TERAPIA CHIRURGICA DELLA DISPLASIA GRAVE IN ESOFAGO DI BARRETT

1
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
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Esophageal adenocarcinoma Melanoma Prostate
Cancer Breast Cancer Lung Cancer Colorectal Cancer
Rate ratio (relative to 1975)
Pohl H, J Natl Cancer Inst 2005
3
5-YR SURVIVAL RATES ACC. TO WALL INFILTRATION
90
80
1 cm
70
30
4
PREVALENCE OF NODE ACC. TO WALL INFILTRATION

Bonavina et al, WJS 2003
5
GASTROESOPHAGEAL REFLUX DISEASE
Barretts metaplasia
Low grade dysplasia
High grade dysplasia (in situ carcinoma)
Invasive carcinoma
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MOLECULAR EVENTS IN THE SEQUENCE BARRETTS
ESOPHAGUS-ADENOCARCINOMA
Diploid cell
p53/p16 mutation
Clonal expansion and multicentricity
Unpredictable molecular alterations (5q,18q,13q)
Adenocarcinoma
Barrett M, Nature Genetics 1999
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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
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CUMULATIVE CANCER INCIDENCE
1.0
0.8
HGD Ca / n 33/76 p lt .001 Negative,
Indefinite, LGD Ca / n 9/251
0.6
Probability
0.4
0.2
0.0
0
6
12
2
4
8
10
14
Years
Reid et al, AJG 2000
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HISTOLOGIC CHANGES AFTER TREATMENT OF BE (median
F/U gt 5 yrs)
Medical group (n45) Surgical group (n58) 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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OUTCOME OF RESECTION ACC. TO SURVEILLANCE
Cumulative survival
plt 0.01
months
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, 2001
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EXTENT OF HGD AND CANCER RISK n100 4-quadrant
biopses every 2 cm
Focal 4/33 (14) Diffuse 28/67 (56)
plt0.001
Buttar et al., Gastroenterology 2001
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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, 2002
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Can extent of high grade dysplasia in Barretts
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
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RATE OF OCCULT INVASIVE CARCINOMA IN HGD
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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)

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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 Barretts lt 20 mm in diameter 2.
Cancers confined to the lamina propria 3.
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
Prompt Attitude (n20)
100
100
80
Expectant Attitude (n13)
60
Cancer-related survival ()
52.5
40
30
p 0.0094
0
0
24
48
72
96
120
144
168
192
Romagnoli, JACS 2003
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FREQUENCY OF ESOPHAGECTOMY AND HOSPITAL MORTALITY
Mortality rate ()
Case load/year
Metzger,Dis Esoph 2004
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PARTIAL ESOPHAGECTOMY AND JEJUNAL INTERPOSITION

• Theoretical drawbacks
• High mediastinal anastomosis
• Incomplete Barretts ablation
• Limited clinical experience (Siewert)

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NERVE SPARING ESOPHAGECTOMY
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LAPAROSCOPIC TRANS-CERVICAL VIDEOASSISTED
MEDIASTINAL DISSECTION
Bonavina et al, J Lap Adv Surg Tech, 2004
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University of Milano, Department of Surgery
ADENOCARCINOMA OF EGJ 506 consecutive
patients (1992-2004)
(31)
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PATIENTS REFERRED FOR HGDn30
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 (n30)
1st endoscopy 7 invasive carcinoma
(gtsurgery) 1 LGD 22 HGD (73) 2nd endoscopy 5
invasive carcinoma (gtsurgery) 1 LGD 17 HGD
(57) 15 surgery (9 TME, 6 TTE) 1 PDT 1 PPI
therapy
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RESULTS OF ESOPHAGECTOMY FOR HGD
n15

• No operative mortality
• Morbidity
• 2 atelectasis
• 1 chylothorax
• Pathology
• 1 LGD
• 4 invasive carcinoma (27)
• 10 confirmed HGD

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ESOPHAGECTOMY FOR HGD Actuarial survival (n15)
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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 5214-5
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FUTURE SCENARIO

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