DR LAYLA S. ABDULLAH,MD,FRCPC

ASSOCIATE PROFESSOR/CONSULTANT

DEPARTMENT OF PATHOLOGY

FACULTY OF MEDICINE

KING ABDULAZIZ UNIVERSITY

Preinvasive lesions ( definition)

Historical review of terminologies

The latest cytological terminology : The

2001 Bethesda System for reporting of PAP

smears .

The LAST classification .

Cervical cancer was the most frequent form of cancer around the world.

Impact of cervical cancer screening: Decrease incidence of invasive tumors and increase incidence in the detection of cervical preinvasive lesions (dysplasia).

Definition:

Derived from the Greek word DYS for ‘‘bad’’

and PLASIA for ‘‘molding’’

used in many areas of medicine to describe a

nonmalignant process.

Dysplasia is an abnormal growth and

maturation of cervical squamous epithelium

Cytological and architectural changes of

cervical cells/ loss of polarity

limited by the basement membrane

Pre-invasive, precancerous, Pre-malignant

lesions

Graded mild, moderate, or severe

HPV related ( Serotypes: High risk: 16, 18, 31, and 33)

Integration of viral genes into host genome inactivate p53 and retinoblastoma tumor suppressor genes.

Historical Review Of

Terminologies For

Cervical Preinvasive

Lesions

The earliest description of intraepithelial

pre-cancer was by Sir John Williams in 1888.

carcinoma in situ (CIS) : cells that

morphologically looked like cancer but had

not invaded below the basement membrane

2-tiered clinical approach :

- Hysterectomy for women with CIS and

- No treatment for women without it

Surface lesions existed on the cervix that had

abnormal histological features that did not

fulfill the criteria for CIS.

Lower risk for progressing to cancer than CIS

does.

( Koss and Durfee)

ballooned cytoplasm koilocytes from the

Greek word for ‘‘empty space,’’

similarity to descriptions of Reagan’s mild

dysplasia.

In 1976, Meisels and Fortin linked

koilocytotic atypia with HPV.

proposed :

cervical carcinogenesis was a continuum of

disease ranging from mild dysplasia to

cervical cancer

He coined the term cervical intraepithelial

neoplasia (CIN) to emphasize its association

as a precursor to cancer

CIN : spectrum of cytological and

histological changes that shared a common

etiology, biology and natural history

All groups (CIN I ,II,III and ca insitu)

represented different stages of a single

biological continuum

CIN terminology was widely adopted for use

both in histology and cytology

CIN I CIN II CIN III/Ca

Insitu

As our understanding of pathogenesis of

cervical cancer and its precursors improved

and increased.

Ostor AG. Natural history of cervical intraepithelial neoplasia :a critical

review. Int J Gynecol Pathol 1993;12:186-92.

regress persist Progress

to CIS

Progress

to

invasion

CIN 1 57% 32% 11% 1%

CIN 2 43% 35% 22% 5%

CIN 3 32% 56% >12%

CIN biological classification as a spectrum

was questioned ???????

Late 1980s : the biology of HPV and cervical

oncogenesis was increasingly understood.

Human papillomavirus interacts with

squamous epithelia in 2 basic ways.

The productive viral infection caused by Low

& high risk HPV (self limited

spontaneously resolve)

and

The true neoplastic process confined to

epithelium but with the capacity to progress

to invasive cancer if not treated.

High grade, high risk HPV, desregulation of

E6&E7,monoclonal with chromosomal

alteration

In 1989 , Bethesda system was introduced to

standardize the reporting of cervical cytology

results and to incorporate new insights

gained from the discovery of HPV.

The name of pre-invasive lesions were

changed to squamous intraepithelial lesions

(SIL)

Subdivided only to 2 grades (Low & High).

Cervical

Cytology

First Bethesda workshop in 1988

Followed by another in 1991

Latest was in 2001

9 forums

Internet based bulletin

1000 comments regarding draft

recommendations

Countries all over the world participated

Clinicians, pathologists, cytopathologists,

cytotechnologists, patient’s advocates,

public organizations

The Bethesda system recommends a specific

format for cytology report including

comments on :

specimen adequacy

general categorization

interpretation/results

Within the two tiered terminology system

Controversy :

Northern America SIL/ASC

BSCC system in UK Dyskaryosis/Borderline

Modified Bethesda in Australia

Europe and some other countries CIN

terminology

Satisfactory for evaluation

A satisfactory squamous component must be

present

Note the presence/absence of endocervical/

transformation zone component

Obscuring elements (inflammation, blood,

drying artifact, other) may be mentioned if

50–75% of epithelial cells are obscured

Specimen rejected/not processed because (specify

reason). Reasons may include:

• lack of patient identification

• unacceptable specimen (e.g. slide broken beyond

repair)

Specimen processed and examined, but

unsatisfactory for evaluation of an epithelial

abnormality because (specify reason). Reasons may

include:

• insufficient squamous component.

• obscuring elements cover more than 75% of

epithelial cells.

LOW GRADE SQUAMOUS

INTRAEPITHELIAL LESION

(CIN I & HPV)

Moderate Dysplasia (CIN II)

Human Papilloma

Virus (HPV)

Ancillary

Tests

Ancillary tests such as HPV testing

HPV Digene (+ or -)

Molecular PCR testing : Sub-typing

P16 immunohistochemistry

Automated screening

recommendations

Histology

reporting of

preinvasive

lesions

Renewed debate about adopting a 2-tiered

low-grade and high-grade terminology for all

LAT HPV-associated intraepithelial lesions.

Better reflects the known biology of HPV-

associated disease, diagnostic variability

is reduced, management & patient outcome

improved.

The Lower Anogenital Squamous Terminology

-Recommend terminology that is unified

across lower anogenital sites. (All sites,

both sex)

-Create a histopathological nomenclature

system that reflects current knowledge of

HPV biology

-Optimally uses available biomarkers

-Facilitates clear communication across

different medical specialties

The Lower Anogenital Squamous Terminology

(LAST) Project was cosponsored by

the College of American Pathologists (CAP)

and

the American Society for Colposcopy and

Cervical Pathology (ASCCP)

5 working groups;

WG 1 provided the historical background

WG 2,3,4 performed comprehensive

literature reviews and developed draft

recommendations for SIL, SISCCA&

biomarkers .

WG 5 will continue to foster implementation

of the LAST recommendations.

Literature review(> 1000 articles)

Inclusion & exclusion criteria.

Data extraction.

Member’s expert opinions

Draft recommendations

Open comment period (15 Jan-15 Feb 2012)

Recommendations were finalized and voted

on at the consensus meeting (March 2012).

A unified histopathological nomenclature for

all HPV-associated of all LAT sites.

A 2-tiered nomenclature is recommended :

squamous intraepithelial lesion (SIL)

(LSIL) and (HSIL), which may be further

classified by the applicable IN

sub categorization.

IN refers to intraepithelial neoplasia.

For a specific location : cervix = CIN 3,

vagina = VaIN 3, vulva = VIN 3, anus = AIN

3,perianus = PAIN 3, and penis = PeIN 3

HSIL vs. Immature

inflamed squamous

metaplasia

HSIL vs. Reparative atypia

P16 CIN 2

Initiate action plans for implementation

of the recommendations.

Disseminate, Implement & Monitor .

Effective communication

educational programs detailing the

recommendations and their appropriate

incorporation into practice

The LAST Project recommendations reflect

the participants’ consensus judgment for

best evidence-based pathology practice and

nomenclature for HPV-associated squamous

lesions of the LAT.

The work is not yet done.

Definition of dysplasia

Bethesda 2001 for PAP smear reporting

Pathological reporting of preinvasive cervical

lesions.

The LAST terminology

THANK YOU