04 CIN and Cervical Cancer UNEDITED

CERVICAL INTRAEPITHELIAL NEOPLASIA and CERVICAL CARCINOMA

Cytology: Normal

Superficial Cells

Parabasal Cells

Intermediate Cells

Metaplastic Cells

The Bethesda System of Repor2ng Cervical Cytology

ADEQUACY OF SAMPLE Sa@sfactory Unsa@sfactory

SQUAMOUS CELL ABNORMALITIES Atypical squamous cells ( ASC )

ASC of undetermined signicance ( ASC US ) ASC, cannot exclude high grade lesion ( ASC H )

Low grade squamous intraepithelial lesion ( LSIL ) High grade squamous intraepithelial lesion ( HSIL ) Squamous cell carcinoma


GLANDULAR CELL ABNORMALITIES Atypical glandular cells, specify site of origin, if possible

Atypical glandular cells, favor neoplas@c Adenocarcinoma in situ Adenocarcinoma OTHER CANCERS ( e.g. lymphoma, metasta@c, sarcoma )


q Incidence: 22.5/100,000 unchanged since the 1970s

q 7,277 es@mated new cases yearly q 3,807 deaths yearly

} 56% of Filipino women with cervical cancer will die within 5 years

} About 2/3 of cervical cancer is diagnosed in the advanced stage, where mortality is high

} Median survival 76 months } Five year survival 51.7%

Incidence starts rising steeply at age 35 2005 Philippine Cancer Society Cancer Facts and Es8mates

Uterine cervix

Es@mated New cases 11,070 cases of invasive

cervical cancer are expected to be diagnosed in 2008

Es@mated Deaths 3,870 deaths from cervical

cancer are expected in 2008

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Natural History of Cervical Ca

5-10 years 15-20 yrs

Long interval from viral infection to cancer development

HPV Infection Low grade

Cervical SIL High Grade Cervical SIL

Invasive Cervical Ca

( page 747 ) FIGURE 28. 4 Diagram of cervical epithelium showing various terminologies used to characterize progressive degrees of cervical neoplasia

Koilocyte

Risk Factors

RISK FACTOR Relative Risk HIV Very High Moderate Dysplasia on Pap Smear within past 5 years Very High Intercourse within 1 year of menarche 16 No prior screening 10 HPV (depending on subtype) 2.5 3.0 Six or more lifetime sexual partners 5 Low socioeconomic class 5 Race (black vs. white) 2.5 Smoking Current smoker Previous smoker of 5 pack years

2 3.42 2.81

OCP use 1.2 1.5 Barrier contraception 0.6

Majority of cases are associated with infection of one or more types of HPV which is sexually transmitted.

Walboomers et al 1999

The most common HPV types in decreasing frequency among cases were HPVs 16, 18, 45, 52, 58 (95% CI OR = 31392). In squamous cell carcinoma, common types were HPVs 16, 18, 45, 52 and 58; whereas it was HPVs 16, 18 and 45 in adenocarcinomas; in contrast to normal cervices, HPVs 16, X, 18, 45, 6, MM4, 31, 52, 11, 54 and IS39 (27).

The prevalence of antibodies to HPV 16 virus-like particles (VLP) is higher in squamous cancers (47%) than in controls (25%) and it is higher in cases where HPV 16 DNA is detectable in cervical cells (62%). However, the sensitivity and specificity of the serological assay are lower than that of HPV DNA (29). Prevalence of HPV in cervical cancer in 22 countries including the Philippines indicated that HPV DNA was detected in 93% of tumors, with no significant variation in HPV positivity, with common HPVs 16, 18, 45 and 31. HPV 16 predominated in squamous cell tumors and HPV 18 in adenocarcinoma and adenosquamous tumors. HPV 16 was the predominant type in all countries except for Indonesia, where HPV 18 predominated. A clustering of HPV 45 was apparent in western Africa, while HPVs 39 and 59 were almost entirely confined to Central and South America (31).

Human Papilloma Virus

Low risk (HPV 6, 11, 40, 41, 42) seen in CIN I or condyloma acuminata

Intermediate (HPV 31, 33, 35, 51, 52) seen in HSIL (CIN II/III)

High risk (HPV 16, 18, 45, 56) seen in invasive CA

Transforma@on Zone

How does HPV causes carcinoma?

Integra@on of DNA of cancer associated HPV into the host cell genome

HPV viral genomes encodes 6 early openings ( E1,E2,E3,E4, E6, E7 ) 2 late openings ( L1, L2 )

How does HPV causes carcinoma?

Low risk HPV -maintained as extrachromosomal DNA episomes

High Risk HPV - integrated into the host cellular DNA E7 binds and inac@vates Rb protein E6 binds p53 Func@onal loss of p53 and Rb protein leads to resistance to apoptosis, causing uncensored cell growth

DIAGNOSIS OF PREMALIGNANT LESIONS OF THE CERVIX

SCREENING and DIAGNOSTIC TESTS

The Cervical Cytology ( Pap test ) HPV DNA tes@ng Colposcopy and Colpo guided biopsy Excisional - Coniza@on, LEEP, LEETZ, Laser

Pap smear

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Conventional vs Liquid Based Cytology

Conven@onal vs Liquid Based Cytology

Require special care to avoid drying of cells

Fixa@on is carried out immediately by spriay or immersion

can be obscured by blood, mucus, and inamma@on

Sampling and cell transfer to a liquid medium

preserves the cells and minimizes cell overlap, blood, mucus, and inamma@on. It creates a mono-layer, a layer one cell thick, with no overlapping cells


The conven@onal Pap smear is made by hand; the physician "smears" the sampling device across a microscope slide to spread a layer of cells. Each physician may do it dierently, leading to some slides with thick lumps and clumps, and some slides with clear areas of no cells

The ThinPrep Pap Test makes Pap smear slides by an automated slide prepara@on unit, the ThinPrep 2000 Processor, that produces uniform thin-layer slides, a one-cell thick monolayer, virtually free of obscuring ar@facts such as blood, mucous, and inamma@on


Up to 90% of those False Nega@ves are due to limita@ons of sampling or slide prepara@on

Discarded amer a single conven@onal smear is done

Return of visits and repeat Pap smears is diminished.

Residual LBC can undergo tes@ng for HPV, herpes simplex virus, N. gonorrhea, C. trachoma@s

Solu@ons Used in Colposcopy

Normal Saline Solu@on 3 - 5 % Ace@c Acid Lugols Iodine

Results of Colposcopy

Sa@sfactory colposcopy: the margins of the lesion(s) and the en@re squamocolumnar junc@on are visible

Acetowhite Leukoplakia Puncta@on Mosacism Atypical Blood vessels

Principles of Ace@c Acid Test

3-5% Ace@c Acid Swelling of epithelial @ssues

Reversible coagula@on of nuclear proteins and cytokera@ns

Colposcopic Features COLOR tone & INTENSITY of acetowhitening MARGINS and SURFACE CONTOUR VASCULAR features COLOR CHANGES amer iodine applica@on (Schillers test)


Acetowhitening is NOT UNIQUE to CIN

Condi2ons with AW Immature sq metaplasia

Inamma@on Leukoplakia Condyloma


Normal Squamous Epith. Lesser coagula@on

Supercial cells are sparsely nucleated

Coagula@on insucient to block color of underlying stroma


Cervical Intraepithelial Neoplasia (CIN)

Cells have high nuclear content Maximal coagula@on Sub-epithelial vessel

parern is obliterated


LSIL (CIN I) Small amount of nuclear protein, lower 1/3 epith. Appearance of whiteness is delayed and less intense


HSIL (CIN II-III) Greater amount of

nuclear protein, 1/3 to full thickness of the epithelium Appearance of whiteness is densely white, opaque and immediate

Principles of Schillers Test Applica@on of Lugols Iodine Uptake of Iodine by glycogen-

rich epithelium Color: Mahogany brown or

black Mature Squamous

Epithelium

Principles of Schillers Test

Glycogen - decient epithelium Color: Par@al staining or thick mustard yellow

Immature squamous epithelium, columnar, leukoplakia, CIN, cervical cancer

Principles of Observed Vascular Features

Vasculature parerns observed amer applica@on of saline solu@on. Use green lter.

Mosaic and Puncta@ons, vessels of abnormal caliber

Principles of Observed Vascular Features

Colpo Guided Cervical Biopsy

Excisional

Coniza@on LEEP LEETZ Laser

Cold Knife Conization

Loop Electrosurgical Procedure

LEETZ

CO2 Laser

Guidelines For Pap Smear Screening 2002 American Cancer Society Guideline for the Early Detec2on of Cervical Neoplasia and Cancer, Smith, Harmon J. Eyre and Carmel C Debbie Saslow, Carolyn D. Runowicz,

Diane Solomon, Anna-Barbara Moscicki, Robert A., 2002;52;342-36 CA Cancer J Clin "

When to start screening Approximately 3 years amer onset of sexual ac@vity When to discon2nue screening Age 70 years with an intact cervix plus a history of 3 consecu@ve normal smears & no history of abnormal cytology within the 10-year period prior to age 70



Screening aYer hysterectomy Not indicated following hysterectomy for benign disease

1. CIN 2/3 are excep@ons to these benign condi@ons and warrant screening even amer hysterectomy.

2. For post-hysterectomy (for a benign disease) high-risk pa@ents, annual Pap smear is s@ll recommended to screen for vaginal intra-epithelial neoplasia (VAIN)



Screening interval Annual with conven@onal cytology OR Every 2 years with liquid-based cytology,

THEN At or amer age 30, amer 3 consecu@ve N smears, may decrease screening interval every 2-3 years

Note: 1. For high-risk pa@ents (> 1 risk factor), annual Pap smear is recommended

Result of LSIL is a good indicator of HPV infec@on Pooled es@mate of high risk (oncogenic) HPV DNA posi@vity

among women with LSIL was 76.6 % Prevalence of CIN 2 or greater iden@ed at ini@al colposcopy

among women with LSIL is 12-16 % Risk of CIN 2,3 is the same in women with LSIL and those with

ASC-US who are high-risk (oncogenic) HPV DNA (+) Colposcopy recommended except in special popula@ons (A

II) Endocervical sampling for non pregnant in whom no lesions

are iden@ed (B II) and those with an unsa@sfactory colposcopy (A II) but is acceptable for those with sa@sfactory colposcopy & a lesion iden@ed in the transforma@on zone (C II)

Immediate LEEP is ACCEPTABLE. When CIN 2,3 is not iden@ed histologically

1. Dx excisional procedure OR 2. observa@on with colposcopy and 3. cytology at 6 months intervals for 1 year is acceptable

PROVIDED: colposcopy is sa@sfactory and endocervical sampling is nega@ve (B III)

Acceptable to review the cytological, histological and colposcopic ndings

If the review yields a revised interpreta@on, mgt shld follow guidelines for the revised interpreta@on

If observa@on with colposcopy & cytology a Dx excisional procedure is recommended for women with repeat HSIL cytological results at either 6 or 12 month visit

Amer 1 yr of observa@on, women with 2 consecu@ve NILM results can return to rou2ne cytological screening

BECAUSE OF THE SPECTRUM LINKED TO AGC, INITIAL EVALUATION MUST INCLUDE MULTIPLE TESTING MODALITIES.

INITIAL WORK-UP

Colposcopy with endocervical sampling for women with all subcategories of AGC & AIS (A II)

Endometrial sampling in conjunc@on with colposcopy and endocervical sampling in women 35 y/o with clinical indica@ons sugges@ng they may be at risk for neoplas@c endometrial lesions (unexplained vaginal bleeding or condi@ons sugges@ng chronic anovula@on)

HPV DNA tes@ng at the @me of colposcopy is preferred in women with ATYP EC , EM or GLAndular cells NOS.

UNACCEPTABLE: HPV DNA Tes@ng alone OR Program of repeat cervical cytology for the ini@al

triage of all subcategories of AGC and AIS (EII)

Colposcopy is recommended When CIN 2,3 is not iden@ed histologically observa@on for

upto 24 months using both colposcopy and cytology at 6-month intervals is preferred

PROVIDED: Colposcopy is sa@sfactory and endocervical sampling is (-)

UNACCEPTABLE: Immediate LEEP

In excep@onal circumstances Dx excisional procedure is acceptable (B III)

If during a up a high grade colposcopic lesion is iden@ed or HSIL cytology persists for 1 year Biopsy is recommended

If CIN 2,3 is iden@ed histologically Mgt shld follow 2006 Consensus

If HSIL persists for 24 months w/o iden@ca@on of CIN 2,3 Dx excisional procedure is recommended (B III)

CASE 1 PAP SMEAR

A 54 year old, grandmultipara, came in at FEU OB OPD with pap test result of ASC US. What is /are your treatment option/s

a.repeat cytology after 6 months b.colposcopy c.HPV DNA testing d.ABC

e. AC

CASE 2 PAP SMEAR A 19 year old, Nulligravied, married for 2 years, came in at FEU

OB OPD with pap test result of LSIL. What is /are your treatment option/s ?

a. Cytology after 12 months b.Colposcopy c. Endocervical Curettage d.ABC e. BC

CASE 3 PAP SMEAR A 49 year old, G2P2, menopause for 2 years, came in at FEU OB

OPD with pap test result of ASC H. What is /are your treatment option/s ?

a. Cytology after 6 months b. Colposcopy c. ECC d. ABC e. BC

CERVICAL INTRAEPITHELIAL NEOPLASIA ( CIN )

Cytology: Koilocytes

Eosinophilic squamous cells with perinuclear empty cavity

Cytoplasmic thickening Moderate nuclear enlargement

CIN 1: Histopathology

( page 747 ) FIGURE 28. 4 Diagram of cervical epithelium showing various terminologies used to characterize progressive degrees of cervical neoplasia

Koilocyte

Natural History of CIN ( From Ostor , 1993 )

Regression (%) Persistence (%) Progression to CIS (%) Progression to Invasion (%) CIN 1 57 32 11 1 CIN 2 43 35 22 5 CIN 3 32 < 56 - > 12

MANAGEMENT Cervical Intraepithelial Neoplasia

( CIN )

RECOMMENDED MANAGEMENT OF WOMEN WITH CIN 2,3 Adolescent & Young women

Either Treatment or Observa@on, provided colposcopy is sa@sfactory

1. Treatment Excision or Abla@on 2. Observa@on Both colposcopy & cytology at 6 months intervals for up to 24 months (B III)

When CIN 2 is specied, observa@on is preferred. When CIN 3 is specied or colposcopy is unsa@sfactory,

treatment is recommended (B III) FOLLOW UP COLPOSCOPY & CYTOLOGY

TWO consecu@ve nega@ve intraepithelial lesion or malignancy and Normal Colpo rou@ne cytological SCREENING

Colposcopic appearance worsens or if HSIL cytology or colposcopic lesion persists for 1 year Repeat biopsy is recommended (B III) CIN3 is subsequently iden@ed or if CIN 2,3 persists for 24 months (B II) TREATMENT

Hysterectomy preferred for women who have completed child-bearing and have histological diagnosis of AIS on a specimen from a Dx excisional procedure (C III)

Conserva2ve mgt acceptable if future fer@lity is desired (A II)

If conserva@ve mgt, but the margins of specimen are involved or endocervical sampling obtained at the @me of excision contains CIN or AIS reexcision to increase the likelihood of complete excision is preferred

CASE 1 CIN 1. A 49 year old, G2P2, menopause for 2 years, came in at FEU

OB OPD with pap test result of ASC H. She underwent colpo guided biopsy. Histopath revealed CIN 1. What is the most appropriate management?

a. hysterectomy b. observe c. conization d.HPV DNA testing e. ECC

CASE 2 CIN 2. A 54 year old, grandmultipara, came in at FEU OB

OPD with pap test result of ASC US. Colpo guided biopsy revealed CIN 3. What is the subsequent management?

a. hysterectomy b. LEEP c. Conization d. ABC e. BC

Treatment Methods in Cervical Intraepithelial Neoplasia

( CIN )

Goal of Treatment in CIN

To remove the lesion Hysterectomy is not recommended ABLATION METHODS

Cryotherapy Thermoabla@on CO2 laser abla@on

EXCISION METHODS LEEP or LEETZ Cold Knife Coniza@on

ABLATIVE PROCEDURE

CO2 Laser Vaporization

Cryotherapy

Electrofulguration

Cervical Carcinoma

MAJOR CATEGORIES OF CERVICAL CARCINOMA

SQUAMOUS CELL CARCINOMA Large cell ( kera@nizing or non kera@nizing ) Small cell Verrucous

ADENOCARCINOMA Typical ( endocervical ) Endometrioid Clear cell Adenoid cys@c ( basaloid cylindroma ) Adenoma malignum ( minimal devia@on adenocarcinoma )

MIXED CARCINOMA Adenosquamous Glassy cell

SCCA, Kera@nizing and Non kera@nizing

Micoinvasive carcinoma (MICA)

2009 FIGO Staging

Case: Diagnosis A 32 year old, G5P4 ( 4014 ) came in at the OB OPD for pap smear. On

speculum examina@on, a funga@ng mass was noted at the anterior lip of the cervix with scanty clear discharge. Per@nent pelvic examina@on revealed normal external genitalia, parous vagina, Cervix measured 5 x 4 cm nodular, with no forniceal involvement, corpus was small, no adnexal mass and tenderness, both parametria were smooth and pliable. What is the best diagnos@c procedure for her?

a. Pap smear b. colposcopy c. biopsy d. ABC e. BC

Case: Diagnosis A 48 year old G7P6 ( 6015), came in for pap smear. Speculum

examina@on revealed a funga@ng mass at 2 oclock to 5 oclock posi@on of the exocervix. IE revealed a nodular cervix measuring 4x4cm , Corpus was small, (-)AMT, Both parametrium were smooth and pliable. Will you perform pap smear? Yes / no If no, what is the BEST op@on for this lady?

Cervical Mass

Cervical biopsy

Cervical Carcinoma FIGO STAGING

Guidelines for Clinical Staging ACCEPTED Biopsy (direct, colpo-guided, cone) Recto-Vaginal examina@on AFTER CONFIRMATION OF BIOPSY: CBC, Renal Func@on tests, LFTs Chest X-ray KUB-IVP Proctosigmoidoscopy Cystoscopy Skeletal survey

FIGO Committee on Gynecologic Malignancy Manual 2006

The following examina@ons are permired:

Intravenous urography X-ray examina2on of the lungs and skeleton Suspected bladder or rectal involvement should be conrmed by biopsy and histologic evidence.

Coniza@on or amputa@on of the cervix

Guidelines For Clinical Staging

Performed as INDICATED BUT NOT ESSENTIAL to complete staging procedures

Barium enema CT scan Ultrasonography MRI PET Scan Lymphangiography Angiography Laparoscopy

FIGO Committee on Gynecologic Malignancy Manual 2006

Guidelines For Clinical Staging

No need for Pap smear No need for frac@onal curerage Cervical cancer is clinically staged! Once invasive cancer is diagnosed, the pa@ent should be referred to a gynecologic oncologist.

SGOP Clinical Practice Guidelines 2008

CASE 1 A 24 year old G5P3 ( 3023), came in for post coital bleeding. She consulted

at our OB OPD. Per@nent PE ndings revealed (-) SCLN, Speculum exam revealed funga@ng necro@c mass, IE revealed that the cervix was converted to 5 x 6cm mass with extension to the lower third of the vagina, corpus was small, (-) AMT, Lem parametrium was nodular xed to pelvic side wall, Right parametrium was smooth and pliable. Biopsy of the mass revealed SCCA , LCNK, Cervix. What is the stage of the disease? a. IIA b. IIB c. IIIA d. IIIB

CASE 2 A 44 year old G7P6 ( 6015), came in for an abnormal pap

smear. Speculum examina@on revealed a clean looking cervix. Colpo guided biopsy was done which revealed CIN3. Cone biopsy was done which revealed SCCA LCK with stromal invasion measured 5 mm width, 3mm depth. What is the stage of the disease?

a. IA1 b. IA2 c. IIA d. IIB

CASE 3

A 29 year old G6P5 ( 5014 ), came in for post coital bleeding. She consulted at our OB OPD. Per@nent PE ndings revealed (-) SCLN, Speculum exam revealed funga@ng necro@c mass, IE revealed that the cervix was converted to 8 x 6cm mass with extension to the upper third of the vagina, corpus was small, (-) AMT, Lem parametrium was nodular and free, Right parametrium was smooth and pliable. Biopsy of the mass revealed SCCA , LCK, Cervix. What is the stage of the disease? a. IIA b. IIB c. IIIA d. IIIB

ROUTE OF SPREAD

Growth Parern Endophy@c Exophy@c

Lympha@c spread Primary nodes Secondary nodes Distal nodes

Hematogenous

Frequency of lymph node metastases in cervical carcinoma

Aortic 27%

obturator 27%

eXternal iliac 27%

common iliac 31%

hypogastric iliac 31%

parametrial 77%

Treatment according to FIGO Staging

TREATMENT 1. Concurrent Chemoradia@on 2. Surgery

TREATMENT CONCURRENT CHEMORADIATION current standard of care and mainstay of treatment

Overall survival advantage for cispla@n based therapy

Risk of death was decreased by 30 - 50 %

RADIATION

External Beam RT/ Teletherapy ( Cobalt or LINAC )

40 - 50Gy in 25 to 30 days Cispla@n 40mg/m2 given weekly

Complica@ons: Anemia, electrolyte irregulari@es

External Beam RT/ Teletherapy

RADIATION

Internal RT / Brachytherapy Intrauterine tandem and intravaginal ovoid Done under general anesthesia Reference Points

Point A Point B Bladder point Rectal point

RADIATION ( Internal RT)

HDR Out pa@ent sezng Eliminate exposure to hospital personnel

Uses Iridium 192

LDR Lem in place for 2 - 3 days

Uses Cesium 137

BRACHYTHERAPY

Complica@ons of Radia@on

Acute GI eects, Cystourethri@s, UTI, Skin erythema

Late Rectal or vaginal stenosis, small bowel obstruc@on, malabsorp@on, chronic cys@@s, radia@on proc@@s, stula forma@on

SURGERY

Cone Biopsy and Radical trachelectomy (if desirous of pregnancy) for stage IA1

SURGERY

Extended Hysterectomy Class I Extrafascial Hysterectomy Class II Modied Radical hysterectomy Class III ( Radical Hysterectomy - Meigs Wertheim Hysterectomy )

Class IV Class V ( pelvic exentera@on )

Radical hysterectomy specimen

Black line - Simple hysterectomy Red line - RH

Radical hysterectomy specimen

Radical vs. simple hysterectomy specimen

FOLLOW-UP

CERVICAL CANCER POST-TREATMENT SURVEILLANCE

Follow-up post cura@ve treatment

Every 3 months for 1st 2 years, every 6 months from years 3-5, then annually

Pap smear every 3 months for 1st 2 years, then pap smear every 6 months for years 3-5, then annual pap smear

Chest X-ray annually or as indicated Annual MRI or CT scan for 1st 3 years

HRT may be given to alleviate menopausal symptoms

04 CIN and Cervical Cancer UNEDITED

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