Struttura Complessa di Ginecologia Oncologica
Direttore: Prof. Stefano Greggi
Carcinoma della Cervice Uterina
Cronoprogramma
Diagnostico-Terapeutico
Pap-test Anormale
L-SIL
H-SIL
Bethesda System, 2001
Pap-test Anormale
Pap-test Anormale
H-SIL 8% ICC  0%
L-SIL 31%
ASC-US
61%
Davey, 2004
ASC-US
INCIDENCE: 1.3-5.0%
CYTOLOGIC REVISION
• Low reproducibility level
• Low PPV
NEGATIVE
RISK OF CIN2+
RISK OF CIN3+
75-85%
12%
5%
Downgraded to neg
40%
Upgraded to L-SIL
20%
Upgraded to H-SIL
2%
Solomon (ALTS Group), 2001
Stoler, 2001
Sherman, 2001
Kristen (ALTS Group), 2006
% Upgrading
CIN 2-3
Cancer
Microinv.
ASC-US
ASC-H
CIN 3
Inv.
5-17
0.2
24-94
6-12
1-2
ASC-US – HPV-test Triage
HPV-test
HR +
HR -
Colposcopia
Pap-test
a 12 mesi
+
Colposcopia
-
Screening
SICPCV, 2006
HPV-test Triage – Raccomandazioni
Statement on HPV DNA test utilization, 2009
p16 Triage (sperimentale)
HPV-test (screening)
HR +
HR -
p16-test
+
Colposcopia
-
HPV-test a un anno
Carozzi, 2008
ASC-US - ASC-H - L-SIL
SICPCV, 2006
H-SIL – Carcinoma squamocellulare
SICPCV, 2006
AGC
SICPCV, 2006
Follow-up
• Citologia e colposcopia ogni 6 mesi per 2 anni
• Controllo annuale per altri 5 anni
• Ritorno a screening
A 6 mesi da trattamento
Colposcopia, citologia e HPV-test
Colposcopia
e/o citologia HPV +
Controllo
a 6 mesi
-
Colposcopia
e/o citologia +
Pap-test e HPV-test
a 12 mesi
Percorso
sec. lesione
+
Colposcopia
-
Screening
SICPCV, 2006
Istotipi
• Carcinoma squamoso in situ
• Carcinoma squamoso inf.
~80%
cheratinizzante, non-cheratinizzante, verrucoso
• Adenocarcinoma in situ / tipo endocerv.
• Adenocarcinoma endometrioide
• Adenocarcinoma a cellule chiare
• Ca. adenosquamoso
• Ca. adenoide cistico
• Ca. a piccole cellule
• Ca. indifferenziato
• Ca. neuroendocrino
~10%
FIGO, 2006
Cervical Cancer - FIGO Staging (2009)
I
IA
IA1
IA2
IB
IB1
IB2
II
IIA
IIA1
IIA2
IIB
III
IIIA
IIIB
IV
IVA
IVB
The carcinoma is strictly confined to the cervix (extension to the corpus
would be disregarded)
Invasive carcinoma which can be diagnosed only by microscopy, with
deepest invasion ≤5mm and largest extension ≤7mm
Measured stromal invasion ≤3mm in depth and horizontal extension ≤7mm
Measured stromal invasion >3mm and not >5mm with an extension of not >7mm
Clinically visible lesions limited to the cervix or pre-clinical cancers > Stage IA
Clinically visible lesion ≤4cm in greatest dimension
Clinically visible lesion >4cm in greatest dimension
Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to
the lower third of the vagina
Without parametrial invasion
Clinically visible lesion ≤4cm in greatest dimension
Clinically visible lesion >4cm in greatest dimension
With obvious parametrial invasion
The tumor extends to the pelvic wall and/or involves lower third of the
vagina and/or causes hydronephrosis or non-functioning kidney
Tumor involves lower third of the vagina (No extension to the pelvic wall)
Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney
The carcinoma has extended beyond the true pelvis or has involved
(biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as
such, does not permit a case to be allotted to Stage IV
Spread of the growth to adjacent organs
Spread to distant organs
Microinvasive CC
• IA
Early CC
• IB1
• IIA1
Locally
Advanced CC
(LACC)
• IB2
Metastatic CC
• IIA2
• IIB
• III
• IVA
• IVB
CONIZZAZIONE CERVICALE
EVISCERAZIONE PELVICA
Microcarcinoma – Staging Criteria
FIGO
IA1: stromal invasion ≤ 3 mm in depth, horizontal extension ≤ 7 mm
IA2: stromal invasion 3-5 mm in depth, horizontal extension ≤ 7 mm
SGO
Stromal invasion ≤ 3 mm in depth, no LVSI
Microcarcinoma – Treatment
• Total abdominal or vaginal hysterectomy
(if VAIN, appropriate cuff of vagina should be removed)
IA1
• Observation after cone biopsy (particularly if fertility is desired)
• Modified RH (Type 2) and pelvic LND
• Consider extrafascial H and pelvic LND (if no LVSI)
IA2
If fertility is desired:
• large cone biopsy + extra-perit. or lpsc pelvic LND
• rad. trachelectomy and extra-perit.or lpsc pelvic LND
Follow-up
Mainly with Pap smears annually after
two normal smears at 4 and 10 mos
FIGO, 2006
Cone: Positive margin
Microcarcinoma – Cone Positive Margin
In patient with positive margins:
• Vaginal
Strict Follow-Up
• Endocervical
or Stromal
Repeat Conization or
Hysterectomy
Fertility-sparing surgery
Cervical Cancer
43% of cervical cancer in women <45y (10-15% during childbearing years)
Radical Trachelectomy
• Vaginal
• Abdominal
• Laparoscopic
• Robotic
Eligibility criteria
• Age < 40-45 years & Strong fertility desire
• Diagnosis of invasive cancer (ideally, disease located
primarily on the ectocervix)
• Exclusion of unfavorable histology
• Stage IA1 with LVSI, IA2, IB1<2 cm
• No evidence of pelvic N met and/or distant met
• Gynecologic oncologist experienced in laparoscopic
and radical vaginal surgery
Dargent, 1994
Fertility-sparing surgery
RVT & Cancer prognosis
Review
n
Recurrence
Rates
Death
Rates
Darsun, 2007
520
4.2
2.8
Sonoda, 2008
548
4.0
2.6
Plante, 2008
603
4.5
2.5
Overall recurrence and death rates comparable to early-stage cervical
cancer treated by RH or RT
Plant, 2004; Seli, 2005
Fertility-sparing surgery
RVT & Pregnancy outcome
Review
Review
(8 studies : 603 RVT / 256 pregnancies)
(16 studies: 355 RVT / 161 pregnancies)
Pregnancy rate
62%
Pregnancy rate
70%
TAB/EUP
1st-2nd trimester loss
Deliveries <32 ws
5%
27%
12%
1st-2nd trimester loss
30%
Deliveries >37 ws
Currently pregnant
65%
6%
Plante, 2008
Boss, 2005
Cerv Microca – Conservative Treatment
Algorythm
CK Conization
IA2
Margins -
Follow-up
LVSI +
Margins +
No Res T
Repeat cone
LVSI Invasive Res T
Pelvic LND
RH
N+
N-
Follow-up
RH + pelvic LND
CERVICAL CARCINOMA
Clinical Assessment
T size
Lymphnode mets
Vaginal infiltration
FIGO Stage
Histotype & Grade
Bladder/Rectum involvement
Parametrial infiltration
Stadiazione Clinica
•
Esame vaginale bimanuale e vagino-rettale (in narcosi)
•
Colposcopia, biopsia / conizzazione
•
Currettage endocervicale
•
Cistoscopia
•
Retto-sigmoidoscopia
•
Rx torace (2 proiezioni)
•
TAC/RMN (PET)
CC apparentemente iniziale
• RX torace
• RMN addome/pelvi
CC localmente avanzato
• Visita ginecologica in narcosi
• RX torace
• RMN addome/pelvi
• Uretrocistoscopia
• Retto-sigmoidoscopia
FIGO, 2006
Cervical Cancer
Comparison of Diagnostic Procedure Utilization
ACRIN 6651/GOG 183 (n=208 ;Stage ≥ IB)
1978
1983
1988-1989
2002
Cystoscopy
64%
80%
52%
8.1%
Sigmoidoscopy
44%
58%
49%
8.6%
Barium enema
58%
60%
32%
0
Intravenous urogram 86%
91%
42%
1.0%
Lymphangiography
18%
11%
14%
0
CT/MRI
16%
54%
70%
100%
Montana, 1995
Amendola, 2005
Cervical Cancer
MRI
MRI staging for cervical cancer is
now widely accepted as an optimal
method for evaluation of tumor
volume, uterine corpus involvement,
parametrial invasion, …
Narayan K, 2003
… but prediction of parametrial,
bladder and rectal involvement is
correct in 75% of cases at best
Bipatt, 2003
Narayan, 2005
Follen, 2003
Cervical Cancer
Detection of Advanced Stage (>IIB) Cancer
by Retrospective Readers of CT & MRI
ACRIN 6651/GOG 183 (n=208 – Stage ≥ IB)
CT
MRI
P Value
Mean sensitivity (%)
28
47
0.104
Mean specificity (%)
90
79
0.099
Mean PPV (%)
55
36
0.001
Mean NPV (%)
83
85
0.305
Hricak, 2007
Cervical Cancer
Performance of CT & MRI in Detecting
Lymph Node Involvement
ACRIN 6651/GOG 183 (n=208 – Stage ≥ IB)
CT
MRI
Sensitivity (%)
31
37
Specificity (%)
86
94
Hricak, 2005
Treatment – Stage IB1, IIA1
• Modified RH (Type 2) or RH (Type 3) and pelvic LND
• Adjuvant pelvic RT plus BRT
• Adjuvant concurrent CTRT (Cisplatin±5FU) ↑ survival in such patients
In younger patients, if post-operative radiation is likely to be given:
• ovaries may be preserved and suspended outside the pelvis
FIGO, 2006
Treatment – Stage IB1-IIA1
• RH tipo III + LA pelvica + sampling N aortici
• RT pelvi + BRT
Se desiderio di prole (solo per IB1):
• trachelectomia radicale + LA pelvica ± sampling N aortici
NCCN, 2009
Radical Hysterectomy – History & Classification
Wertheim (1900)
Okabayashi (1921)
Meigs (1951)
Piver-Rutledge (1974)
Nerve-sparing (1990s)
Mota-EORTC (2008)
Robotics (2000s)
Querleu-Morrow (2008)
Radical Hysterectomy – Piver-Rutledge Classification
• Type I (Extrafascial hysterectomy): simple hysterectomy to remove the
entire cervical tissue
• Type II (Modified RH): basically, the RH described by Wertheim, to
remove more paracervical tissue while still preserving the blood supply
to the distal ureters and bladder
• Type III (RH): first described by Meigs in 1944, with the purpose of a
wide excision of parametrial and paravaginal tissue
• Type IV (Extended RH): complete removal of the periureteral tissue
and a more extensive resection of the paravaginal tissue
• Type V (Partial exenteration): radical removal of disease involving the
distal ureter and/or bladder
Piver, 1974
THE POINT OF TRANSECTION OF THE UTEROSACRAL
AND CARDINAL LIGAMENTS IN CLASS II AND III RH
Type 3 RH
Type 3 RH
Type 2 RH
Radical Hysterectomy – Querleu-Morrow Classification
• Type A (Minimum resection of paracervix): extrafascial hysterectomy,
corresponds to the type I RH, with a <10 mm vaginal resection
• Type B (Transection of paracervix at the ureter): corresponds to the
type II RH, with (B2) or without (B1) additional removal of the lateral
paracervical lymph nodes, and >10mm vaginal resection
• Type C (Transection of paracervix at junction with internal iliac vascular
system): corresponds to type III RH, with the ureter completely mobilized,
15-20mm of vagina and corresponding paracolpos resected routinely;
with (C1) or without (C2) autonomic nerve preservation
• Type D (Laterally extended resection): ultraradical procedures mostly
indicated at the time of pelvic exenteration, with the entire paracervical
resection at the pelvic sidewall including the hypogastric vessels (D1);
type D2 includes the resection of adjacent fascial-muscular structures
Querleu, 2008
Quality control and results comparison in RH
The term paracervix replaces others such as cardinal or Mackenrodt’s
ligament, or parametrium, and includes that usually named as paracolpium
It is recommended to include the following information in the operative
report:
• All parts defining the type of RH (transection of paracervix and
vagina, uterine artery)
• Surgical (fresh sample) and pathological (fixed sample) length of
ventral, dorsal and lateral extent of paracervix resection
• Surgical/pathological minimum length of vagina resected
• Minimum distance between tumor and resection margins (when
applicable)
Querleu, 2008
Type A
Type B1
Type C2
Surgery-related Complications
Rad. Hysterectomy
(type III)
+ Pelvic Lymph.
10-15% Severe
Perioperative Compl.
20-30% Early/Late
Bladder/Rectal Disf.
75% vs 10% (III vs II)
Temp. Bladder Disf.
Literature Review
LN Involvement by Stage
FIGO, 2006
Treatment – Stage IB2, IIA2
• Primary CTRT
• Primary RH and pelvic LND + Adjuvant RT
• Neoadjuvant CTRT (3 courses of platinum based CT)
+ RH and pelvic LND ± Adjuvant post-operative CT or RT
If positive common iliac or paraaortic nodes:
• extended field radiation should be considered
FIGO, 2006
Treatment – Stage ≥ IIB
• Primary CTRT (RT plus BRT)
• Primary pelvic exenteration (Stage IVA not involving pelvic sidewall)
If positive common iliac or paraaortic nodes:
• extended field radiation should be considered
IIB-IVA
• Primary CT (Cisplatin)
Unclear impact of CT on palliation and survival
IVB
FIGO, 2006
Treatment – Stage IB2-IVA
• RH tipo III + LA pelvica + sampling N aortici
IB2-IIA2
• CTRT (RT pelvi + Cisplatino + BRT)
• CTRT (RT pelvi + Cisplatino + BRT) + isterectomia adiuvante
IIB-IVA
• CTRT (RT pelvi + Cisplatino + BRT)
NCCN, 2009
Terapia Adiuvante & Follow-up
N pelvici +
Margini +
Parametrio +
N-
RT pelvi + CT(P) ± BRT (margini vaginali +)
• RT pelvi (volume, invasione stromale, LVSI) ± CT(P)
• Follow-up
EO gen & gin
Pap-test
• ogni 3 mesi (1° anno)
• ogni 4 mesi (2° anno)
• ogni 6 mesi (3-5° anno)
• annuali (> 6° anno)
Rx Torace
ogni anno (opzionale)
Laboratorio
ogni 6 mesi (opzionali)
CT/MRI/PET
su indicazione clinica
NCCN, 2009
(Neo)adjuvant Setting
NACT – Rationale
NACT
SHRINKAGE OF
PRIMARY TUMOR
TREATMENT OF LOCO-REGIONAL
AND DISTANT MICROMETASTASES
ADDITIONAL LOCAL
TREATMENT
BETTER DISEASE
CONTROL
SURVIVAL
BENEFIT
NACT + Surgery vs Exclusive RT (LACC)
Italian Multicenter Randomized Study, 2001
Stage
IB2-IIB
Stage
III
NACT & Radical Surgery
(Locally Advanced Cervical Cancer)
Review & Meta-analysis
Endpoint
Survival
DFS
Loco-regional DFS
Metastases-free survival
Nr. of events
/ patient
368/872
414/872
402/872
381/872
HR
(p value)
0.65 (0.00004)
0.68 (0.0001)
0.68 (0.0001)
0.63 (0.00001)
The absolute improvement in survival of 15% (8-21%) at 5years obtained by NACT is of the same magnitude as that
achieved with the standard cisplatin-based CTRT
Cochrane Coll., 2009
EORTC Trial 55994
Study Coordinators:
S. Greggi
G. Kenter
F. Landoni
Cervical Cancer
(age 18-75)
IB2; IIA2; IIB
RANDOM
NACT +
Radical Surgery
Exclusive
CTRT
Flow-Chart
Sospetto K cervice uterina
Biopsia cervicale
Ca invasivo
Ca microinvasivo
Conizzazione Cervicale
Stadiazione clinica
RMN addome / pelvi
Colposcopia, Rx torace,
SCC Ag, Visita gin. in narcosi,
Cistoscopia e Rettoscopia
IB1
IR tipo B o C +
LA pelvica o
CTRT
MRC Parametri N-
FU
IB2 - II
III - IVA
CTNA + IR tipo C +
LA pelvica o
CTRT
CTRT o
Pelvectomia +
LA pelvica
MRC +
parametri +
N+
Inf stroma cerv >90%
RT
CT +/- RT
Ca non definito / CIN III
Ca invasivo
Ca microinvasivo
IVB
IA1 (margini -)
CT sistemica
FU
IA2
Vedi algoritmo
dedicato
Follow-up
Carcinoma della Cervice non Radiotrattato
1° e 2° anno
3° e 4° anno
Ogni 6
mesi
Ogni 6
mesi
Ogni 12
mesi
5° anno
> 5° anno
Ogni 12
mesi
Ogni 12
mesi
A 30
gg
Ogni 3
mesi
Visita ginecologica
X
X
X
X
X
E.O. generale
X
X
X
X
X
Colposcopia
X
X
X
X
Pap-Test
X
X
X
X
Rx torace
X
X
X
RMN addome-pelvi*
X
X
X
Urinocoltura (+ ev. Abg)
X
X
X
CA125
X
X
X
SCC
X
X
X
Follow-up
Carcinoma della Cervice Radiotrattato
1° e 2° anno
3° e 4° anno
Ogni 6
mesi
Ogni 6
mesi
Ogni 12
mesi
5° anno
> 5° anno
Ogni 12
mesi
Ogni 12
mesi
A 45
gg
Ogni
3
mesi
Visita ginecologica
X
X
X
X
X
E.O. generale
X
X
X
X
X
Colposcopia
X
X
X
X
X
X
X
X
Pap-Test
X
Rx torace
X
X
X
X
X
X
RMN addome-pelvi*
Urinocoltura (+ ev. Abg)
X
X
X
X
CA125
X
X
X
SCC
X
X
X
Rettoscopia
*TAC addome/pelvi qualora RMN controindicata
X
X