This document discusses the terminology used for preinvasive cervical lesions. It begins with definitions of dysplasia and provides a historical review of terminology, including carcinoma in situ (CIS) and cervical intraepithelial neoplasia (CIN). It then describes the 2001 Bethesda System for cervical cytology reporting and the Lower Anogenital Squamous Terminology (LAST) project. The LAST project aimed to create a unified histopathological nomenclature for HPV-associated preinvasive lesions across anatomical sites, recommending a two-tiered system of low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL).

1. DR LAYLA S. ABDULLAH,MD,FRCPC
ASSOCIATE PROFESSOR/CONSULTANT
DEPARTMENT OF PATHOLOGY
FACULTY OF MEDICINE
KING ABDULAZIZ UNIVERSITY

2.  Preinvasive lesions ( definition)
 Historical review of terminologies
 The latest cytological terminology : The
2001 Bethesda System for reporting of PAP
smears .
 The LAST classification .

3.  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).

4.  Definition:
Derived from the Greek word DYS for ‘‘bad’’
and PLASIA for ‘‘molding’’
used in many areas of medicine to describe a
nonmalignant process.

5.  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

9.  HPV related ( Serotypes: High risk: 16,
18, 31, and 33)
 Integration of viral genes into host genome
inactivate p53 and retinoblastoma tumor
suppressor genes.

10. Historical Review Of
Terminologies For
Cervical Preinvasive
Lesions

11.  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

12.  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.

13.  ( 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.

15. 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

16.  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

17. CIN terminology was widely adopted for use
both in histology and cytology

19. CIN I CIN II CIN III/Ca
Insitu

20.  As our understanding of pathogenesis of
cervical cancer and its precursors improved
and increased.

21. 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%

22.  CIN biological classification as a spectrum
was questioned ???????

24.  Late 1980s : the biology of HPV and cervical
oncogenesis was increasingly understood.

25.  Human papillomavirus interacts with
squamous epithelia in 2 basic ways.

26.  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

27.  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).

29. Cervical
Cytology

30.  First Bethesda workshop in 1988
 Followed by another in 1991
 Latest was in 2001

31.  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

32.  The Bethesda system recommends a specific
format for cytology report including
comments on :
specimen adequacy
general categorization
interpretation/results

34.  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

41. 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

42.  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.

50. LOW GRADE SQUAMOUS
INTRAEPITHELIAL LESION
(CIN I & HPV)

53. Moderate Dysplasia (CIN II)

58. Human Papilloma
Virus (HPV)
Ancillary
Tests

59.  Ancillary tests such as HPV testing
HPV Digene (+ or -)
Molecular PCR testing : Sub-typing
 P16 immunohistochemistry
 Automated screening
 recommendations

60. Histology
reporting of
preinvasive
lesions

61.  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.

62. The Lower Anogenital Squamous Terminology

63. -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

65. 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)

66. 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.

67.  Literature review(> 1000 articles)
 Inclusion & exclusion criteria.
 Data extraction.
 Member’s expert opinions
 Draft recommendations
 Open comment period (15 Jan-15 Feb 2012)

68.  Recommendations were finalized and voted
on at the consensus meeting (March 2012).

69.  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

71. HSIL vs. Immature
inflamed squamous
metaplasia

72. HSIL vs. Reparative atypia

73. P16 CIN 2

74.  Initiate action plans for implementation
of the recommendations.
 Disseminate, Implement & Monitor .
 Effective communication
 educational programs detailing the
recommendations and their appropriate
incorporation into practice

75.  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.

76. The work is not yet done.

77.  Definition of dysplasia
 Bethesda 2001 for PAP smear reporting
 Pathological reporting of preinvasive cervical
lesions.
 The LAST terminology

78. THANK YOU