Cervical cancer

Pathology

Dr. Marten Schilthuis

Prof. Fiebo ten Kate
Origin
transformation zone
 Cervical cancer

Strongly associated
with HPV
Prevalention of high risk HPV in cervix

age
• 14-19: 33%
• 20-29: 28%
• 30-39: 14%
• 40-49: 11%
• 50-65: 6%

85% sexual active males and females between 15 -

49 year have been infected
100% of cervical cancers are positive voor HR HPV
 HPV 16, 18, 31, 33

- •p53 supp oncogen

E6, E7 proteins •Rb supp oncogen

apoptose

DNA damage repair

HPV may result in dysplasia and
eventually cancer

Slow proces with premalignant

phase

Prevention of cancer possible

 Prevention by cytology
Screening

•What age?
•How often?
•Cytology?, what types
•HPV?
•Effect of screening
 Screening?
Netherlands experience

•What age: 30 – 55 yrs

•Every 5 years, N=7
•Cervical cytology
•HPV will be introduced shortly
diagnostics of cervical neoplasia
sampling instruments for cytology
diagnostics of cervical neoplasia
cytology
cytology
 Classification
of cytology
• Bethesda
•ASCUS (atyp squam cell undet sig)
•Low grade SIL
•High grade SIL

• Pap system (KOPAC)

•PAP I - V
Classification of cytology
KOPAC
 Classification
of cytology
•Examples of cytology
•New methods (liquid)
•Computer techniques
 Cytology screening
Netherlands facts
•Since 1985
•65 % response (550.000 / yr)
•7200 for colposcopy (1,3%)
•330: cervical cancer
•5500 preinvasive abnormality
•1400 normal biopsy
 Cytology screening
Netherlands facts
•40 females develop later cancer despite nl
cytology
•700 new cases with cervical cancer / yr
•50% detected by screening (330)
•370 missed cases:
• 300 nonresponders
• 70 misdiagnosed
•Of 700 new cases, 200 †
•Without screening: 375 †
 Consequences
of cytology
• Bethesda
•SIL
• Pap system (KOPAC) NL
•PAP => IIIa

• Colposcopy
Diagnostic procedure abnormal
cytology:
colposcopy combined with biopsy
 Diagnosis of CIN
colposcopy
without appl. acetic acid jodine (lugol)
 Diagnosis of CIN
colposcopy
without appl. acetic acid jodine (lugol)
 Diagnosis of CIN
colposcopy

Always confirm diagnosis by

biopsy
 Original squamocolumnar junction

Transformation zone Ectocervix

Indifferent Columnar Immature Mature

Squamous Squamous

from P. C. Crum 2006

 Squamous metaplasia

• replacement of endocervical epithelium by

undifferentiated reserve cells
• reserve cells differentiate into
squamous epithelium
• overlies endocervical glands
• extends into the endocervical
glandular clefts
 Squamous metaplasia

• replacement of endocervical epithelium by

undifferentiated reserve cells
• reserve cells differentiate into
squamous epithelium
• overlies endocervical glands
• extends into the endocervical
glandular clefts
 Squamous metaplasia

• replacement of endocervical epithelium by

undifferentiated reserve cells
• reserve cells differentiate into
squamous epithelium
• overlies endocervical glands
• extends into the endocervical
glandular clefts
 Squamous Intraepitelial Neoplasia (CIN)

• abnormal maturation
• nuclear enlargement
• atypia
pleomorphism
coarse chromatin clumping
irregular nuclear contours
• CIN grade 1,2 and 3
• CIN is limited by the border with the
native squamous epithelium of the
ectocervix
• proximally CIN can extend even to the
endometrium and rarely to the
peritoneal surface.
 Squamous Intraepitelial Neoplasia (CIN)

• abnormal maturation
• nuclear enlargement
• atypia
pleomorphism
coarse chromatin clumping
irregular nuclear contours
• CIN grade 1,2 and 3
• CIN is limited by the border with the
native squamous epithelium of the
ectocervix
• proximally CIN can extend even to the
endometrium and rarely to the
peritoneal surface.
 Atypia in CIN

• atypia is the hallmark of dysplasia (CIN)

• Two forms of atypia:
1. in lower layers immature atypical
parabasal cells
2. in intermediate and superficial layers
with maturing cells: koilocytosis
 Abnormal mitotic figures in CIN

• three-group metaphases
• two group metaphases
• ring mitosis
• V-shaped metaphase
• tripolar and quadripolar mitosis
• dispersed metaphase
• giant mitosis
 Treatment of CIN
•CINI: wait and see
•CIN II – III:
• Destruction
Cryo
Laser
 Excision
LLETZ
Exconisation (always in case of
suspicion of invasion or abnomal cyl.)
 Treatment
Cryo

Advantage: easy technique

fast
oral painkillers sufficient

Disadvantage: no pathology
 Treatment
LLETZ
Advantage: easy technique
fast
local anaesthesia needed
pathology

Disadvantage: margins difficult for

pathology investigation
often irradical
 Treatment
LLETZ
LLETZ
 LLETZ – specimen
Superficial LLetz Deep LLetz

L R
 Diagnostic dilemma

•Signs of invasion in biopsy?

•Definitions: lin extension + depth
•Abnormalities cylindric epithelium
•Vsi?
•Always exconisation for
confirmation of diagnosis
 Treatment
Exconisation
Advantage: Accurate pathology diagnosis

Disadvantage: always general anesthetics

more complications: hemorrhage
functional damage cervix
 Treatment
exconisation
 Diagnostic procedure
Exconisation
•How to deliver: fresh!!
• Beware of delivery time (< 1 hr)
• Stitch 12:00 hrs
• Beware of drying up and temperature
•Howto prepare
•What to do with the result
 Treatment
exconisation
conization – fresh specimen for pathologist
Pathology exconisation
Pathology exconisation
Pathology exconisation
Normal epithellium CIN1 CIN3 CIN 3

Basement membrane

Extravasation Extravasation Invasive carcinoma

Lymph/blood
vessel

Endothelial
cell

Micrometastasis
MT

Macrometastasis

from Thierry et al
 Pathological report cervical carcinoma
 
• Microinvasive squamous cell carcinoma

• depth of invasion

0,15mm
 Microinvasive cervical
carcinoma:
•St Ia:
• Lin extension < = 7 mm
• Depth of invasion < 5 mm

St Ia1
St Ia2
 Microinvasive cervical
carcinoma: treatment
•Invasion ≤ 3 mm ± vsi (Ia1)
•Invasion 3 - 5 mm, vsi - (Ia2)
• Fertility wish +: exconisation
• Fertility wish -: hysterectomy
•Invasion 3 – 5 mm, vsi + (Ia2)
• Fertility wish +: lapsc.lymphadenectomy
+ radical trachlectomy (SN -) or 2 tempi
• Fertility wish -: Radical hysterectomy
Macro invasive cervical
carcinoma
 Macro invasive cervical
carcinoma

symptoms findings
irregular bloodloss exophytic tumor
contact bleeding endophytic tumor
fluor ulceration
pain (late)
 Cervical carcinoma
diagnostics
► General and gynecological evaluation
► Cystoscopy only in combination with eua in
advanced stages (> St Ib)
► MRI pelvis in advanced cases CT (paraaortic
ly. nodes)
► X-thorax
► tumor markers (response evaluation)
 SCC with squamous cell carcinoma
 CA125, CEA with adenocarcinoma
Cervical carcinoma
• dissemination:
•Lymphogenic
•Local extension
•Hematogenic

•Clinical Staging
(FIGO)
Cervical carcinoma
imaging
Cervix carcinoma macroinvasive
treatment
► stageIB-IIA: radical hysterectomy
with bilateral pelvic lymphadenectomy

► stageIIB-IV: combined radiotherapy

and chemotherapy (chemo-radiation)
 Cervical carcinoma
treatment fertility sparing
 Clinical size ≤ 2cm: radical vaginal
trachelectomy (SN-, MRI nl)
 Clinical size 2 – 4 cm: abdominal
radical trachlectomy (SN-,
distance top tumor <-> isthmus ≥
1.5 cm, MRI nl
 Wertheim Okabayashi

• Radicale hysterectomy and pelvic

lymphadenectomy
Lymphadenectomy
 Wertheim Okabayashi

• Pelvic lymphadenectomy:
• Commune nodes (+ -> PAO irr)
• External nodes
• Obturator nodes
• Evt. other places
Lymphnodes from different regions
 Frozen section
indication
•Only if consequences: stop or
adjustment procedure (ovaries?)
•Suspicious lymph nodes (communis)
•Bulky lymph nodes (> 2,5 cm)
•Extention of tumor outside uterus?
• Bladder/rectum
• Parametrium
 Frozen section
Problems
•Duration of procedure
•Selection
•How many slides
•Freeze artefacts
•No optimal diagnostic possibilities
Radical hysterectomy schedule
 Cervical carcinoma radical surgery
1 incision vagina
final steps
2 ligm vesicocervicale
3 ligm vesicovaginale
4 ureter
5 paravaginal tissue
6 insertion lateral
parametrium
7 divided lateral
parametrium
8 a uterina
 Pathology Report Cervix

► Macroscopical
 Specimen, surgical procedure
(exconisation, LLETZ, hysterectomy
radical or simple etc)
 Tumor diameter after fixation
 Macroscopic extension
 Configuration (exophytic, barrel shaped)
 Pathology Report Cervix
► Microscopical
 Histological type
 Grade
 Depth of invasion (measurement in mm)
 Size / linear extension
 Margins / radicality of tumor
 Pathology Report Cervix
► Microscopical
 Parametrial involvement
 Involvement of vagina
 If positive, mention CIN or invasive
cancer
 Margins parametrium/vagina, if positive
distance to surgical resection plane
 vsi
 Pathology Report Cervix
► Microscopical
 Lymphnodes: number involved/examined
 Region: commune, external, obturator,
PAO
 Extracapsular growth
 Try to examine at least 10 lymph nodes
per left and right pelvis
 Cervical carcinoma

80% squamous cell carcinoma

16% adenocarcinoma
3% adenosquamous carcinoma (poor
prognosis) dd collision tumor
1% other types

(Netherlands Cancer Registration)

 Classification of cervical carcinoma
 
• Squamous cell carcinoma
 
• large masses of squamous cells with
little intervening stroma
• or: cords and individual infiltrating
cells
• central keratinization and necrosis
may be present
• subdivision: keratinizing (keratin-
pearls) and non-keratinizing
• histologic grading has no prognostic
value
• method of measuring depth of
stromal invasion: from the point of
origin to the deepest point of
invasion
 
• large masses of squamous cells with
little intervening stroma
• or: cords and individual infiltrating
cells
• central keratinization and necrosis
may be present
• subdivision: keratinizing (keratin-
pearls) and non-keratinizing
• histologic grading has no prognostic
value
• method of measuring depth of
stromal invasion: from the point of
origin to the deepest point of
invasion
 
• Example of keratinizing squamous cell
carcinoma
 Adenocarcinoma
 
• irregularly infiltrating glands that
lack lobular architecture of
endocervical glands

• glandular budding

• papillarity and confluent

inflammatory cell response
• stromal desmoplasia

• extention of the glands beyond the

normal glandular depth
 
• adenoarcinoma

• depth of invasion
 
• squamous cell carcinoma

• Vascular space invasion

 
• squamous cell carcinoma

• Vascular space invasion

 
• Adeno squamous cell carcinoma
 
• Adeno squamous cell carcinoma
 
• Adeno squamous cell carcinoma
 
• Adeno squamous cell carcinoma
 Cervical carcinoma

80% squamous cell carcinoma

16% adenocarcinoma
3% adenosquamous carcinoma (poor
prognosis) dd collision tumor
1% other types

(Netherlands Cancer Registration)

 cervical carcinoma
histology

1% other types (small cell

neuroendocrine cervical cancer)

(Netherlands Cancer Registration)

Small cell neuroendocrine
cervical cancer
•Treatment: chemoradiation
• Cisplatinum (80 mg/m²) day1 &
etoposide (100 mg/m²) day1-3
every 3 wk, total 4 cycles
• Day 1 second cycle start with
EBR (25x 1.8Gy) + brachytherapy
(24 Gy)
Small cell neuroendocrine
cervical cancer
•Treatment:
• Only if tumor consists of more than
50% of small cell carcinoma
Thank you and terima kasih