Cervical intraepithelial neoplasia

• Cervical intraepithelial neoplasia (CIN) is a premalignant condition of the cervix. • It is usually asymptomatic and is detected by routine cytological screening.

Risk factors :
• • •

Behavioral :
Early coitarche Multiple sexual partners Male partner who has multiple sexual partners.

1. 2. 3. 4. 5. 6. 7.
• • •

Human papilloma virus (HPV) Smoking Imunosuppression Dietary deficiencies Oral contraceptive pills Poor uptake of screening programs. Indirect risk factors
High parity Low socioeconomic status Ethnicity: Black races

• The ectocervix is covered by stratified squamous epithelium. • The canal of the cervix is lined by columnar epithelium . • point where these two epithelia meet is called the squamocolumnar Junction . • It lies just at the external os, but as the cervix increases in volume during puberty and also pregnancy, the SCJ is said to roll out onto the ectocervix. • The delicate columnar epithelium exposed to the acid environment of the vagina undergoes a process of metaplasia whereby it becomes squamous epithelium.

• The transformation zone is that part of the cervix that extends from the widest part of skin that was originally columnar epithelium into the current SCJ.

 Dysplasia occurs in the stratifies squamous epithelium leading to disordered squamous epithelium.  HPV is a factor in the dysplastic changes.  Smoking and immune suppression appear to be additional factors .  Dysplastic epithelium lacks the normal maturation of cells .  Dysplasias are now usually referred to as cervical intraepithelial neoplasia (CIN).

:Dysplastic changes
• Architectural changes:
– Loss of stratification of cells – Loss of differentiation of cells

Nuclear changes:
– – – – Hyperchromasia Increase N\C ratio Anisonucleosis Presence of mitotic figures

Grades of CIN
They are graded as mild, moderate or severe, depending on:
– The degree of cytological atypia – The thickness of the epithelium involved.

 CIN I.  CIN II.  CIN III.  CIS .
CIN I is considered as ' low-grade squamous intraepithelial lesions (LSIL) ' and CIN II and III as 'high-grade SIL (HSIL)'.


• Without treatment, 30 - 50% of cases of severe cervical dysplasia may lead to invasive cancer. • Progression to cancer typically takes 15 (3 to 40) years. • Evidence suggests that cancer can occur without first detectably progressing through these stages and that a high grade intraepithelial neoplasia can occur without first existing as a lower grade.

1. Cytology - cervical smears(Pap smear):

Cont.diagnosis :
1. Cytology - cervical smears(Pap smear):

:Three components of Pap smear ).V. Posterior vaginal fornix: (by blunt end of spatula C. Exocervical (TZ) by 360o rotation of bifurcated end of spatula into .external os E. Endocervical: by mopping endocervical secretions using cotton-tipped .rod

Cont.diagnosis :
1. Cytology - cervical smears(Pap smear):
Results: • Normal (negative) smear: with no dyskaryosis at all-women having negative smears are assured and advised for annual smear later. • Abnormal (positive) smear: with variable degrees of dyskaryosis: mild, moderate or severe.

Cont.diagnosis :
• The cervix is first examined for abnormal vessel patterns • premalignant and malignant lesions of the cervix abnormal findings includes:
1-Leukoplakia: white lesions without adding acetic acid. 2-Aceto white lesions: white lesions on adding acetic acid. 3- Abnormal blood vessels: punctate,mosaicism,cork skrew,spagetti like.

2.Colposcopy Findings may be: -Normal colposcopy. -Abnormal colposcopy. -Unsatisfactory colposcopy: can't visualize T-zone.

3.Schiller's iodine test
Normal, mature squamous epithelium contains abundant glycogen that stains dark brown with iodine, and the test involves the application of Lugol's iodine solution to the ectocervix. Results: • Negative: The normal squamous epithelium will stain dark brown • Positive: Abnormal squamous epithelium will not.

4.Cervical biopsy
• • Biopsy will be taken from the most abnormal areas of the epithelium to confirm the diagnosis. Types:
1. Directed Biopsy: by Colposcopy or Schiller's test 2. Endocervical curettage (ECC): in unsatisfactory colposcopy. 3. Cone Biopsy: (Diagnostic conization).

4.Cervical biopsy Cone Biopsy:
Conization is both a diagnostic and therapeutic procedure
Indicated in:
• • • • Unsatisfactory colposcopy/+ve ECC Multifocal lesion Suspicion of microinvasion Discrepancy between Pap smear, colposcopy and biopsy.

Treatment of CIN
• CIN has the potential to be an invasive malignancy but does not have malignant properties so treatment involves completely removing the abnormal epithelium. This can be done either by an excisional technique or by destroying the abnormal epithelium.

,(:Treatment of CIN (cont
Ablative therapy is appropriate when the following conditions exist: • There is no evidence of microinvasive or invasive cancer on cytology, colposcopy, • endocervical curettage, or biopsy. • The lesion is located on the ectocervix and can be seen entirely. • There is no involvement of the endocervix with high-grade dysplasia as determined by • colposcopy and endocervical curettage.

,(:Treatment of CIN (cont
• • • • • Cryotherapy Laser Ablation Loop Electrosurgical Excision Conization Hysterectomy

:Invasive Cervical cancer
• Cervical cancer is the second most common malignancy in women worldwide. • Internationally, 500,000 new cases are diagnosed each year. • Cervical cancer is more common in Hispanic, African American, and Native American women than in white women. • Cervical cancers usually affect women 40 – 50 years old, but it may be diagnosed in any reproductive-aged woman.

Causes & Risk factors
• • • • • • • • HPV infection Lack of regular Pap tests Smoking Weakened immune system Sexual history Using birth control pills for a long time: Having many children DES (diethylstilbestrol) in utero exposure

Having an HPV infection or other risk factors does not mean that a woman will develop cervical cancer. Most women who have risk factors for cervical cancer never develop it.

Symptoms: • Clinically, the first symptom is abnormal vaginal bleeding, usually postcoital. • Vaginal discomfort, malodorous discharge, and dysuria are common. • tumor growth:
constipation, fistula, and ureteral obstruction frequency, dysuria and hematuria, leg edema, pain, and hydronephrosis, back aches Somatic pain Deeply seated pelvic pain, loin pain

• Pelviabdominal mass

• Signs:
General: Cachexia in advanced cases Ureamia if the ureter is compressed Leg edema suggests lymphatic/vascular obstruction from tumor. Abdominal: Kidneys may be enlarged if hydronephrosis occurred, Pelviabdominal mass may be felt in case of pyometria with tender uterus & high fever. • If the disease involves the liver, hepatomegaly may develop. •  • • •  •

 Vaginal:
• In patients with early-stage cervical cancer, physical examination findings can be relatively normal. • As the disease progresses, the cervix may become abnormal in appearance, with gross erosion, ulcer, or mass. These abnormalities can extend to the vagina. • Rectal examination may reveal an external mass or gross blood from tumor erosion. • Bimanual examination findings often reveal pelvic metastasis.


Tumor spread

• •

LOCAL TUMOR EXTENSION DISTANT METASTASIS: lungs, ovaries, liver, and bone are the most frequently affected organs. DIRECT IMPLANTATION into lower part of vagina or vulva may occur during operation

• Cytology - cervical smears • Colposcopy • Schiller's test
• After the diagnosis is established, a complete blood cell count and serum chemistry for renal and hepatic functions should be ordered to look for abnormalities from possible metastatic disease.

Imaging Studies
• A routine CXR should be obtained to help rule out pulmonary metastasis. • CT scan & MRI of the abdomen and pelvis is performed to look for metastasis in the liver, lymph nodes, or others • In patients with bulky primary tumor, barium enema studies can be used to evaluate extrinsic rectal compression from the cervical mass. • IV pyelography to detect ureteric obstruction or presence of non functioning kidney. • The use of positron emission tomography (PET) scan is recommended for patients with stage IB2 disease or higher • US of the abdomen and pelvis to detect local extension to adjacent organs, hepatic metastasis, & lymph node enlargement.

CT scan of a large, lobulated mass that is replacing the cervix and

MRI of stage IIb cervical cancer with anterior parametrial and anterior vaginal fornix invasion

Transverse TVUS shows a circumscribed hypoechoic tumor in the left posterior aspect of the cervix

• Preventive measures: A. Vaccination Human Papillomavirus (HPV) vaccine:

:Human Papillomavirus (HPV( vaccine
• Is a vaccine that prevents infection with certain species of human Papillomavirus associated with the development of cervical cancer, genital warts, and some less common cancers. Two HPV vaccines are currently on the market: Gardasil and Cervarix. Both vaccines protect against two of the HPV types (HPV-16 and HPV18) that can cause cervical cancer. • Both gardasil and cervarix have shown a nearly 100% efficacy in preventing development of cervical cancer for the HPV strains that they are targeted • This effect has lasted 4 years after vaccination for gardasil and more than 6 years for cervarix.

• Studies found that the HPV vaccine was safe and caused no serious side effects. The most common adverse event was injection site pain. This reaction was common but mild. • There have been reports of syncope after vaccination. Syncope after any vaccination is more common in adolescents • Guillain-Barré Syndrome (GBS)has been rarely reported after vaccination

Targeted populations
• It’s recommended for women who are 9 to 25 years old who have not been exposed to HPV • Currently the vaccine is not recommended for pregnant women. The long-term effects of the vaccine on fertility are not known, but no effects are anticipated.
• In the UK, HPV vaccines are licensed for boys aged 9–15 & they have been FDA approved for use in males age 9 to 26 for prevention of genital warts and precancerous lesions caused by HPV.

Mechanism of action
• The latest generation of preventive HPV vaccines is based on hollow virus-like particles assembled from recombinant HPV coat proteins. The vaccines target the two most common high-risk HPVs, types 16 and 18. Together, these two HPV types currently cause about 70 percent of all cervical cancer. Gardasil also targets HPV types 6 and 11, which together currently cause about 90 percent of all cases of genital warts. • Gardasil and Cervarix are designed to elicit virusneutralizing antibody responses that prevent initial infection with the HPV types represented in the vaccine.

• The vaccine should be delivered through a series of three intra-muscular injections over a six-month period. The second and third doses should be given two and six months after the first dose. • The vaccine can be administered at the same visit as other age-appropriate vaccines. • Providers should consider a 15-minute waiting period for vaccine recipients following vaccination.

,(:Preventive measures (cont
B. Screening & proper treatment of CIN
• • Cervical cancer screening recommendations have not changed for females who receive the HPV vaccine Cytological & colposcopical screening

C. Others
• • • Male circumcision Penile hygiene Use of condoms to prevent STDs

Active treatment
 The treatment of cervical cancer varies with the stage of the disease: • For early invasive cancer, surgery is the treatment of choice. • In more advanced cases, radiation combined with chemotherapy is the current standard of care. • In patients with disseminated disease, chemotherapy or radiation provides symptom palliation.

:Surgical treatment
i. • ii. • • Extended hysterectomy It's indicated in stage I A. It involves removal of the uterus – adnexa – upper vagina – parametrium & pelvic lymph nodes all in one mass. Werthiem hysterectomy (radical abdominal hysterectomy & bilateral dissection of pelvic lymph nodes) It's indicated in stages I B & II A. It involves removal of uterus – adnexa – upper vagina – parametrium - & pelvic lymph nodes all in one mass The ovaries may be preserved in young females to avoid post menopausal manifestations as they are rarely involved in cervical carcinoma Radical vaginal hysterectomy ( schuata operation ) : This operation include removal of uterus – adnexa – vagina – parametrium without removal of pelvic lymph nodes

iii. •

,(:Surgical treatment (cont
iv. • i. • Pelvic exentration (ultra radical surgery): Indicated in stage IV A. It includes: Anterior Pelvic exentration It's indicated if there is extension to urinary bladder. It consists of radical abdominal hysterectomy & removal of urinary bladder with implantation of ureters into an ileal loop Posterior pelvic exentration It's indicated in case of rectal involvement. It consists of radical abdominal hysterectomy & removal of the rectum with aterminal colostomy Total pelvic exentration It's indicated in case of spread to both rectum & urinary bladder. It It consists of radical abdominal hysterectomy & removal of both the bladder and rectum with implantation of the ureters into an ileal loop & a terminal colostomy is performed.

ii. •

iii. •

Pelvic exentration

Werthiem hysterectomy

 It's recommended in: • All stages of invasive cervical carcinoma. • Combined with surgery. • Palliative treatment.  It has a lethal effect on cancer cells as well as indirect effect through fibrosis of stroma and devascularization .  A carcinocidal dose of cervical carcinoma is about 8000 rad fractionated over a period 4-5 weeks

,(:Radiotherapy (cont
 2 methods are used to deliver that dose: • Teletherapy ( external beam whole pelvic irradiation ):
• It aims at: • Shrinkage of primary cervical tumor mass to make the subsequent intra cavitery radiation more effective • Treat pelvic lymph node involvement

,(:Radiotherapy (cont
• Brachytherapy (intra cavitary radiation ):
• Using caesium or radium deliver a lethal dose of irradiation to primary cervical tumor & adjacent parametrium. Three techniques are used: Stockholm, Paris & Manchester techniques. • The radium contained in tubes is introduced into cervical canal & uterine cavity after gentle dilatation of the cervix under anesthesia. Radium contained in ovoids is placed in the vault of vagina. The vaginal fornices are packed with gauze to keep radium containers in place.

,(:Radiotherapy (cont
 Contraindications of radiotherapy: • Radio resistant adenocarcinoma • Recurrence after irradiation • Stage IV B (distant metastasis) • Bladder or rectal involvement • Pelvic sepsis • Vaginal stenosis • Associated fibromyoma or ovarian cyst • Late pregnancy

,(:Radiotherapy (cont
Complications of radiotherapy: • Radiation sickness • Cystitis, proctitis, urinary or rectal fistula • Sepsis • Vaginal stenosis • Menopausal symptoms • Avascular necrosis & spontaneous fracture of neck of femur

:Combined surgery and radiotherapy
 i. ii. iii. iv. It aims at preventing recurrence & improving the 5 years survival rate and include using different combinations Preoperative intracavitary radium followed by a radical surgery External pelvic irradiation followed by a radical surgery, Full irradiation with intracavitary radium followed by pelvic lymphadenectomy, Radical surgery followed by post operative external pelvic irradiation for pelvic lymph nodes.

:Palliative treatment
Pain relief: • Analgesics & narcotics e.g. Pethidine or morphia • Intrathecal injection of phenol • Lateral cordotomy (cutting spinothalamic tract which is the pain pathway to higher cortical centers) • Posterior rhizotomy (cutting post. Roots of of spinal nerves to relieve somatic pain)

,(:Palliative treatment (cont
 Control bleeding:
• • • • Packing the vagina with gauze Ligation of cervical branch of uterine artery Electrocautery or cryosurgery Ligation of internal iliac artery

 Palliative radiotherapy: to deal with recurrence after surgery or to relieve pain of secondaries  Palliative chemotherapy: may be used tin advanced cases or to treat recurrence after surgical or radiological treatment or in case of secondaries

Treatment of cervical cancer In :pregnancy
 Depends on duration of pregnancy and stage of disease: • In early pregnancy: Radical hysterectomy in operable cases (stages I & II A) or radiotherapy after evacuation of uterus irrespective of stage of the disease • In late pregnancy: C-section is performed followed by: Radical hysterectomy in operable cases (stages I & II A) or radiotherapy irrespective of stage of the disease.

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