CIN and mimics
Dr Michael Coutts
Consultant Gynaecological Pathologist
West Kent Gynae Oncology Centre, Maidstone, UK
and Centre Hospitalier Universitaire, Nice, France
Cervical intraepithelial neoplasia (CIN)
• Abnormal proliferation, nuclear atypia and lack of
maturation of squamous cells within the epithelium
Natural history of CIN
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Conflicting data from various studies, however:
90% of CIN 1 regresses in 2 years
50% of CIN 2 regresses in 2 years
Approx 10% of CIN 1 and 20% of CIN 2 will progress
to CIN 3
• Approx 30% of CIN 3 will regress but roughly 20%
will progress to invasive squamous ca
• Mean time for progression from CIN to invasive
cancer approx 10 – 20 years
Human papillomavirus (HPV)
• Present in 99.7% of cervical cancer
• A causative agent for virtually all cervical cancer (and
CIN and CGIN/ACIS)
• 55nm non-enveloped DNA virus
Human papillomavirus
• Over 100 sub-types according to gene sequence of L1
capsid protein
• Highest risk 16, 18, 31, 45
• HPV 16 and 18 together cause 70% of cervical cancer
• HPV infection starts at TZ (squamocolumnar junction)
• Most HPV infection is cleared by the immune system but
a minority progresses to CIN or invasive carcinoma
• Factors influencing progression include HPV type, viral
load, host immunity, parity, smoking, oral contraceptives
<10%
Infection with HPV
15-25 yrs
>90%
Lesions
Asymptomatic infection
Koilocytosis and CIN 1
Most
20%
CIN 2
Elimination of virus
20%
Regression of lesions
? Appx 30% regression
of CIN2/3
Effective immune system
CIN 3
20% progression
If untreated
Invasive carcinoma
Normal cervix
CIN 1 (LSIL)
• Nuclear atypia
with mitoses and
a high N:C ratio
confined to the
lower 1/3
• Koilocytosis most
obvious in the
upper levels of
epithelium
Koilocytosis
• Perinuclear clearing
which is sharply defined
• Eccentric,
hyperchromatic nucleus
with coarse chromatin
• Nuclei may be
multinucleate or raisinshaped
Koilocytosis without CIN (LSIL)
Condyloma acuminatum
• Benign papilloma caused
by HPV
• Usually low risk 6, 11
• More common on vulva
• Cauliflower-like growth of
fibrovascular cores lined by
squamous mucosa with
koilocytosis, parakeratosis
• Essentially LSIL, but
occasionally high grade CIN
may occur in a condyloma
CIN 2 (HSIL)
• Nuclear
atypia with
failure of
maturation
and mitoses
in lower 2/3
• Abnormal
mitoses may
be seen
• Koilocytosis
in upper
layers
CIN 3 (HSIL)
• Nuclear atypia
with failure of
maturation in
upper 1/3
• Abnormal
mitoses
• Koilocytes
hard to find
• No invasion
CIN 3
CIN 3
CIN 3 in endocervical crypt
Keratinising CIN 3
Pleomorphic CIN 3
Immunohistochemistry in CIN 3
Ki67
p16
Mimics of CIN: Immature metaplasia
• Stratified layers of cells with little maturation
(a high N:C ratio) which may extend into crypts
But:
• Nuclei evenly spaced, without much crowding
• Regular nuclear outline, without coarse chromatin
• Low mitotic rate, without abnormal forms
• Layer of residual endocervical epithelium may be present
on the surface (rare over high grade CIN)
Mimics of CIN:
Immature squamous metaplasia
Mimics of CIN: Immature metaplasia
Immunohistochemistry of immature
squamous metaplasia
Ki67
p16
Mimics of CIN: Atrophy
• Stratified layer of cells with little maturation
(ie with a high N:C ratio)
But:
• Epithelium is thin
• Nuclei are evenly spaced, without crowding
• Nuclear pleomorphism and mitoses are absent
• Nuclei may be ovoid with longitudinal grooves (socalled ‘transitional metaplasia’, probably a variant of
atrophy)
Mimics of CIN: Atrophy
Mimics of CIN:
Atrophy and inflammation
Mimics of CIN:
Reactive, inflammatory changes
• Inflammation can cause nuclear enlargement,
nucleolar prominence and scattered mitotic figures
But:
• Pleomorphism is mild and N:C ratio generally normal
• Mitoses are few and only in lower layers
• Nucleolar prominence is not a typical feature of CIN
• Acute and chronic inflammatory cells are present in the
epithelium together with intercellular oedema
• Mild perinuclear clearing of squamous cells may be seen
as an inflammatory phenomenon
Mimics of CIN: Inflammation
(with atrophy and tangential sectioning)
Mimics of CIN: inflammation
Inflamed CIN 3
Mimics of CIN: diathermy artefact
• Artefact in surface epithelium adjacent to resection
margins due to heat from the loop
• Nuclear hyperchromasia and elongation
• Changes most marked in the basal layers with the
overlying surface epithelium often normal
• Mitoses not identified
• Adjacent epithelium often normal
• Low immunohistochemical staining with Ki67
Mimics of CIN: Diathermy artefact
Mimics of CIN: tangential sectioning
• Poor orientation of the biopsy during paraffin
embedding so that the histological section is not 90°
to the epithelial surface
• The basal layer is sectioned obliquely so that it
appears thicker than normal and gives a false
impression of lack of maturation
• However, cellular spacing is generally even, without
crowding
• Deeper levels cut from the block may clarify the
overall architecture of the lesion
Mimics of CIN: tangential sectioning
Mimics of CIN: tangential sectioning
Tangential sectioning (deeper levels)
Conclusions
• HPV infection is common but only a minority
progresses to CIN or invasive carcinoma
• This progression is slow and so CIN can be detected
by screening before invasion occurs
• CIN is graded 1 to 3
• Mimics of CIN include immature squamous
metaplasia, atrophy, inflammation, diathermy
artefact, tangential sectioning