PRE-MALIGNANT & MALIGNANT DISEASES of the CERVIX

Jose B. Moran, MDAssistant Professor IIIDepartment of Obstetrics and GynecologySection of Gynecologic OncologySt. Luke’s College of Medicine-W.H. Quasha Memorial

Highlights of the discussion:∏Brief review of cervical anatomy§ formation of the transformation zone§ histology of the cervical epithelium

∏Epidemiology § role of HPV infection§ risk factors

∏Screening and the role of Pap smear§ present recommendations

Highlights of discussion:∏Premalignant lesions§ symptoms & classification§ diagnosis & treatment

∏Malignant/Invasive lesions§ symptoms§ diagnosis and staging classification§ treatment and its complications§ prognostic factors & follow-up

∏Preventive measures: Gardasil, Cervarix

VAGINA

UTERUS

REVIEW OF CERVICAL ANATOMY

ENDOCERVICAL GLANDS

SQUAMOUS EPITHELIUM

OSCJ

SQUAMOUS EPITHELIUM

OSCJ

COLUMNAREPITHELIUM

OSCJ

COLUMNAR EPITHELIUM

SQUAMOUS EPITHELIUM

CERVICAL EVERSION(ECTROPION)

OSCJ

COLUMNAREPITHELIUM

NSCJ

TRANSFORMATION ZONE

SCCA:80-90%

Adenocarcinoma:10-20%

TRANSFORMATION ZONE

SQUAMOUS EPITHELIUM

BASEMENT MEMBRANE

GLANDULAR EPITHELIUM

STROMA

EPIDEMIOLOGY∏most common gynecologic cancer in developing countries.

∏third most common gynecologic

cancer in developed countries.

∏400,000 women affected: third most common cancer in women worldwide

∏Affects women 44-55 years old.

∏current trend towards the younger age group being affected.

∏Runs an indolent course starting on thesurface layer of the cervix.

EPIDEMIOLOGY

∏A pre-cancerous phase (dysplasia, CIN) may gradually progress into cancer.

∏Dysplasia is 100% curable, often withoutthe need for hysterectomy.

∏Cervical cancer is preventable!!!

EPIDEMIOLOGY

SCREENING: The Pap smear

∏based on the concept that cervical cancer is the endpoint of a continuum

∏The whole spectrum may be found within one cervix.

SCREENING: The Pap smear

CIN 1

CIN 2

CIN 3

MICA

InvasiveCA

GLANDULAREPITHELIUM

STROMABASEMENT MEMBRANE

SQUAMOUSEPITHELIUM

TRANSFORMATION ZONE

SCREENING: The Pap smear

GRADE TRANSIT TIME PROGRESSION

CIN 1-2 7 yrs to CIS 50%

CIN 3

MICA

7-10 yrs to MICA 66%

100%2 yrs to invasive CA

SCREENING: The Pap smear

∏Simple, painless screening test

∏Sample exfoliation taken from the transformation zone

∏It is the most powerful tool in a woman’s arsenal to prevent cervical cancer.§ cost-effective§ high specificity§ high sensitivity

SCREENING: The Pap smear∏If every woman would submit herself to it annually, the incidence would dramatically drop or would nearly be eliminated.

∏At what age do you start?

SCREENING: The Pap smear∏Recommendations of the ACOG:

Mۀ starts when a woman become sexually active or reach the age of 18 years

Mۀ done annually but less frequently after 2-3negative smears, if low risk

Mۀ should be done no less than annually for those considered at risk

∏Who are considered at risk?

ETIOLOGY∏Undoubtedly related to HPV

p53

Rb

E6E7

VIRUS HOST

§ HPV subtypes 16, 18, 31, 33, 35, 45, 51, 58, 59, 68

E6

E7

ETIOLOGY∏Common Risk FactorsMۀ young age at coitarcheMۀ multiple sexual partnersMۀ sex with high-risk malesMۀ history of sexually-transmitted diseasesMۀ smokingMۀ low socio-economic statusMۀ immunodeficient states•whole-organ transplantation•Hodgkin’s disease•HIV-AIDS

SCREENING: The Pap smear

∏Your role as responsible healthcare givers

is not only to diagnose and treat diseases

but more importantly to prevent it by

proper EDUCATION!

SIGNS & SYMPTOMS∏Early symptoms:

Mۀ vaginal dischargeMۀ unexpected coital bleedingMۀ abnormal vaginal bleeding

∏Late symptoms:

Mۀ pain in the pelvic areaMۀ unpleasant vaginal dischargeMۀ heavy vaginal bleedingMۀ pedal edema/uremia

DIAGNOSIS∏Abnormal Pap result without a gross lesion need colposcopic evaluation.

∏Gross cervical lesions should undergosimple cervical biopsy of the tumor.

colposcopy

biopsy

SCREENING: Colposcopy

biopsy tip

SCREENING: Colposcopy

SCREENING: Colposcopy

DIAGNOSIS: Guidelines

∏Patients with colposcopically identified abnormal epithelium should undergo biopsy and endocervical curettage.

∏A conization or loop electrosurgical excisionis sometimes needed for a more accurate diagnosis.

∏Abnormal Pap result without a gross lesion need colposcopic evaluation.

∏Gross cervical lesions should undergosimple cervical biopsy of the tumor.

DIAGNOSIS: Conization∏The premise is that:

Mۀ conclusive microscopic diagnosis cannot be made based on the tissue submitted.

Mۀ the tissue previously submitted has alarming features of a possible more serious disease.

∏The purpose is to obtain adequate amount of tissue for conclusive microscopic diagnosis.

DIAGNOSIS: Conization∏Indications for conization or LEEP:

Mۀ colposcopically directed biopsy does not adequately explain abnormal cells on Pap.

Mۀ atypical epithelium extends into the endocervical canal (unsatisfactory colposcopy)

Mۀ abnormal cytologic findings with no visible colposcopic lesion

DIAGNOSIS: Conization∏Indications for conization or LEEP:

Mۀ MICA found on directed biopsy

Mۀ endocervical curettings showing intraepithelial neoplasia

DIAGNOSIS: Conization

DIAGNOSIS: Conization

GLANDULAREPITHELIUM

STROMA

SQUAMOUSEPITHELIUM

TRANSFORMATION ZONE

BASEMENT MEMBRANE

HISTOLOGIC TYPES

∏Squamous cell carcinomaMۀ large cell type§ keratinizing § non-keratinizingMۀ small cell type

∏Adenocarcinoma Mۀ endometrioid typeMۀ clear cell typeMۀ verrucousMۀ adenosquamous

STAGING

∏Primarily done by palpation & inspectionof the cervix, vagina, parametrium andpelvic side walls

Mۀ extrapelvic areas such as supraclavicular nodes

∏Extent of the disease should be determined:

Mۀ chest X-ray

Mۀ cystoscopy

Mۀ sigmoidoscopy

Mۀ bone survey

STAGING

∏Newer imaging technology may be useful to determine the extent of the disease and assist in treatment planning, but they are not considered by FIGO as tools for staging:

Mۀ lymphangiography

Mۀ computerized tomography (CT scan)

Mۀ magnetic resonance imaging (MRI)

STAGING: FIGO classification (1998)

∏Stage 0Mۀ carcinoma-in-situ∏Stage I: tumor confined to the cervix.

Extension to the corpus is disregarded. Mۀ Stage Ia: MICA*1

§ Ia1: minimal microscopically evident stromal invasion.§ Ia2: depth of invasion <3mm plushorizontal spread < 7mm

*conization is ideally required1lymphvascular space involvement should be indicated but does not change the stage

STAGING: FIGO classification (1998)

Ib1 Ib2

> Ia2< 4cm

> 4cmStage I

STAGING: FIGO classification (1998)

IIa IIb

Stage II

STAGING: FIGO classification (1998)

IIIa IIIb

Stage III*

*All cases with hydronephrosis or non-functioning kidney are included unless they are known to be due to other causes.

STAGING: FIGO classification (1998)

∏Stage IV: tumor has extended beyond the true pelvis or has clinically involved the bladder* or rectum.(*bullous edema is not assigned Stage IV)

Mۀ Stage IVa: spread to adjacent organs

Mۀ Stage IVb: spread to distant organs

TREATMENT∏Destructive methods for CIN lesions:

Mۀ electrocautery Mۀ cryosurgeryMۀ CO2 laser vaporization

Mۀ LEEP

TREATMENT

∏Criteria for destructive methods:

Mۀ colposcopy is satisfactoryMۀ endocervix is free Mۀ conization is not indicatedMۀ invasive cancer is ruled outMۀ cytologic, colposcopic, and histologic evaluations correlate

TREATMENT∏Surgery: Radical hysterectomyMۀ good candidates: young, healthy Mۀ allowable for up to stage IIa onlyMۀ small lesions (less than 4 cm) Mۀ advantage over radiation: assessment, sexual function preservation

∏Radiotherapy

Mۀ can be used for all stages Mۀ It is the treatment of choice in an ideal setting

TREATMENT∏Chemotherapy:

Mۀ adjuvant

Mۀ neoadjuvant

Mۀ concurrent

Mۀ indications

Mۀ current trends

TREATMENTAbnormal Pap smear

Colposcopicevaluation

NOYESRepeat

Pap smear

Destructive Methods• Chemical cautery• Electrocautery • Cryotherapy• Diathermy/LEEP • Vaporization

Fertilitypreservation

desired

YES

NO

• CIN I• CIN II• CIN III

TAH

• Normal

Conization MICA

Findingssignificant

• MICA

Biopsy & ECC

• Margins clear• No lymph vascular space involvement• Follow-up assured• Completion surgery later • Complications:-bleeding (2 wks)-stenosis (6 mos)

Invasive CA

CHEMOTHERAPY

TREATMENT

Major advantage:• applicable for all stages

Major advantage:• preservation of the ovaries• preservation of vagina

St. Ib to IIa

lesion < 4 cm

lesion > 4 cm

Radical HysterectomyPelvic lymphadenectomy

good surgical risk

Radiotherapy• external beam• intracavitary

CHEMOTHERAPY

deep stromal invasion lymph node (+)

YES

NO

Stage IIb & higher

• young patient• poor histology• bulky lesions

TREATMENT∏Complications of treatment modalities:

Mۀ hemorrhage

Mۀ infection/sepsis

Mۀ incontinence

Mۀ fistula formation

Mۀ post-radiation fibrosis and scarring

Cervical cancer coexistent with pregnancyCervical cancer coexistent with pregnancy

∏Difficulty and ease in diagnosis∏Limitations of some procedures: ECC and

conization∏Definitive treatment for CIN is postponed

until after puerperium.∏Is the prognosis worse if the disease is

associated with pregnancy?

∏The AOG is the primary consideration in treating invasive lesions associated with pregnancy:Mۀ less than 20 weeks, manage as if notpregnant.Mۀ beyond 20 weeks, wait until fetal viabilityMۀ ethical considerations

Cervical cancer coexistent with pregnancyCervical cancer coexistent with pregnancy

PROGNOSTIC FACTORS

∏Age at diagnosis∏Stage of the disease∏Histologic type∏Size of the tumor∏Depth of stromal invasion∏Status of the regional nodes∏Attending medical problems

FOLLOW-UP

∏The risk of recurrence is highest during the first year after treatment, but wanes thereafter.∏Metastasis can occur in any organ but more commonly in the central pelvis, bones, lungs and liver.∏Cases can be classified as cured after a disease-free interval of 5 years.

FOLLOW-UP

∏Cytologic monitoring of recurrence

∏Regular survey for metastatic disease

∏Disease-free interval versus Cure

∏Palliative treatment for persistent

progressive disease

SUMMARY

∏Cervical cancer is a preventable disease.

∏Pap smear is the most cost-effective

screening tool.

∏Human Papilloma Virus infection is a

major risk factor in its genesis.

SUMMARY…

∏Biopsy is essential in establishing the

diagnosis:Mۀ with guidance: Lugol’s solution, acetic acid

Mۀ colposcopy

Mۀ conization

Mۀ simple punch biopsy

SUMMARY

∏MICA requires a cone biopsy.

∏Treatment and prognosis are largely

dependent on the extent of the disease

Mۀ Conservative treatment for premalignant

Mۀ Radiotherapy

Mۀ Radical surgery

∏Uremia is the most common form of

exit.