Carcinoma della Cervice UterinaCarcinoma della Cervice UterinaCronoprogramma Cronoprogramma

Diagnostico-TerapeuticoDiagnostico-Terapeutico

Pap-test Anormale

Bethesda System, 2001

L-SIL

H-SIL

Pap-test Anormale

ASC-USASC-US61%61%

L-SIL 31%L-SIL 31%

H-SIL 8%H-SIL 8% ICC ICC 0% 0%

Pap-test Anormale

Davey, 2004

Solomon (ALTS Group), 2001 Stoler, 2001

Sherman, 2001Kristen (ALTS Group), 2006

INCIDENCE: 1.3-5.0%INCIDENCE: 1.3-5.0%

CYTOLOGIC REVISION

Downgraded to neg 40%

Upgraded to L-SIL 20%

Upgraded to H-SIL 2%

• Low reproducibility level• Low PPV

ASC-US

NEGATIVE 75-85%

RISK OF CIN2+ 12%

RISK OF CIN3+ 5%

CIN 2-3CIN 2-3 CancerCancer

Microinv. Inv.Microinv. Inv.

ASC-USASC-US 5-175-17

ASC-HASC-H 24-9424-94

CIN 3 CIN 3 6-126-12 1-21-2

% Upgrading% Upgrading

0.2 0.2

ASC-US – HPV-test Triage

SICPCV, 2006

HPV-testHPV-test

HR +HR + HR -HR -

ColposcopiaColposcopia Pap-test Pap-test a 12 mesia 12 mesi

++ --

ColposcopiaColposcopia ScreeningScreening

Statement on HPV DNA test utilization, 2009

HPV-test Triage – Raccomandazioni

p16 Triage (sperimentale)

HPV-test (screening)HPV-test (screening)

HR -HR - HR +HR +

p16-testp16-test

++ --

ColposcopiaColposcopia HPV-test a un annoHPV-test a un anno

Carozzi, 2008

ASC-US - ASC-H - L-SIL

SICPCV, 2006

H-SIL – Carcinoma squamocellulare

SICPCV, 2006

AGC

SICPCV, 2006

• Citologia e colposcopia ogni 6 mesi per 2 anni• Controllo annuale per altri 5 anni• Ritorno a screening

Follow-up

SICPCV, 2006

Colposcopia, citologia e HPV-testColposcopia, citologia e HPV-test

Colposcopia Colposcopia e/o citologia +e/o citologia +

--

Percorso Percorso sec. lesionesec. lesione

Pap-test e HPV-test Pap-test e HPV-test a 12 mesia 12 mesi

++ --

ColposcopiaColposcopia ScreeningScreening

Colposcopia Colposcopia e/o citologia -e/o citologia -

HPV +HPV +

Controllo Controllo a 6 mesia 6 mesi

A 6 mesi da trattamento

• • Carcinoma squamoso Carcinoma squamoso in situin situ• • Carcinoma squamoso inf.Carcinoma squamoso inf. cheratinizzante, non-cheratinizzante, verrucosocheratinizzante, non-cheratinizzante, verrucoso

• • Adenocarcinoma Adenocarcinoma in situ / in situ / tipo endocerv. tipo endocerv. • • Adenocarcinoma endometrioideAdenocarcinoma endometrioide• • Adenocarcinoma a cellule chiareAdenocarcinoma a cellule chiare• • Ca. adenosquamosoCa. adenosquamoso• • Ca. adenoide cisticoCa. adenoide cistico• Ca. a piccole celluleCa. a piccole cellule• • Ca. indifferenziatoCa. indifferenziato• Ca. neuroendocrinoCa. neuroendocrino

IstotipiIstotipi

FIGO, 2006FIGO, 2006

~10%~10%

~80%~80%

I The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded)IA Invasive carcinoma which can be diagnosed only by microscopy, with deepest invasion ≤5mm and largest extension ≤7mmIA1 Measured stromal invasion ≤3mm in depth and horizontal extension ≤7mmIA2 Measured stromal invasion >3mm and not >5mm with an extension of not >7mmIB Clinically visible lesions limited to the cervix or pre-clinical cancers > Stage IAIB1 Clinically visible lesion ≤4cm in greatest dimensionIB2 Clinically visible lesion >4cm in greatest dimensionII Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to

the lower third of the vaginaIIA Without parametrial invasionIIA1 Clinically visible lesion ≤4cm in greatest dimensionIIA2 Clinically visible lesion >4cm in greatest dimensionIIB With obvious parametrial invasionIII The tumor extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or non-functioning kidneyIIIA Tumor involves lower third of the vagina (No extension to the pelvic wall)IIIB Extension to the pelvic wall and/or hydronephrosis or non-functioning kidneyIV 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 IVIVA Spread of the growth to adjacent organsIVB Spread to distant organs

Cervical Cancer - FIGO Staging (2009)

Microinvasive CC

• IA

Early CC

• IB1

• IIA1

Locally Advanced CC

(LACC)

• IB2

• IIA2

• IIB

• III

• IVA

Metastatic CC

• IVB

CONIZZAZIONE CERVICALE

EVISCERAZIONE PELVICA

FIGOIA1: stromal invasion ≤ 3 mm in depth, horizontal extension ≤ 7 mm IA2: stromal invasion 3-5 mm in depth, horizontal extension ≤ 7 mm

SGOStromal invasion ≤ 3 mm in depth, no LVSI

Microcarcinoma – Staging Criteria

Microcarcinoma – Treatment

• Total abdominal or vaginal hysterectomy (if VAIN, appropriate cuff of vagina should be removed)

• Observation after cone biopsy (particularly if fertility is desired)

FIGO, 2006

IA1

• Modified RH (Type 2) and pelvic LND• Consider extrafascial H and pelvic LND (if no LVSI)

If fertility is desired:• large cone biopsy + extra-perit. or lpsc pelvic LND• rad. trachelectomy and extra-perit.or lpsc pelvic LND

IA2

Mainly with Pap smears annually after two normal smears at 4 and 10 mos

Follow-up

Cone: Positive margin

In patient with positive margins:

• Vaginal Strict Follow-Up

• Endocervical Repeat Conization or or Stromal Hysterectomy

Microcarcinoma – Cone Positive Margin

Fertility-sparing surgeryCervical Cancer

Radical Trachelectomy

Eligibility criteria

Dargent, 1994

43% of cervical cancer in women <45y (10-15% during childbearing years)

• Vaginal• Abdominal• Laparoscopic• Robotic

• 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

Fertility-sparing surgeryRVT & Cancer prognosis

Overall recurrence and death rates comparable to early-stage cervical cancer treated by RH or RT

Plant, 2004; Seli, 2005

Review n Recurrence Rates

DeathRates

Darsun, 2007 520 4.2 2.8

Sonoda, 2008 548 4.0 2.6

Plante, 2008 603 4.5 2.5

Fertility-sparing surgeryRVT & Pregnancy outcome

Pregnancy rate Pregnancy rate 70%70%

11stst-2-2ndnd trimester loss trimester loss 30%30%

Review (16 studies: 355 RVT / 161 pregnancies)

Boss, 2005

Pregnancy rate Pregnancy rate 62%62%

TAB/EUP TAB/EUP 5% 5%11stst-2-2ndnd trimester loss trimester loss 27%27%Deliveries <32 ws Deliveries <32 ws 12%12%

Deliveries >37 ws Deliveries >37 ws 65%65%Currently pregnant Currently pregnant 6% 6%

Review (8 studies : 603 RVT / 256 pregnancies)

Plante, 2008

CK ConizationCK Conization

Follow-upFollow-up

Margins +Margins +

Repeat coneRepeat coneLVSI +LVSI +

Margins -Margins -

Pelvic LNDPelvic LND

N +N +RHRH N -N - Follow-upFollow-up

No Res TNo Res T

Invasive Res TInvasive Res T

RH + pelvic LNDRH + pelvic LND

Cerv Microca – Conservative Treatment Cerv Microca – Conservative Treatment Algorythm Algorythm

IA2IA2

LVSI -LVSI -

CERVICAL CARCINOMA

Clinical AssessmentClinical Assessment

Histotype & Grade

Bladder/Rectum involvement

Parametrial infiltration

FIGO StageFIGO Stage

Vaginal infiltration

Lymphnode mets

T size

• Esame vaginale bimanuale e vagino-rettale (in narcosi)

• Colposcopia, biopsia / conizzazione

• Currettage endocervicale

• Cistoscopia

• Retto-sigmoidoscopia

• Rx torace (2 proiezioni)

• TAC/RMN (PET)

FIGO, 2006

Stadiazione Clinica

CC localmente avanzatoCC localmente avanzatoCC apparentemente inizialeCC apparentemente iniziale

• RX torace

• RMN addome/pelvi

• Visita ginecologica in narcosi• RX torace• RMN addome/pelvi• Uretrocistoscopia• Retto-sigmoidoscopia

Cervical Cancer Cervical Cancer Comparison of Diagnostic Procedure UtilizationComparison of Diagnostic Procedure Utilization

ACRIN 6651/GOG 183 (n=208 ;Stage ≥ IB)ACRIN 6651/GOG 183 (n=208 ;Stage ≥ IB)

1978 1978 19831983 1988-19891988-1989 20022002

Cystoscopy Cystoscopy 64%64% 80% 80% 52% 52% 8.1%8.1%

Sigmoidoscopy Sigmoidoscopy 44% 44% 58%58% 49% 49% 8.6%8.6%

Barium enema Barium enema 58% 58% 60% 60% 32% 32% 00

Intravenous urogram Intravenous urogram 86% 86% 91% 91% 42% 42% 1.0%1.0%

Lymphangiography Lymphangiography 18% 18% 11% 11% 14% 14% 00

CT/MRI CT/MRI 16% 16% 54% 54% 70% 70% 100%100%

Montana, 1995Montana, 1995Amendola, 2005Amendola, 2005

Narayan K, 2003

MRI staging for cervical cancer is now widely accepted as an optimal method for evaluation of tumor volume, uterine corpus involvement, parametrial invasion, …

Cervical CancerMRI

… but prediction of parametrial, bladder and rectal involvement is correct in 75% of cases at best

Bipatt, 2003Narayan, 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)

CTCT MRIMRI P ValueP Value

Mean sensitivity (%)Mean sensitivity (%) 2828 47 47 0.1040.104

Mean specificityMean specificity (%)(%) 9090 7979 0.0990.099

Mean PPV (%)Mean PPV (%) 5555 3636 0.0010.001

Mean NPV (%)Mean NPV (%) 8383 8585 0.3050.305

Hricak, 2007

Cervical Cancer Performance of CT & MRI in Detecting

Lymph Node Involvement

ACRIN 6651/GOG 183 (n=208 – Stage ≥ IB)

CT CT MRIMRI

Sensitivity (%)Sensitivity (%) 3131 37 37

Specificity (%)Specificity (%) 8686 94 94

Hricak, 2005

FIGO, 2006

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

• 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

Treatment – Stage IB1-IIA1

Wertheim (1900)

Okabayashi (1921)

Meigs (1951)

Nerve-sparing (1990s)

Robotics (2000s)

Piver-Rutledge (1974)

Mota-EORTC (2008)

Querleu-Morrow (2008)

Radical Hysterectomy – History & 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

Radical Hysterectomy – Piver-Rutledge Classification

Piver, 1974

THE POINT OF TRANSECTION OF THE UTEROSACRAL AND CARDINAL LIGAMENTS IN CLASS II AND III RH

Type 3 RHType 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

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)

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

Querleu, 2008

Type AType A

Type B1Type B1 Type C2Type C2

Surgery-related Complications

Rad. Hysterectomy Rad. Hysterectomy (type III) (type III)

+ Pelvic Lymph.+ Pelvic Lymph.

10-15% Severe 10-15% Severe Perioperative Compl.Perioperative Compl.

20-30% Early/Late 20-30% Early/Late Bladder/Rectal Disf.Bladder/Rectal Disf.

75% vs 10% (III vs II) 75% vs 10% (III vs II) Temp. Bladder Disf. Temp. Bladder Disf.

Literature Review

FIGO, 2006

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

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

• Primary CT (Cisplatin)

Unclear impact of CT on palliation and survival

FIGO, 2006

IIB-IVA

IVB

• RH tipo III + LA pelvica + sampling N aortici

• CTRT (RT pelvi + Cisplatino + BRT)

• CTRT (RT pelvi + Cisplatino + BRT) + isterectomia adiuvante

IB2-IIA2

NCCN, 2009

Treatment – Stage IB2-IVA

• CTRT (RT pelvi + Cisplatino + BRT)IIB-IVA

• RT pelvi (volume, invasione stromale, LVSI) ± CT(P)

• Follow-up N -

RT pelvi + CT(P) ± BRT (margini vaginali +)N pelvici +Margini +Parametrio +

NCCN, 2009

Terapia Adiuvante & Follow-up

• ogni 3 mesi (1° anno)• ogni 4 mesi (2° anno)• ogni 6 mesi (3-5° anno)• annuali (> 6° anno)

EO gen & gin Pap-test

Rx Torace

Laboratorio

CT/MRI/PET

ogni anno (opzionale)

ogni 6 mesi (opzionali)

su indicazione clinica

(Neo)adjuvant Setting

NACT

SHRINKAGE OF PRIMARY TUMOR

TREATMENT OF LOCO-REGIONAL AND DISTANT MICROMETASTASES

ADDITIONAL LOCAL TREATMENT

BETTER DISEASE CONTROL

SURVIVAL BENEFIT

NACT – Rationale

Italian Multicenter Randomized Study, 2001

NACT + Surgery vs Exclusive RT (LACC)

Stage

IB2-IIB

Stage

III

Endpoint Nr. of events / patient

HR

(p value)

Survival

DFS

Loco-regional DFS

Metastases-free survival

368/872

414/872

402/872

381/872

0.65 (0.00004)

0.68 (0.0001)

0.68 (0.0001)

0.63 (0.00001)

NACT & Radical Surgery (Locally Advanced Cervical Cancer)

Review & Meta-analysis

The absolute improvement in survival of 15% (8-21%) at 5-years obtained by NACT is of the same magnitude as that achieved with the standard cisplatin-based CTRT

Cochrane Coll., 2009

EORTC Trial 55994EORTC Trial 55994Study Coordinators:Study Coordinators:

S. GreggiS. GreggiG. KenterG. Kenter

F. LandoniF. Landoni

IB2; IIA2; IIBIB2; IIA2; IIB

Cervical Cancer Cervical Cancer (age 18-75)(age 18-75)

RANDOMRANDOM

NACT + NACT + Radical SurgeryRadical Surgery

ExclusiveExclusiveCTRTCTRT

Flow-Chart

IR tipo B o C +LA pelvica o

CTRT

IB1

FU

MRC -Parametri -

N -

RT

MRC + parametri + N + Inf stroma cerv >90%

CT +/- RT

CTNA + IR tipo C + LA pelvica o

CTRT

IB2 - II

CTRT oPelvectomia +LA pelvica

III - IVA

CT sistemica

IVB

RMN addome / pelvi Colposcopia, Rx torace,

SCC Ag, Visita gin. in narcosi,Cistoscopia e Rettoscopia

Stadiazione clinica

Ca invasivo

Ca invasivo

FU

IA1 (margini -)

Vedi algoritmo dedicato

IA2

Ca microinvasivo

Conizzazione Cervicale

Ca microinvasivo Ca non definito / CIN III

Biopsia cervicale

Sospetto K cervice uterina

  Carcinoma della Cervice non Radiotrattato

1° e 2° anno 3° e 4° anno 5° anno > 5° anno

  A 30 gg

Ogni 3 mesi

Ogni 6 mesi

Ogni 6 mesi

Ogni 12 mesi

Ogni 12 mesi

Ogni 12 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 Radiotrattato1° e 2° anno 3° e 4° anno 5° anno > 5° anno

  A 45 gg

Ogni 3

mesi

Ogni 6 mesi

Ogni 6 mesi

Ogni 12 mesi

Ogni 12 mesi

Ogni 12 mesi

Visita ginecologica X X   X   X X

E.O. generale X X   X   X X

Colposcopia X X   X   X X

Pap-Test     X X   X X

Rx torace     X   X X  

RMN addome-pelvi*   X X   X X  

Urinocoltura (+ ev. Abg) X X   X      

CA125   X   X   X  

SCC   X   X   X  

Rettoscopia       X X    

*TAC addome/pelvi qualora RMN controindicata

Follow-up