desire
preservation of reproductive function.
Such relatively conservative therapy is improper
a. If the margins of the specimen are not adequate,
b. If the tumor penetrates to a depth of more than
3mm, if its lateral spread is greater than 7mm , or if
tumor cells are found in vascular (lymphatic or
capillarylike) spaces
3. Invasive Carcinoma-
• There are 2 effective methods for the treatment of
invasive carcinoma:
1. Radiotherapy
2. Radical surgery.
• Radiotherapy is more widely used throughout the world
because it is applicable to all primary cervical cancers,
• Whereas radical hysterectomy is definitive only in stage I
to stage IIA lesions.
• The overall 5-year cure rates for surgery and for
radiotherapy in operable patients are approximately
equal..
• The immediate complications of radiotherapy are less
frequent and less severe.
• Irradiation may be used either as a curative or as a
palliative measure
• There are specific circumstances in which the surgical
approach to carcinoma of the cervix may be indicated or
preferred.
• Radical hysterectomy may be considered in the young
woman in whom preservation of the ovaries is important.
• Carcinoma of the cervix metastasis to the ovaries is rare
in stage I-IIA patients
• Radical surgery may be better
1. For patients who are poor candidates for
radiotherapy (e.g. chronic salpingitis, extensive
bowel adhesions from endometriosis or previous
peritonitis, diverticulitis, or ulcerative colitis)
2. For those who cannot tolerate radiation therapy
3. For those whose tumor demonstrates a poor
response to radiation.
• Finally, surgery is the only effective method of treating
cancers that persist or recur centrally following adequate
radiation therapy.
• In such instances, pelvic exenteration is often necessary
to make certain that all of the cancer has been removed
The surgical treatment of invasive cancer of the cervix
consists of one of the following:
1. Extended hysterectomy without pelvic lymph node
dissection (abdominal or vaginal);
2. Radical hysterectomy with pelvic lymph node
dissection; or
3. Pelvic exenteration – anterior, posterior, or total.
Complications of radical Surgery
• The operative mortality rate in radical hysterectomy
with pelvic lymph node dissection has been reduced to
less than 1%.
• The most common complication is fistula formation;
ureterovaginal fistula is the most frequent type (1-2%),
Followed by vesicovaginal and rectovaginal fistulas.
• Modifications in technique to preserve the blood supply
to the distal ureter and bladder and the use of prolonged
catheter drainage of the urinary bladder (6-8 weeks)
have reduced the frequency of urinary tract fistulas from
10% to less than 3%.
• Other complications are urinary tract infections,
o Lymphocysts in the retroperitoneal space
o Wound sepsis,
o Dehiscence,
o Thromboembolic disease,
o Ileus,
o Post-operative hemorrhage,
o Intestinal obstruction
Palliative Care of Cervical Cancer
• About half of patients cannot be cured of cervical cancer
and thus are candidates for management of persistent or
recurrent disease.
• The vast majority of these women would not benefit
from pelvic exenteration operations.
• Eventually they develop symptoms related principally to
the site and extent of the malignant disease.
• The expert management of the patient with incurable
cancer is an integral part of cancer therapy.
• The comfort and well-being of the patient can be
considerably enhanced even though cure cannot be
effected.
Common Problems
• Ulceration of the cervix and adjacent vagina produces a
foul-smelling discharge.
• Tissue necrosis and slough may initiate life-threatening
hemorrhage.
• If the bladder or rectum is involved in the tissue
breakdown, fistulas result in incontinence of urine and
feces..
• Pain due to involvement of the lumbosacral plexus, soft
tissues of the pelvis, or bone is frequently encountered
in advanced disease.
• Ureteral compression leading to hydronephrosis and, if
bilateral, to renal failure and uremia is a frequent
terminal event
Solutions
• A foul, purulent discharge may be ameliorated by
astringent douches (potassium permanganate, 1:4000)
and antimicrobial vaginal creams (e.g., sulfathiazole,
sulfacetamide, and benzoylsulfanilamide cream [sultrin
Cream]) and nitrofurazone suppositories.
• Necrotic ulcers may be treated with enzymatic
debridement
• Necrotic tissue may be removed by coating the normal
vaginal mucosa with petrolium and packing the ulcer
with small cotton balls wrung out in acetone and left in
place for several minutes.
• Occasionally, ulcerated areas will heal with the
administration of high-dose estrogen therapy
(diethylstilbestrol, 100 mg daily), although this may
cause some nausea
• Hemorrhage from the vagina often can be controlled by
packing the area with gauze impregnated with a
hemostatic agent.
• Embolization of the pelvic blood vessels by an
interventional radiologist often controls intractable
bleeding and may avoid the need for a major operative
procedure.
• Rarely, it may be necessary to ligate the hypogastric
arteries on both sides to control an exsanguinating
vaginal hemorrhage
• Codeine may be required when skeletal pain becomes
worse or when the pain is visceral.
• Severe pain requires the use of more potent, addicting
drugs such as morphine, hydromorphone (Dilaudid),
meperidine (Demerol), alphaprodine (Nisentil), and
levorphanol (Levo-Dromoran).
• A useful combination of drugs in terminal patients is
Schlesingerr’s solution (morphine sulphate, 3%;
ethylmorphine, 6%; and hyoscine hydrobromide, 0.02%),
5-10 drops in water every four hours.
• Tranqulizing agents, eg, chlorpromazine, often help to
alleviate fear and anxiety, and when used in conjunction
with non-addictive analgesics may reduce the need for
narcotic drugs
• Radiotherapy may be of great value in the relief of pain
due to bony metastases or in the treatment of lesions
that recur following primary surgical treatment of
cervical cancer.
• In general, if initial therapy has been accomplished by
adequate radiotherapy, re-treatment is contraindicated
since it does little good and carries the potential of
massive radiation necrosis.
• The general management of incurable cancer demands
that the physician maintain a sympathetic and
understanding relationship with the patient.
• Her nutritional status and general body functions must be
maintained.
• Anxiety, fear, and depression should be dealt with by
means of friendly counselling, reassurance, and the
discreet use of psychic energizing drugs.
Prognosis
The factors to be considered in the assessment of prognosis in
cervical cancer are the following:
1. Age of the patient,
2. General physical condition,
3. Socioeconomic status,
4. Gross features of the cancer,
5. Cytological features of the cancer,
6. Histologic characteristics of the cancer,
7. The skill of the therapist, and
8. Clinical staging (extent of the disease, lymph node
metastases).
• The more extensive the tumor, the higher the incidence
of regional lymph nodes metastases:
stage I, 15%; stage II, 30%; and stage III, 60%.
• The cure rate for stage I lesions when the nodes are
involved by tumor is about 40% of what can be achieved
if the nodes are free of cancer.
• There is evidence that this is true when radiation
treatment is given as well as when radical surgery is used
• When cancer of the cervix is untreated or fails to
respond to treatment, death occurs in 95% of patients
within 2 years of the onset of symptoms
• The cancer patient should be encouraged to continue her
normal activities as long as she can and should be given
every possible support in the effort.
• The hospice concept of patient care, which originated in
the United Kingdom, has been very useful and supportive
for these patients.

FIVE YEAR SURVIVAL RATES FOR CERVICAL CANCER

• Stage I 80%
• Stage II 65%
• Stage III 30%
• Stage IV 15%