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Carcinoma della Cervice Uterina Cronoprogramma Diagnostico-Terapeutico

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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  1. Carcinoma della Cervice Uterina Cronoprogramma Diagnostico-Terapeutico

  2. Pap-test Anormale L-SIL H-SIL Bethesda System, 2001

  3. Pap-test Anormale

  4. Pap-test Anormale H-SIL 8% ICC  0% L-SIL 31% ASC-US 61% Davey, 2004

  5. 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

  6. % Upgrading CIN 2-3Cancer Microinv. Inv. ASC-US5-17 ASC-H24-94 CIN 3 6-121-2 0.2

  7. HPV-test HR - HR + Colposcopia Pap-test a 12 mesi - + Colposcopia Screening ASC-US –HPV-test Triage SICPCV, 2006

  8. HPV-test Triage – Raccomandazioni Statement on HPV DNA test utilization, 2009

  9. p16 Triage (sperimentale) HPV-test (screening) HR + HR - p16-test - + Colposcopia HPV-test a un anno Carozzi, 2008

  10. ASC-US- ASC-H - L-SIL SICPCV, 2006

  11. H-SIL – Carcinoma squamocellulare SICPCV, 2006

  12. AGC SICPCV, 2006

  13. 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

  14. 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

  15. 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 IIIA 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 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

  16. Microinvasive CC Early CC • IA • IB1 • IIA1 Locally Advanced CC (LACC) Metastatic CC • IB2 • IIA2 • IIB • III • IVA • IVB

  17. CONIZZAZIONE CERVICALE EVISCERAZIONE PELVICA

  18. 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

  19. 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

  20. Cone: Positive margin

  21. Microcarcinoma – Cone Positive Margin • In patient with positive margins: • Vaginal Strict Follow-Up • Endocervical Repeat Conization or • or Stromal Hysterectomy

  22. 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

  23. 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

  24. 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

  25. 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

  26. CERVICAL CARCINOMA ClinicalAssessment FIGO Stage T size Histotype & Grade Lymphnode mets Bladder/Rectum involvement Parametrial infiltration Vaginal infiltration

  27. 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

  28. 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

  29. 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

  30. Cervical Cancer Detection of Advanced Stage (>IIB) Cancerby 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

  31. 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

  32. 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

  33. 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

  34. Radical Hysterectomy – History & Classification Wertheim (1900) Okabayashi (1921) Meigs (1951) Nerve-sparing (1990s) Robotics (2000s) Piver-Rutledge (1974) Mota-EORTC (2008) Querleu-Morrow (2008)

  35. 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

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

  37. Type 3 RH Type 2 RH Type 3 RH

  38. 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

  39. 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

  40. Type A Type B1 Type C2

  41. 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

  42. LN Involvement by Stage FIGO, 2006

  43. 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

  44. 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

  45. 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

  46. 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

  47. (Neo)adjuvant Setting

  48. NACT – Rationale NACT TREATMENT OF LOCO-REGIONAL AND DISTANT MICROMETASTASES SHRINKAGE OF PRIMARY TUMOR ADDITIONAL LOCAL TREATMENT BETTER DISEASE CONTROL SURVIVAL BENEFIT

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