TERAPIA CHIRURGICA DELLA DISPLASIA GRAVE IN ESOFAGO DI BARRETT Luigi Bonavina,MD Cattedra e U.O. Chirurgia Generale, Policlinico San Donato Università degli Studi di Milano

XXIV Congresso Nazionale A.C.O.I. Montecatini Terme, 27 Maggio 2005

5 4 7 6 3 2 1 0 1975 Esophageal adenocarcinoma Melanoma Prostate Cancer Breast Cancer Lung Cancer Colorectal Cancer 1980 1985 1990 1995 2000 Pohl H,

J Natl Cancer Inst

2005

5-YR SURVIVAL RATES ACC. TO WALL INFILTRATION 1 cm 90% 80% 70% 30%

PREVALENCE OF NODE+ ACC. TO WALL INFILTRATION

Positive nodes (%) % 100 80 60 40 20 0 0 Tis 25 T 1 64,2 T2 86,1 100 T3 T4

Bonavina et al, WJS 2003

GASTROESOPHAGEAL REFLUX DISEASE Barrett’s metaplasia Low grade dysplasia High grade dysplasia (

in situ carcinoma

) Invasive carcinoma

MOLECULAR EVENTS IN THE SEQUENCE BARRETT’S ESOPHAGUS-ADENOCARCINOMA

Diploid cell p53/p16 mutation Clonal expansion and multicentricity Unpredictable molecular alterations (5q,18q,13q) Adenocarcinoma

Barrett M, Nature Genetics 1999

HIGH-GRADE DYSPLASIA

Dysplasia is the histological expression of genetic alterations that favor cell growth and neoplasia. Glands show severe cytologic atypia, gland complexity with cribriform change and complete loss of nuclear polarity

1.0

CUMULATIVE CANCER INCIDENCE 0.8

0.6

0.4

0.2

HGD

# Ca / n = 33/76

p < .001

Negative, Indefinite, LGD

# Ca / n = 9/251

0.0

0 2 4 6 Years 8 10 12 14 Reid et al,

AJG

2000

HISTOLOGIC CHANGES AFTER TREATMENT OF BE (median F/U > 5 yrs) Dysplasia “de novo” Medical group (n=45) Surgical group (n=58) Successful surgical group (n= 49) 20% 6% 2% HGD 2/8 2/3 0/2

Parrilla et al, 2003

OUTCOME OF RESECTION ACC. TO SURVEILLANCE p< 0.01

months Incarbone et al, Surg Endosc 2002

DIFFICULTIES WITH THE DIAGNOSIS OF HGD • Interobserver agreement is 85% for distinguishing HGD from lesser lesions • There can be substantial disagreement when distinguishing HGD from intramucosal cancer • Dysplastic areas and foci of invasive cancer can be missed by 4-quadrant biopsy technique

EXTENT OF HGD

• FOCAL (histologic abnormalities confined to single focus involving up to 5 crypts) • DIFFUSE (abnormalities present in more than 5 crypts or in multiple biopsy specimen) Buttar, 2001

EXTENT OF HGD AND CANCER RISK

n=100 4-quadrant biopses every 2 cm Focal 4/33

(14%)

p<0.001

Diffuse 28/67

(56%)

Buttar et al., Gastroenterology 2001

RECCOMENDATION OF PRACTICE PARAMETERS COMMITTEE OF A.C.G.

“…patients with focal HGD may be followed with intensive endoscopic surveillance (every 3 months), whereas intervention (e.g. endoscopic ablation or esophagectomy) should be considered for patients with diffuse HGD” Sampliner et al, 2002

Can extent of high grade dysplasia in Barrett’s oesophagus predict the presence of adenocarcinoma at oesophagectomy?

• Revision of preop biopsy specimen in 42 patients who had esophagectomy for HGD • Acc. to Cleveland Clinic criteria, 48% with focal and 67% with diffuse HGD had cancer (pNS) • Acc. to Mayo Clinic criteria, 72% with focal and 54% with diffuse HGD had cancer (pNS) Dar et al, Gut 2003

RATE OF “OCCULT” INVASIVE CARCINOMA IN HGD

Author Skinner (1983) Lee (1985) Hamilton (1987) Reid (1988) DeMeester (1990) Altorki (1991) Pera (1992) Rice (1993) Edwards (1996) Heitmiller (1996) Peracchia (1999) N pts 3 2 4 4 2 8 18 16 11 30 22 120 N adenok 8 13 7 50 2 1 2 0 1 3 9 6 % 67 50 50 0 50 38 50 38 73 43 32 42

HIGH RATE OF OCCULT CARCINOMA • Erroneous definition of HGD (missed intramucosal ADC) • Inclusion of patients with warning signs (presence of nodules/ulcers) • Failure to f/u closely during the first year (cancer missed at 1st endoscopy because of sampling error)

TREATMENT OF HIGH-GRADE DYSPLASIA •Intensive surveillance •Endoscopic ablation •Endoscopic mucosectomy •Esophagectomy

ENDOSCOPIC MUCOSAL RESECTION FOR HGD/IM-Ca 1. Area of Barrett’s < 20 mm in diameter 2. Cancers confined to the lamina propria 3. Involved peripheral or deep margins or extension through muscularis mucosa require esophagectomy

S.B., male, 62 yr old: S/P endoscopic mucosectomy: invasive adenocarcinoma on the resected specimen

TIMING OF SURGERY AND SURVIVAL Prompt Attitude (n=20) 100 80 60 40 100% Expectant Attitude (n=13) 52.5% 30

p =

0.0094

0 0 24 48 72 96 120 144 168 192 Romagnoli, JACS 2003

FREQUENCY OF ESOPHAGECTOMY AND HOSPITAL MORTALITY 30 25 20 15 10 5 0 0 10 20 30 Case load/year 40 50 Metzger,

Dis Esoph

2004

PARTIAL ESOPHAGECTOMY AND JEJUNAL INTERPOSITION

Theoretical drawbacks •High mediastinal anastomosis •Incomplete Barrett’s ablation •Limited clinical experience (Siewert)

NERVE SPARING ESOPHAGECTOMY Introduced by Professor Hiroshi Akiyama.

Esophageal Plexus Left Vagal Trunk Right Vagal Trunk

J Am Coll Surg 1994;178:83

Invaginated Esophagus

LAPAROSCOPIC + TRANS-CERVICAL VIDEOASSISTED MEDIASTINAL DISSECTION Bonavina et al, J Lap Adv Surg Tech, 2004

351

ADENOCARCINOMA OF EGJ 506 consecutive patients (1992-2004)

Barrett's* Type II-III 155 (31%)

University of Milano, Department of Surgery

PATIENTS REFERRED FOR HGD n=30 Sex (M/F) Mean age (yrs) Range GERD Surveillance Symptom duration (yrs) Mean no. previous endoscopies 27/3 58 35-78 23/30 22/30 7 6

STAGING PROTOCOL • Operative risk assessment • Repeat endoscopy + Lugol staining • Brushing cytology • 4-quadrant biopsies every cm • Look for nodules/ulcers • EUS/CT scan if doubtful • High-dose PPI if less than HGD • Repeat endoscopy (at 1-3 months)

RESULTS OF STAGING AND THERAPY (n=30) 1st endoscopy: 7 invasive carcinoma (>surgery) 1 LGD 22 HGD (73%) 2nd endoscopy: 5 invasive carcinoma (>surgery) 1 LGD 17 HGD (57%) 15 surgery (9 TME, 6 TTE) 1 PDT 1 PPI therapy

RESULTS OF ESOPHAGECTOMY FOR HGD n=15 •No operative mortality •Morbidity 2 atelectasis 1 chylothorax •Pathology 1 LGD 4 invasive carcinoma (27%) 10 confirmed HGD

ESOPHAGECTOMY FOR HGD Actuarial survival (n=15)

ONGOING RESEARCH PROTOCOLS Tailored lymphadenectomy based on the sentinal node concept

Endoscopic peritumoral ink injection Laparoscopic nodal removal Histopathological assessment

CONCLUSIONS •Prevalence of adenocarcinoma detected at endoscopy was 40% in patients referred with diagnosis of HGD •27% of patients with confirmed endoscopic diagnosis of HGD had cancer in the resected specimen •E.M.R. should be recommended only in patients with low likelihood of lymphatic spread •Videoassisted transmediastinal esophagectomy is the approach of choice in intramucosal tumors

“Surgery remains radical prophylaxis.…offering a massive macroscopic morbid solution for a microscopic mucosal problem”

Barr, Gut 2003; 52:14-5

FUTURE SCENARIO • Improved reflux control by fundoplication • Barrett’s ablation and chemoprevention of genomic instability (Aspirin?) • Tailored surgical approach (vagal sparing procedures, sentinel node technology)