Luigi Bonavina,MDCattedra 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

TERAPIA CHIRURGICA DELLA DISPLASIA GRAVE IN ESOFAGO DI BARRETT

0

1

2

3

4

5

6

7

1975 1980 1985 1990 1995 2000

Rat

e ra

tio

(rel

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197

5)

Esophageal adenocarcinomaMelanomaProstate CancerBreast CancerLung CancerColorectal Cancer

Pohl H, J Natl Cancer Inst 2005

1 cm

5-YR SURVIVAL RATES ACC. TO WALL INFILTRATION

90%

80%

70%

30%

0

25

64,2

86,1

100

0

20

40

60

80

100

Tis T 1 T2 T3 T4

Positive nodes (%)%

PREVALENCE OF NODE+ ACC. TO WALL INFILTRATION

Bonavina et al, WJS 2003

Barrett’s metaplasia

High grade dysplasia(in situ carcinoma)

Low grade dysplasia

Invasive carcinoma

GASTROESOPHAGEAL REFLUX DISEASEGASTROESOPHAGEAL REFLUX DISEASE

MOLECULAR EVENTS IN THE SEQUENCE

BARRETT’S ESOPHAGUS-ADENOCARCINOMA

Barrett M, Nature Genetics 1999

Diploid cell

p53/p16 mutation

Clonal expansion and multicentricity

Unpredictable molecularalterations (5q,18q,13q)

Adenocarcinoma

HIGH-GRADE DYSPLASIADysplasia 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

0.8

0.6

0.4

0.2

0.00 2 4 6 8 10 12 14

Pro

babi

lity

Years

HGD# Ca / n = 33/76

p < .001

Negative, Indefinite, LGD# Ca / n = 9/251

Reid et al, AJG 2000

CUMULATIVE CANCER INCIDENCE

HISTOLOGIC CHANGES AFTER TREATMENT OF BE (median F/U > 5 yrs)

Medical group (n=45)

Surgical group (n=58)

Successful surgical group (n= 49)

Dysplasia

“de novo”20% 6% 2%

HGD 2/8 2/3 0/2

Parrilla et al, 2003

p< 0.01

OUTCOME OF RESECTION ACC. TO SURVEILLANCE

months

Cum

ulative survival %

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, 2001Buttar, 2001

EXTENT OF HGD AND CANCER RISK n=100

4-quadrant biopses every 2 cm

Focal 4/33 (14%)

Diffuse 28/67 (56%)

Buttar et al., Gastroenterology 2001

p<0.001

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, 2002Sampliner 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 2003Dar et al, Gut 2003

RATE OF “OCCULT” INVASIVE CARCINOMA IN HGD

Author N pts N adenok %

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

120 50 42

• 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)

HIGH RATE OF OCCULT CARCINOMA

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 diameter2. Cancers confined to the lamina propria3. 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

Romagnoli, JACS 2003

Prompt Attitude (n=20)

100%

Expectant Attitude (n=13)

52.5%

p = 0.0094

Can

cer-

rela

ted

surv

ival

(%

) 100

80

60

40

30

00 24 48 72 96 120 144 168 192

0

5

10

15

20

25

30

0 10 20 30 40 50

FREQUENCY OF ESOPHAGECTOMY AND HOSPITAL MORTALITY

Mor

tali

ty r

ate

(%)

Case load/yearMetzger,Dis Esoph 2004

PARTIAL ESOPHAGECTOMY AND JEJUNAL INTERPOSITION

Theoretical drawbacksTheoretical drawbacks

•High mediastinal anastomosisHigh mediastinal anastomosis

•Incomplete Barrett’s ablationIncomplete Barrett’s ablation

•Limited clinical experience Limited clinical experience (Siewert)(Siewert)

EsophagealPlexus

Left VagalTrunk

Right Vagal Trunk

InvaginatedEsophagus

Introduced byProfessor

Hiroshi Akiyama.

J Am Coll Surg 1994;178:83

NERVE SPARING ESOPHAGECTOMYNERVE SPARING ESOPHAGECTOMY

LAPAROSCOPIC + TRANS-CERVICALLAPAROSCOPIC + TRANS-CERVICALVIDEOASSISTED MEDIASTINAL DISSECTIONVIDEOASSISTED MEDIASTINAL DISSECTION

Bonavina et al, J Lap Adv Surg Tech, 2004Bonavina et al, J Lap Adv Surg Tech, 2004

University of Milano, Department of Surgery

ADENOCARCINOMA OF EGJ506 consecutive patients

(1992-2004)

155

351

Barrett's*Type II-III

(31%)

PATIENTS REFERRED FOR HGDn=30

Sex (M/F) 27/3

Mean age (yrs) 58

Range 35-78

GERD 23/30

Surveillance 22/30

Symptom duration (yrs) 7

Mean no. previous endoscopies 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

•No operative mortality

•Morbidity

2 atelectasis

1 chylothorax

•Pathology

1 LGD

4 invasive carcinoma (27%)

10 confirmed HGD

RESULTS OF ESOPHAGECTOMY FOR HGDn=15

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)