luigi bonavina,md cattedra e u.o. chirurgia generale, policlinico san donato università degli studi...
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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
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Rat
e ra
tio
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ativ
e to
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Esophageal adenocarcinomaMelanomaProstate CancerBreast CancerLung CancerColorectal Cancer
Pohl H, J Natl Cancer Inst 2005
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1 cm
5-YR SURVIVAL RATES ACC. TO WALL INFILTRATION
90%
80%
70%
30%
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64,2
86,1
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20
40
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Tis T 1 T2 T3 T4
Positive nodes (%)%
PREVALENCE OF NODE+ ACC. TO WALL INFILTRATION
Bonavina et al, WJS 2003
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Barrett’s metaplasia
High grade dysplasia(in situ carcinoma)
Low grade dysplasia
Invasive carcinoma
GASTROESOPHAGEAL REFLUX DISEASEGASTROESOPHAGEAL REFLUX DISEASE
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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
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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
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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
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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
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p< 0.01
OUTCOME OF RESECTION ACC. TO SURVEILLANCE
months
Cum
ulative survival %
Incarbone et al, Surg Endosc 2002
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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
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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
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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
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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
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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
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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
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• 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
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TREATMENT OF HIGH-GRADE DYSPLASIA
•Intensive surveillance
•Endoscopic ablation
•Endoscopic mucosectomy
•Esophagectomy
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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
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S.B., male, 62 yr old: S/P endoscopic mucosectomy: invasive adenocarcinoma on the resected specimen
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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
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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
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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)
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EsophagealPlexus
Left VagalTrunk
Right Vagal Trunk
InvaginatedEsophagus
Introduced byProfessor
Hiroshi Akiyama.
J Am Coll Surg 1994;178:83
NERVE SPARING ESOPHAGECTOMYNERVE SPARING ESOPHAGECTOMY
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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
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University of Milano, Department of Surgery
ADENOCARCINOMA OF EGJ506 consecutive patients
(1992-2004)
155
351
Barrett's*Type II-III
(31%)
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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
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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)
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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
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•No operative mortality
•Morbidity
2 atelectasis
1 chylothorax
•Pathology
1 LGD
4 invasive carcinoma (27%)
10 confirmed HGD
RESULTS OF ESOPHAGECTOMY FOR HGDn=15
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ESOPHAGECTOMY FOR HGD
Actuarial survival (n=15)
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ONGOING RESEARCH PROTOCOLS
Tailored lymphadenectomy based on the sentinal node concept
Endoscopic peritumoral ink injection
Laparoscopic nodal removal
Histopathological assessment
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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
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“Surgery remains radical prophylaxis.…offering a massive
macroscopic morbid solution for a microscopic mucosal problem”
Barr, Gut 2003; 52:14-5
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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)