glandular epithelium squamous epithelium

productive infection

transforming infection

latent infection

persistent infection

Inactivation of pRB by HR-HPV E7 results in marked overexpression of p16INK4a

E2FpRB E7 E2FpRB

Promoterp16INK4a Promoterp16INK4a

Persistent HPV infection

CIN2 CIN3

p16 immuno-positive in transforming infection

WHO Histologic Terminology 2003

• Condyloma

• CIN I, II, III (with koilocytosis)

• Adenocarcinoma in situ

• Micro-invasive squamous carcinoma

• Invasive squamous or glandular carcinoma

Squamous cell carcinoma

(SCC)

High-grade SIL (HSIL)

Low-grade SIL (LSIL)

E6/E7/p16INK4A

expression

columnar epithelium squamous epithelium

transforming infection

latent infection productive infection

squamous epithelium

Bergeron et al Minireview IJC 2014 online

WHO Histologic Terminology 2014

• LSIL

• HSIL (CIN2 or 3 in young patients)

• Adenocarcinoma in situ

• Superficially invasive squamous carcinoma

• Invasive squamous or glandular carcinoma

If morphologicinterpretation isw/o doubt

• NILM• -IN 1• -IN 3

LAST Dx• NILM• LSIL• HSIL

no p16 stain

If morphologic interpretation is• –IN 2 vs NILM mimic• –IN 3 vs NILM mimic• –IN 2 • < -IN 1 with HSIL cytology

If p16 stain is negative LAST Dx

• NILM• LSIL• non-HPV pathology

If p16-stain is positive LAST DX HSIL

any identified p16-positive area must meet H&E

morphologic criteria for a high grade lesion

p16 stain should beperformed

Biopsy

Darragh et al, 2012 LAST of the American Society of Colposcopy and Cervical Pathology

The 2001 Bethesda system terminology

• Negative for intraepithelial lesion or malignancy

• Epithelial cell abnormalitieso Squamous cells

- Atypical squamous cells (ASC)- of undetermined significance (ASC-US)- cannot exclude HSIL (ASC-H)

- Low grade squamous intraepithelial lesion (LSIL) encompassing :HPV/mild dysplasia/CIN 1

- High grade squamous intraepithelial lesion (HSIL) encompassing :moderate and severe dysplasia, CIS/CIN 2 and CIN 3

- Squamous cell carcinoma

o Glandular cells- Atypical glandular cells (AGC) (specify endocervical, endometrial, or not

otherwise specified)- Atypical glandular cells, favor neoplastic (specify endocervical or not otherwise

specified)- Endocervical adenocarcinoma in situ (AIS)- Adenocarcinoma (endocervical, endometrial, extra-uterine, not otherwise

specified)• Other

- Endometrial cells in a woman ≥40 years of age

ASC-US and LSIL: clinical meaning

• Comparison rates with international data

• Porcentage of HPV + lesions

• Correlation of cytology and histology

Ascus Nos/Test HPV positivity: cytotechs Lab Cerba

% %

Hpv positifAsc

-us

Nos

0,0

10,0

20,0

30,0

40,0

50,0

60,0

70,0

80,0

0

1

2

3

4

4 6 8 A B D G I K L O P Q R S T W Y Z

Asc-us Nos (2,03%) HPV Positif (57,8%)

Consequences of HPV based screening on cytology

•Conversion to HPV-based screening will decrease volume of cytology

•Quality of cytology interpretation of hrHPV+ slides:

•Automated cytology will become more interesting

•Need for centralised cytolabs

MORPHOLOGY AND MOLECULAR BIOLOGY