A. Ruol - SocietÃ Triveneta di Chirurgia

IL CANCRO DEL CARDIAS 

Intervento di Ivor Lewis: 

come, quando e perche’ 

Dr. A. Ruol 

Responsabile UOS di Chirurgia delle prime vie digestive 

Clinica Chirurgica 1° 

Azienda Ospedaliera – Universita’ di Padova 

Centro di Alta Specializzazione per le Malattie dell’Esofago 

Direttore: Prof. E. Ancona

Esophageal 

and 

Esophagogastric 

Junction 

Cancers 

v. 2.2011 

Esophagogastric Junction cancers 

TNM - 7 th edition, 2010 

• A tumour the epicentre of which 

is within 5 cm of the 

esophagogastric junction and 

also extends into the oesophagus 

is classified and staged 

according to the esophageal 

cancer scheme 

• All other tumours with an 

epicentre in the stomach greater 

than 5 cm from the EG-J or 

those within 5 cm of the EG-J 

without extension into the 

oesophagus are staged using the 

gastric carcinoma scheme

Classification for adenocarcinoma at the esophago-gastric junction 

Siewert 1996, 2000 

Type I. Adenocarcinoma of the distal 

esophagus which may infiltrate the E-G 

junction from above & mostly develops 

in Barrett’s esophagus 

Type II. True carcinoma of the 

cardia, arising at the E-G 

junction 

Type III. Subcardial gastric 

carcinoma which infiltrates the E-G 

junction from below

Adenocarcinoma of the esophagus & 

esophago-gastric junction 

• Type I 

• Type II 

? 

• Type III 

transthoracic esophago-gastric resection 

& gastric pull-up (above azygos vein) 

transthoracic esophago-gastric resection 

& gastric pull-up (above azygos vein) 

total gastrectomy (D2) + res. lower esophagus 

& Roux-en-Y esophago-jejunostomy 

limited resection for early cancer : 

short esophageal resection + proximal gastrectomy 

& Merendino jejunal interposition 

total gastrectomy (D2) 

& Roux-en-Y esophago-jejunostomy

Is there a “standard of care” operation 

for esophageal cancer ? Kaiser, Ann Surg 2001 

There is no single right or ideal operation 

for every patient with esophageal cancer 

It is important to recognize that the results achieved by 

surgeons who ... have a large clinical volume may not 

be achievable by the occasional esophageal surgeon 

We need to continue to work toward 

reducing the rate of perioperative complications 

associated with esophagectomy and 

defining the variables that relate to long-term survival

The impact of complications on outcomes after resection for esophageal 

and gastroesophageal junction carcinoma Rizk, J Am Coll Surg 2004 

510 consecutive patients operated between 1996 and 2001 

at the Memorial Sloan-Kettering Cancer Center 

pts. Postop. Mortality 3-year Survival 

Surgical 

Complications 

138 12,3 % 31 % 

NO Surgical 

Complications 372 3,8 % 48 % 

Technical complications have a large negative impact on survival after 

esophagectomy for cancer (HR 1,41 p = 0,008) 

Strategies to optimize surgical technique & minimize complications 

improve outcomes

AdenoCa of the esophagus and E-G junction 

Achieving R0 complete resection should be the goal 

of surgery (it is the most significant independent prognostic factor) 

• resection margins free of tumor 

• adequate lymph node dissection 

Strong individual preference & some degree of surgical 

mystique often govern selection of operation for GE junction 

adenocarcinoma ( Rusch 2004 ) 

The optimal surgical strategy remains controversial

AdenoCa della giunzione esofago-gastrica 

problemi ancora controversi relativi all’intervento chirurgico 

• via di accesso 

• volume di resezione esofagea 

• volume di resezione gastrica 

• estensione della linfoadenectomia 

The type of operation selected may affect : 

• the ability to achieve a complete (R0) resection, 

• the quality of lymph node clearance and staging, 

• the long-term chance of local control and survival, 

• patient’s quality of life

AdenoCa of the esophagus & esophago-gastric junction 

problemi ancora controversi relativi all’ intervento chirurgico: 

• volume di resezione esofagea : 

– almeno 8-10 cm di esofago indenne a monte del tumore, 

per via toracotomica dx (oppure sx) 

– tutta la mucosa con metaplasia intestinale (Barrett) 

– ? esofagectomia totale a torace chiuso 

– ? resezione esofagea distale per via transiatale ( sec. Pinotti ) 

– ??? resezione esofago per via addominale esclusiva

Adenocarcinoma of the E-G junction 

Microscopic evidence of cancer (R1) 

at a resection margin (on prefixed fresh specimen) 

cm proximal margin length distal margin length 

< 2 14/30 (47%) 3/ 8 (37.5%) 

2 -3.9 1/ 9 (11%) 2/17 (12%) 

4 - 5.9 2/ 8 (25%) 0/37 (0%) 

> 6 0/24 (0%) 

Total 23% 6% 

Ito 2004

Centro di Alta Specializzazione 

per le Malattie dell’ Esofago 

University of Padova, Italy 

AdenoCa giunzione esofago-gastrica Tipo II 

1980-2003: 267 resecati 

trancia di sezione prossimale positiva per tumore 

Livello anastomosi 

Trancia sup. positiva 

esofago cervicale 1/34 2.9% 

apice torace 1/28 3.6% 

sopra arco v. azigos 0/56 0% 

arco v. azigos 1/50 2% 

sotto arco v. azigos 4/35 11% 

vena polmonare inf. 2/35 5.7% 

sotto vena polmonare inf. 1/22 4.5% 

3/168 = 1.8% 

10 / 260 

= 3.8 % 

7/92 = 7.6%


Residual cancer at the resection margin 

2.5 - 35% microscopic evidence of cancer (i.e. R1) 

Papachristou 1980, Mandard 1981, Sons 1986, Husemann 1989, Peracchia 1991, Stipa 1992, Bozzetti 1982 e 2000, Fekete 1997, 

Kodera 1999, Guillem 1999, Mattioli 2001, Mariette 2003, Ito 2004 

– palpation & gross inspection: unreliable 

– intraoperative frozen section: 9-21% false negative rates 

proximal resection margin length: at least 6-8 cm (on prefixed fresh 

resected specimen *) Papachristou 1980, Suzuki 1990, Cordiano 1996, Mattioli 2001, Mariette 2003, Ito 2004 

distal resection margin length: 

at least 4 cm (on prefixed fresh 

resected specimen *) Siewert 2000, Mattioli 2001, Ito 2004 

* prefixed fresh specimen measures 44-55% of the in situ length before resection




Paziente con adenoCa del cardias di tipo Siewert II, 

al quale era stato proposto in altra sede 

l’intervento per sola via addominale 

Tumore cardiale 

Seconda 

localizzazione 

(da diffusione linfatica 

intraparietale ?)




ESOPHAGEAL 

SECTION MARGIN 

with microscopic tumor nests in the submucosa 

ANASTOMOTIC 

RECURRENCE 

the safety resection margin proximal to the tumor (as measured 

in vivo) should be at least 6 cm long, but preferably 8 cm long




Take down & Colon interposition

ISDE Consensus Conference 1995 

Carcinoma of the thoracic esophagus and EG-junction 

the role of lymph node dissection 

• improves the accuracy of pathologic staging 

• reduces local-regional recurrences 

• the need for & extent of lymphadenectomy is debated: 

possible improvement of long-term prognosis, but 

no randomized study has shown a survival advantage related to a 

more extensive lymph node dissection 

number of lymph nodes to be examined 

in the operative specimen = at least 15

AdenoCa della giunzione esofago-gastrica 

problema ancora controverso 

• linfoadenectomia: almeno 15 linfonodi 

– LN paracardiali, piccola curva gastrica, tripode celiaco, origine 

art. epatica e splenica, periesofagei medi e inferiori, sottocarenali 

= linfoadenectomia mediastino inferiore + addominale D2 

– linfoadenectomia D0 linfoadenectomia D1 = solo LN peritumorali 

– linfoadenectomia D3 o D4 = D2 + LN paraortici, interaortocavali, 

retropancreatici + LN mediastinici superiori, recurrenziali, sovraclaveari




v. porta art. epatica moncone art. gastrica sx 

art. splenica




arco v. azigos bronco sx bronco dx pericardio esofago

Differential pathologic variables and outcomes across the 

spectrum of adenocarcinoma of the esophagogastric junction 

Reynolds, World J Surg 2010;34:2821–2829 

AEG type I = 180, type II = 182, type III = 158 

Factor 

Multivariate analysis for survival 

Hazard 

ratio 

95% CI p Value 

AEG type I vs. II vs. III 0.976 0.911, 1.008 0.367 

Node status 3.578 1.678, 3.987 < 0.0001 

No. involved nodes 2.367 1.076, 2.987 < 0.0001 

pT 1.099 1.001, 1.189 0.079

Prevalence of LN metastases in Distal Esophagus (DE) 

and Gastro-Esophageal Junction (GEJ) cancers 

Leers, DeMeester et al. J Thor Cardiovasc Surg 2009;138:594- 

Lymph node status DE tumors (n = 301) GEJ tumors (n = 208) P 

• N classification 

N + 150 ( 49.8% ) 118 ( 56.7% ) .18 

• No. of involved nodes 

1-4 66 (21.9%) 50 (22.1%) .74 

5-8 24 (8.0%) 22 (11.1%) 

> 8 61 (20.3%) 42 (21.1%) 

*Depth of invasion & N+ DE tumors (n = 245) GEJ tumors (n = 172) P 

Intramucosal 2/71 ( 2.8%) 1/36 ( 2.8%) 1.0 

Submucosal 11/38 (28.9%) 6/29 (20.7%) .59 

Intramural 15/30 (50.0%) 8/16 (50.0%) 1.0 

Transmural 96/106 (90.6%) 79/91 (86.8%) .92 

( * patients with neoadjuvant therapy excluded )

Prevalence and location of node metastases in patients who 

had en-bloc resection (patients not having en-bloc resection excluded) 


DE tumors (n = 150) GEJ tumors (n = 100) P 

•Prevalence of N1 disease 83 (55%) 61 (61%) 

.43 

•Location of positive LN 

Mediastinal: 39 ( 26% ) 25 ( 25% ) .88 

Paratracheal 3 (2%) 0 

Subcarinal 12 (8%) 3 (3%) 

Paraesophageal 38 (25%) 25 (25%) 

Abdominal: 70 (47%) 52 (52%) .44 

Parahiatal 33 (22%) 20 (20%) 

Perigastric 52 (35%) 45 (45%) 

Celiac 9 (6%) 3 (3%) 

Other 13 (9%) 8 (8%)

Prevalence and location of node metastases in patients who 

had en-bloc resection (patients not having en-bloc resection excluded) 


Lymph node status DE tumors (n = 150) GEJ tumors (n = 100) P 

Prevalence of N1 disease 83 (55%) 61 (61%) .43 

Location of positive LN: 

Mediastinal 39 ( 26% ) 25 ( 25%) .88 

Abdominal 70 (47%) 52 (52%) .44 

• Positive mediastinal LN 

in pts with N+ 

• Positive mediastinal LN 

as the only site of N+ 

47% 41% n.s. 

9% 8% n.s.

The pattern of lymph node involvement in patients 

with N1 disease after en bloc esophagectomy (n = 144) 

with distal esophageal (DE) and gastroesophageal junction (GEJ) tumors 


DE 

GEJ 

In 9% of pts. 

with DE tumors, 

a positive 

mediastinal LN 

was the only 

site of LN 

involvement 

In 8% of pts. 

with GEJ 

tumors, 

a positive 

mediastinal LN 

was the only 

site of LN 

involvement

Lymph node metastasis in adenocarcinoma of the 

gastroesophageal junction (GEJ) and distal esophagus (DE) 


a lower mediastinal node dissection needs to be 

included in the surgical therapy of both tumors 

• the danger with recommending total gastrectomy for GEJ cancer 

is the tendency (especially among low-volume centers) to minimize 

the mediastinal dissection 

inadequate mediastinal lymph node dissection 

increased frequency of a positive proximal resection margin

Location of nodal metastases according to Siewert 

classification for the 111 patients with pN+ disease 

Pedrazzani, DeManzoni 2007 

Site of 

nodal metastasis 

Abdomen 

(n = 87) 

Abdomen and chest 

(n = 23) 

Chest 

(n = 1) 

Type I 

(n = 13) 

Siewert classification 

Type II 

(n = 44) 

Type III 

(n = 54) 

7 (53.8%) 31 (70.5%) 49 (90.7%) 

6 (46.2%) 13 (29.5%) 4 (7.4%) 

— — 1 (1.9%)


Frequency of metastasis in mediastinal lymph nodes 

Peracchia 1987 Type II 20% 

Aikou 1989 Type II 12% 

Wang 1993 Type II 18% 

Clark 1994 Type I-II 28% 

Tachimori 1996 Type II 19% 

Nigro 1999 Type II 33% 

Mauvais 2000 Type II 19% 

Siewert 2000 Type II 16% 

Mattioli 2001 Type II 7% 

Altorki 2002 Type I-II 32% 

Monig 2002 Type II 11% 

Nakamura 2002 Type II 3.6% 

Ichikura 2003 Type II 14% 

Lerut 2004 Type II 22% 

Ancona- Ruol 2005 Type II 20.5% 

Leers-DeMeester 2009 Type II 25% 

7 - 33%

Total gastrectomy is not always necessary 

for advanced Type II cancer of the cardia 

LN # 4d : along right gastroepiploic vessels 

LN # 5 : suprapyloric 

LN # 6 : infrapyloric 

% metastatic LN 

in Type II cancer 

of the EG-J: 

LN # 4d 5% 

LN # 5 5% 

LN # 6 0% 

(Kobayashi, 2002 

Ichikura, 2003)

Type II-III adenocarcinoma of the E-G junction 

• Total gastrectomy + distal esophagectomy 

+ D2 LN-dissection (88 patients) 

- frequency of metastasis to LN # 4d , 5 , 6 : all < 6% 

- no long-term survivor among patients with these metastases 

• Proximal gastrectomy + subtotal esophagectomy 

+ D2 LN-dissection, excluding LN # 4d, 5, 6 (89 patients) 

- same survival curves for total gastrectomy and proximal 

gastrectomy ( p = 0.3 for pT1; p = 0.7 for pT2-4 ) 

Kodera, 1999

Cancer of the esophagus and EG-junction 

Sentinel node mapping ( 99m TC-radioguided or blue dye technique) 

• Sentinel node mapping theoretically could allow the extent of 

lymphadenectomy to be tailored to the individual patient 

• High false-negative rate, especially after neoadjuvant treatments 

• Skip metastases can lead to positive distant LN, despite of negative SLNs 

• High rate of positive sentinel nodes in >1 nodal stations 

• High rate of metastases also in non-sentinel nodes 

still experimental and requires validation, 

including the need of a method for intraoperative 

examination with rapid immunohistochemisty

Adenoca della giunzione esofago-gastrica di Tipo II 

Conclusioni 

l’intervento di riferimento e’ 

• la resezione esofago-gastrica 

• con linfoadenectomia 

del mediastino medio-inferiore e addominale D2 

• e’ consigliabile che l’intervento venga eseguito 

in Centri ad alto volume da chirurghi esperti in 

questo tipo di chirurgia




• Neoadjuvant therapy decreases the frequency of regional lymph 

node metastases, and also changes their location 

• The map of the distribution of nodal metastasis after neoadjuvant 

therapy might be useful to plan the operative technique and 

adequate lymphadenectomy




Adenocarcinoma of the esophagus & EG-junction: 

Main metastatic lymph node sites 

The area of the circles is proportional to the frequency of nodal metastasis 

Adenocarcinoma 

29.6% 

p=0.49 

21.9% 

37.1% 

p=0.002 

12.5% 

35.6% 

p=0.20 

18.8% 

Surgery alone 

Neoadjuvant Ther. + Surgery




pTNM (Adenocarcinoma n = 181) 

Pathological stage 

T0-Tis N0 

T0 N+ 

T1 N0 

T1 N+ 

T2 N0 

T2 N+ 

T3 N0 

T3 N+ 

T4 N0 

T4 N+ 

Surgery alone 

n= 132 (%) 

0 

0 

2 ( 1.5) 

2 ( 1.5) 

14 (10.6) 

10 ( 7.6) 

27 (20.5) 

73 (55.3) 

1 ( 0.8) 

3 ( 2.3) 

Neoad. Ther. + surgery 

n= 49 (%) 

6 (12.2) 

5 (10.2) 

1 ( 2.0) 

1 ( 2.0) 

8 (16.3) 

6 (12.2) 

5 (10.2) 

15 (30.6) 

1 ( 2.0) 

1 ( 2.0) 

p=0.002 

Median number of examined 

nodes: 

19.5 (15-27) 

20 (15-25) 

p=n.s. 

Median number of 

metastatic nodes: 

2 (0-5.5) 

1 (0-2) 

p=0.03




Adenocarcinoma of the EG-junction 

Survival after Surgery alone and Neoad.Ther.+Surgery 

100 

80 

60 

40 

20 

0 

100 

80 

60 

40 

20 

0 

0 1 2 3 4 5 

0 1 2 3 4 5 

N0 

N1 

N2 

N3 

N0 

N1 

N2 

N3 

Surgery alone 

(n=132) 

(p

AdenoCa localmente avanzato dell’esofago inferiore e cardias 

Chemioterapia versus Chemio-Radioterapia neoadiuvante 




Analisi retrospettiva, eseguita su dati raccolti 

prospetticamente, mediante un database dedicato 

Gennaio 1992 – Dicembre 2007 

Adenocarcinoma dell’esofago e 

della giunzione esofago-gastrica 

Stadio clinico localmente avanzato ( T1N+, T2N+, T3-T4 ogni N ) 

Assenza di metastasi a distanza




RISULTATI 

1752 pazienti 

con cancro dell’esofago e del cardias, osservati tra 1992 e 2007 

- 1238 pazienti 

Esclusi per istologia diversa da 

Adenocarcinoma 

- 192 pazienti 

Esclusi per stadiazione clinica 

T1-2 N0 o M+ 

- 45 pazienti 

Esclusi per trattamento 

palliativo 

277 pazienti 

Trattati con intento curativo 

179 pazienti 

Trattati con INTERVENTO 

CHIRURGICO DI PRIMA ISTANZA 

39 pazienti 

Trattati con 

CHEMIOTERAPIA 

NEOADIUVANTE 

98 pazienti 

Trattati con TERAPIA 

NEOADIUVANTE 

59 pazienti 

Trattati con 

CHEMIO-RADIOTERAPIA 

NEOADIUVANTE




RISULTATI 

39 pazienti 

Trattati con 

CHEMIOTERAPIA 

NEOADIUVANTE 

59 pazienti 

Trattati con 

CHEMIO-RADIOTERAPIA 

NEOADIUVANTE 

179 pazienti 

Trattati con INTERVENTO 

CHIRURGICO DI PRIMA ISTANZA




RISULTATI 

Pazienti sottoposti a sola 

chemioterapia neoadiuvante (39) 

Pazienti sottoposti a chemioradioterapia 

neoadiuvante (59) 

• 98% Siewert I-II 

• 65.8% dei pazienti era in 

classe ASA 1-2 

p: n.s 

• 98% Siewert I-II 

• 66.1% dei pazienti era in 

classe ASA 1-2 

• 95% stadio clinico 3-4 

• 94.9% cN + 

• 95% stadio clinico 3-4 

• 89.8% cN +




RISULTATI 



78,4% chemioterapia con 

derivati del platino e 5-FU 



77,6% chemioterapia con 

derivati del platino e 5-FU 

90% >40 Gy di RT 

p: n.s 

Nessun decesso per tossicità 

Nessun decesso per tossicità 

Tossicità di grado WHO 3-4 

nel 12,8% 

Tossicità di grado WHO 3-4 

nel 18,6%




RISULTATI 



27 pazienti (69,2%) sottoposti a 

intervento resettivo 

96,3% R0 



44 pazienti (74,6%) sottoposti a 

intervento resettivo 

93.2% R0 

Nessun decesso perioperatorio 

Nessun decesso perioperatorio 

Morbilità postop. 29,6% Morbilità postop. 20,5% 

p: n.s 

Complicanze postop. Chirurgiche: 7,4% 

Complicanze postop. Mediche: 18,5% 

Complicanze postop. Chir.+Med: 3,7% 

Complicanze postop. Chirurgiche: 11,4% 

Complicanze postop. Mediche: 9,1%




RISULTATI 

Valutazione istopatologica del Tumore primitivo (pT) 

e del Downstaging linfonodale (pN) 

RISPOSTA AL TRATTAMENTO 

pT 0 

pT 1-2 

pT 3-4 

CHEMIOTERAPIA 

NEOADIUVANTE 

27 pazienti operati 

0 

6 (22.2%) 

21 (77.8%) 

CHEMIO-RT 

NEOADIUVANTE 


11 (25.0%) 

13 (29.6%) 

20 (45.4%) 

Downstaging da cN+ a pN0 5/26 (19.2%) 20/38 (52.6%) 

p 0,009




RISULTATI 

Risposta patologica pTNM 

RISPOSTA AL TRATTAMENTO 

CHEMIOTERAPIA 

NEOADIUVANTE 


CHEMIO-RT 

NEOADIUVANTE 


Risposta patologica Completa 

(p T0 N0 M0) 

0 6 (13.6%) 

Risposta Parziale 12 (44.4%) 28 (63.6%) 

Nessuna risposta 15 (55.6%) 10 (22.7%) 

p 0,006

% 




RISULTATI 

Sopravvivenza globale dei pazienti sottoposti a trattamento 

neoadiuvante e successivo intervento resettivo R0 

100 

p 0,05 

80 

60 

40 

20 

Chemioradioterapia 

neoadiuvante 

Chemioterapia 

neoadiuvante 

58% 

29% 

0 

0 1 2 3 4 5 

Anni

A. Ruol - SocietÃ Triveneta di Chirurgia

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