CIN &CANCER CERVIX

DR Manal Behery 2014

Introduction

– Exocervix – stratified squamous epithelium

● Basal, parabasal, intermediate and superficial layers

– Endocervix – cylindrical epithelium,

– arranged in branching folds– Squamocolumnar junction

Squamocolumnar junction

– Embryogenesis – upward migration of squamous epi from vaginal plate replacing mullerian epi.

– Location of SCJ – varies with age & hormonal status

● Everts outwards during adolescence, pregnancy & OCP use● Regresses into endocervix with menopause, low estrogen

states

Transformation zone

– Adjacent to SCJ – Most active zone of – squamous metaplasia –– prone to carcinogenic effects

Most active zone of squamous metaplasia

Dysplasia

*Lack of normal maturation of cell as they move from basal layer to superficial layer

*Large nuclei more variable in size &shape

*more actively dividing nuclei.

Dysplasia are now referred to as cervical intraepithelial neoplasia ( CIN)

Precursor lesions for cervical cancer

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History of the Conventional Pap Smear

• Developed by Dr. George N. Papanicolaou in 1940’s

• Most common cancer screening test

• Key part of annual gynecologic examination

Ferris et al. Modern Colposcopy. 2004: 2-4, 49.Photo accessed from http://www.cytology-iac.org/Cytopaths/1998/cytoFall98.htm

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Screening with the Conventional Pap Smear

• Widely available

• Inexpensive

• But not perfect– Screening test – not diagnostic– 7-10% of women need further evaluation– Low sensitivity – need regular repeats

Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27.

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New Liquid Pap Tests

• More accurate test– Thin, uniform layer of cells

– Screening errors reduced by half

• Screening needed less often• Can test for HPV with same

specimen if abnormal cells found

• Expensive

Linder J. et al. Arch Pathol Lab Med. 1998; 122: 139-144.

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Cervical Cancer Screening Guidelines

• First screen 3 years after first intercourse or by age 21

• Screen annually with regular Paps or every 2 years with liquid-based tests

• After three normal tests, can go to every three years

• Stop at 65-70 years with history of negative tests

Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27.

Squamo-Columnar Junction

• Junction of pink cervical skin and red endocervical canal

• Inherently unstable • Key portion of the cervix to

sample• Most likely site of dysplasia

Ayers Spatula

• Concave end to fit the cervix

• Convex end for vaginal wall and vaginal pool scrapings

•Use concave end •Rotate 360 degrees•Don’t use too much force (bleeding, pain)•Don’t use too little force (inadequate sample)

Cytobrush

• Insert ~ 2 cm (until brush is fully inside canal)

• Rotate only 180 degrees (otherwise will cause bleeding)

Percusion before a Pap Smear

– Avoid menstruation

– Abstain from intercourse, douching, use of vaginal tampons, or contraceptive creams for min of 24-48 hrs

– Avoid touching the cervix before Pap smear

– Discharge from cervix may be removed with a swab without touching the cervix

PAP Smear Classification

● The Class System (I to IV)

● The CIN System – Based on degree of cellular abnormalities

● The Bethesda System

Bethesda (2001) reporting of Pap Smear:

– Specimen type – conventional, LBC

– Specimen adequacy – satisfactory, unsatisfactory

– General Categorisation:

● Negative for intra-epithelial lesion● Epithelial cell abnormality● Glandular cell abnormality

COLPOSCOPY

In office Colposcopy done after an abnormal pap smear result

Vinegar solution is applied to cervix, abnormal tissue will turn white in color ACETOWHITE ARES

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Fig. 6 Punctation seen with carcinoma-insituand microinvasion.

Fig. 8 Loop diathermy apparatus

Guidelines for colposcopy

– Negative for intraepithelial abnormality – routine cytological screening

– ASC-H, LSIL, HSIL – colposcopy and biopsy

– AGC – colposcopy, endocervical and endometrial evaluation

– AIS – excision biopsy

Risk factors

– HPV Infection– Cigarette smoking– Parity– Oral Contraceptive use– Early sexual activity, Multiple partners– STDs– Chronic Immunosuppression

JA Kahn, NEJM, 2009;361:271

The HPV Life Cycle

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Natural history of HPV infection to Cervical cancer

0–1yrs 0–5yrs

Cervical Cervical CancerCancer

Persistent infection

Low GradePrecancers

(CIN 1)

1–20yrs

HPV infection

High Grade

Precancers (CIN 2/3)

Pinto AP, Crum CP. Clin Obstet Gynecol. 2000;43:352–362.

Recovery: HPV clearance…90%

• The vaccine only worked in women and

girls who were not already infected with

HPV.

• Gardasil (2006) or Cervarix (2009) are

routinely given to 11- and 12-year-old girls,

and allowed for girls as young as 9.

HVP vaccination

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GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.*VLP = Virus-like particle. 1. Villa LL, Costa RL, Petta CA, et al. Lancet Oncol. 2005;6:271–278.

HPV Vaccine technology

Image courtesy of Dr. Ian Frazer

Real Real ViruViru

ssVacciVacci

nene

– Empty Shell formed by recombinant biotechnology to mimic the viral 3D shape.

– Does not contain infectious DNA。

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Dosing schedule

GARDASIL Intramuscular injection (IM)

Recommended schedule

3 doses at month 0,2,6

CERVARIX Vaccine: 3 doses at month 0,1,6

month

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To prevent vaccine type related

Female: Cervical 、 vaginal 、 vulvar Cancers and genital warts

Male:

+

4-in-1 HPV vaccination Regular Pap screening

HPV vaccine is for men and women

LEEP VS Conization

Cervical carcinoma

Understanding Cancer

• Normally, cells grow and divide to form

new cells as the body needs them. When

cells grow old, they die, and new cells take

their place.

Understanding Cancer

• Sometimes, this orderly process goes wrong.

New cells form when the body does not need

them, and old cells do not die when they

should. These extra cells can form a mass of

tissue called a growth or tumor.

Background• Worldwide, cervical cancer is the 2nd leading

cause of cancer death in women

• Squamous cell carcinoma (85%)

• Adenocarcinoma (15%)

• Risk factors for squamous cell cancer– Early coitarche– Greater than 6-8 partners– Cigarette smoking– Oral contraceptives

• Cervical cancer is most strongly associated with sexually transmitted HPV infection

• During the sexual lifespan of a woman, approximately 70% will have been exposed to HPV

• HPV subtypes are classified into high and low risk groups

Clinical Picture

● Asymptomatic● Vaginal Bleeding

– Post coital– Intermenstrual spotting– Irregular or Postmenopausal bleeding

● Discharge P/V● Pain referred to flanks● Dysuria, hematuria, rectal bleeding● Massive Haemorrhage, uraemia

Diagnosis

1- History.• Many women are a symptomatic .• Presented with abnormal routine cx smear• Complain of abnormal vaginal bleeding• I M bleeding• post coital bleeding• perimenopausal bleeding• postmenopausal bleeding• blood stain vaginal discharge

2- Examination:

• PV exam using cuscu’s speculem

• nothing is found in early stage .

• Mass ,ulcerating fungating in the cervix

• P/V P/R is very helpful.

Investigations

● Physical Examination– Lymph node examination– Per Vaginum – Bimanual rectovaginal examination

● Radiology Colposcopy – IVP CX biopsy– Barium Enema– X Ray Chest– Skeletal X Ray

Cervical Biopsy

– Punch biopsy

– LEEP● Outpatient procedure● Diagnosis and therapy at same time● Main side effect – secondary haemorrhage

Conization

– Cold knife– Laser– If cut margins free from cancer, then almost 100%

disease free follow-up

CT and MRI

– Evaluation of lymphnodes, liver, urinary tract and bony structures

– Can detect only changes in size of nodes, < 1cm considered as positive

Patterns of spread

• Direct invasion cervical stroma, vagina, and parametrium.

• Lymphatic spread pelvic and then par aortic lymph nodes

• Hematogenous spread such as lungs, liver, and bone

Lymphatic Spread

– Primary Group● Parametrial nodes● Paracervical/ureteral nodes● Obturator nodes● Hypogastric nodes● External iliac nodes● Sacral nodes

– Secondary Group● Common Iliac nodes● Inguinal nodes (deep and superficial)● Periaortic nodes

Cervical carcinoma staging

• Staging is clinical

• FIGO staging

• Based on EUA, cystoscopy +/- sigmoidoscopy

• Does NOT include MRI

FIGO Staging (2009)

● Stage I – carcinoma confined to cervix– IA: invasive carcinoma diagnosed microscopically.

Stromal invasion depth upto 5 mm and width less than 7 mm

● IA1 – stromal invasion <3mm depth and <7mm width● IA2 – stromal invasion 3-5 mm and <7mm width

– IB: clinically visible lesion confined to the cervix● IB1 – lesion <4 cm or less● IB2 – lesion >4 cm

Stage II – carcinoma invading beyond uterus but not to pelvic wall or lower 1/3 of vagina

– IIA – Tumour without parametrial invasion● IIA1 – lesion < 4 cm● IIA2 – lesion > 4 cm

– IIB – Tumour with parametrial invasion

Stage III – tumour extending to lateral pelvic wall/lower third of vagina

● causing hydronephrosis or non-functioning kidney– IIIA – Tumour involves lower 1/3 of vagina, no

extension to pelvic wall– IIIB – Tumour extends to pelvic wall or causing

hydronephrosis/non-functioning kidney

Stage IV

Widespread introduction of the Pap begins

Conventional Pap smear LBC

1949 1996 2000’s

HPV testing Vaccine

Cervical cancer prevention: Where have we been and where are we going?

Markers

The choice of treatment will depend on

• Fitness of the patients

• Age of the patients

• Stage of disease.

• Type of lesion

• Experience and the resources available.

Therapy

Cervical conization

Simple hysterectomy

Radical hysterectomy

Radiation therapy with chemosensitization

Stage 1 disease

• Treatment = LLETZ

• Conization

Stage 1 disease

• Confined to cervix• Treatment • = surgical for 1B1

• Chemo Radiotherapy for 1B2

Surgical procedure

• The classic surgical procedure is the wertheim’s hystrectomy for stage Ib,IIa, and some cases of IIb in young and fat patient

Werthemeim’s hystrectomy• Total abdominal hystrectomy including the

parametrium.• Pelvic lymphadenectomy• 3 cm vaginal cuff• The original operation conserved the

ovaries ,since squamouss cell carcinoma does not spread dirctly to the ovaries.

• Oophorectomy should be performed in cases of adenocarcinoma as there is 5-10% of ovarian metastosis

5 year Survival

• Stage I 70%

• Stage II 51%

• Stage III 33%

• Stage IV 17%

COMPLICATIONS OF SURGERY

• Haemorrhage: primary or secondary.

• Injury to the bladder, uerters.

• Bladder dysfunction.

• Fistula.

• Lymphocele.

• Shortening of the vagina.

Lymphedema

Radiation therapy

Radiation Therapy

External BeamWhole pelvis or para-aortic window

4000-6000 cGyOver 4-5 weeks

BrachytherapyIntracavitary or interstitial

2000-3000 cGyOver 2 implants

Pros and Cons

Surgery

Bladder dysfunctionVesico/uretero fistulaBowel obstruction

Ovarian preservationVaginal preservation

Radiation

SigmoiditisRectovaginal fistulaBowel obstructionVesico/uretero fistula

Ovarian failure

Staging and treatment

• Surgical in women up to stage 1b1

• Chemotherapy

• (cisplatin) ± radiotherapy

• with disease > stage 1b1