Carcinoma della Cervice Uterina
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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

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Carcinoma della Cervice Uterina Cronoprogramma Diagnostico-Terapeutico

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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

Downgraded to neg 40%

Upgraded to L-SIL 20%

Upgraded to H-SIL 2%

  • Low reproducibility level

  • Low PPV

NEGATIVE 75-85%

RISK OF CIN2+ 12%

RISK OF CIN3+ 5%

Solomon (ALTS Group), 2001

Stoler, 2001

Sherman, 2001

Kristen (ALTS Group), 2006


% Upgrading

CIN 2-3Cancer

Microinv. Inv.

ASC-US5-17

ASC-H24-94

CIN 3 6-121-2

0.2


HPV-test

HR -

HR +

Colposcopia

Pap-test

a 12 mesi

-

+

Colposcopia

Screening

ASC-US –HPV-test Triage

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


Colposcopia, citologia e HPV-test

-

Colposcopia e/o citologia +

Colposcopia e/o citologia -

HPV +

Pap-test e HPV-test

a 12 mesi

Percorso sec. lesione

Controllo

a 6 mesi

-

+

Colposcopia

Screening

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

SICPCV, 2006


Istotipi

  • • Carcinoma squamoso in situ

  • • Carcinoma squamoso inf.

  • 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

~80%

~10%

FIGO, 2006


Cervical Cancer - FIGO Staging (2009)

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 ≤7mm

IA1 Measured stromal invasion ≤3mm in depth and horizontal extension ≤7mm

IA2 Measured stromal invasion >3mm and not >5mm with an extension of not >7mm

IB Clinically visible lesions limited to the cervix or pre-clinical cancers > Stage IA

IB1 Clinically visible lesion ≤4cm in greatest dimension

IB2 Clinically visible lesion >4cm in greatest dimension

II Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina

IIA Without parametrial invasion

IIA1 Clinically visible lesion ≤4cm in greatest dimension

IIA2 Clinically visible lesion >4cm in greatest dimension

IIB With obvious parametrial invasion

III The tumor extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or non-functioning kidney

IIIATumor involves lower third of the vagina (No extension to the pelvic wall)

IIIB Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney

IV 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

IVA Spread of the growth to adjacent organs

IVB Spread to distant organs


Microinvasive CC

Early CC

  • IA

  • IB1

  • IIA1

Locally Advanced CC (LACC)

Metastatic CC

  • IB2

  • IIA2

  • IIB

  • III

  • IVA

  • IVB


CONIZZAZIONE CERVICALE

EVISCERAZIONE PELVICA


Microcarcinoma– Staging Criteria

FIGO

IA1: stromal invasion ≤ 3 mm in depth, horizontal extension ≤ 7 mmIA2: 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)

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

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

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 Repeat Conization or

  • or Stromal Hysterectomy


Fertility-sparing surgery

Cervical Cancer

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

  • Vaginal

  • Abdominal

  • Laparoscopic

  • Robotic

Radical Trachelectomy

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

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

(8 studies : 603 RVT / 256 pregnancies)

Review

(16 studies: 355 RVT / 161 pregnancies)

Pregnancy rate 70%

1st-2nd trimester loss 30%

Pregnancy rate 62%

TAB/EUP 5%

1st-2nd trimester loss 27%

Deliveries <32 ws 12%

Deliveries >37 ws 65%

Currently pregnant 6%

Boss, 2005

Plante, 2008


CervMicroca – Conservative Treatment Algorythm

CK Conization

IA2

Margins -

Margins +

Repeat cone

Follow-up

LVSI +

No Res T

LVSI -

Invasive Res T

Pelvic LND

RH

N +

N -

Follow-up

RH + pelvic LND


CERVICAL CARCINOMA

ClinicalAssessment

FIGO Stage

T size

Histotype & Grade

Lymphnode mets

Bladder/Rectum involvement

Parametrial infiltration

Vaginal 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

CC localmente avanzato

  • RX torace

  • RMN addome/pelvi

  • 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 19831988-19892002

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) Cancerby Retrospective Readers of CT & MRI

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

CTMRIP Value

Mean sensitivity (%) 2847 0.104

Mean specificity(%)90790.099

Mean PPV (%)55360.001

Mean NPV (%)83850.305

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)

Nerve-sparing (1990s)

Robotics (2000s)

Piver-Rutledge (1974)

Mota-EORTC (2008)

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 2 RH

Type 3 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

  • CTRT (RT pelvi + Cisplatino + BRT)

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

IB2-IIA2

IIB-IVA

  • CTRT (RT pelvi + Cisplatino + BRT)

NCCN, 2009


Terapia Adiuvante & Follow-up

N pelvici +

Margini +

Parametrio +

RT pelvi + CT(P) ± BRT (margini vaginali +)

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

  • Follow-up

N -

  • 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

ogni anno (opzionale)

Laboratorio

ogni 6 mesi (opzionali)

CT/MRI/PET

su indicazione clinica

NCCN, 2009


(Neo)adjuvant Setting


NACT – Rationale

NACT

TREATMENT OF LOCO-REGIONAL AND DISTANT MICROMETASTASES

SHRINKAGE OF PRIMARY TUMOR

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

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 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

Ca non definito / CIN III

Conizzazione Cervicale

Stadiazione clinica

RMN addome / pelvi

Colposcopia, Rx torace,

Ca invasivo

Ca microinvasivo

SCC Ag, Visita gin. in narcosi,

Cistoscopia e Rettoscopia

IB1

IB2 - II

III - IVA

IVB

IA1 (margini -)

IA2

IR tipo B o C +

CTNA + IR tipo C +

CTRT o

Vedi algoritmo dedicato

LA pelvica o

LA pelvica o

Pelvectomia +

CT sistemica

FU

CTRT

CTRT

LA pelvica

MRC -

MRC + parametri +

Parametri -

N +

Inf stroma cerv >90%

N -

FU

RT

CT +/- RT


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 Radiotrattato

1° 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


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