Esophagogastric Metaplasia Relates to Nodal Metastases in Adenocarcinoma of Esophagus and Cardia

Alberto Ruffato, MD, PhD, Sandro Mattioli, MD, Ottorino Perrone, MD, Marialuisa Lugaresi, MD, PhD, Massimo Pierluigi Di Simone, MD, Antonietta D’Errico, MD, Deborah Malvi, MD, Maria Rosaria Aprile, MD, Giandomenico Raulli, MD, and Luca Frassineti, MD Division of Thoracic Surgery, Centre for the Study and Therapy of Diseases of the Esophagus, GVM Care and Research, PhD Course in Medical and Surgical Sciences, Department of Medical and Surgical Sciences (DIMEC), and Pathology Unit, “Felice Addarii” Institute, University of Bologna, Division of Pathology, Ausl Ravenna, and IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy

Background. Immunohistochemical profiles of esophageal and cardia adenocarcinoma differ according to the presence or absence of Barrett’s epithelium (BIM) and gastric intestinal metaplasia (GIM) in the fundus and antrum. Different lymphatic spreading has been demonstrated in esophageal adenocarcinoma. We investigated the correlation among the presence or absence of intestinal metaplasia in the esophagus and stomach and lymphatic metastases in patients who underwent radical surgery for esophageal and cardia adenocarcinoma. Methods. The mucosa surrounding the adenocarcinoma and the gastric mucosa were analyzed. The BIMⴙ patients underwent subtotal esophagectomy and gastric pull up, and the BIM– patients underwent esophagectomy at the azygos vein, total gastrectomy, and esophagojejunostomy. The radical thoracic (station numbers 2, 3, 4R, 7, 8, and 9) and abdominal (station numbers 15 through 20) lymphadenectomy was identical in both procedures except for the greater curvature.

Results. One hundred ninety-four consecutive patients were collected in three major groups: BIMⴙ/GIM–, 52 patients (26.8%); BIM–/GIM–, 90 patients (46.4%); BIM–/ GIMⴙ, 50 patients (25.8%). Two patients (1%) were BIMⴙ/GIMⴙ. A total of 6,010 lymph nodes were resected: 1,515 were recovered in BIMⴙ, 1,587 in BIM–/ GIMⴙ, and 2,908 in BIM–/GIM– patients. The percentage of patients with pNⴙ stations 8 and 9 was higher in BIMⴙ (p ⴝ 0.001), and the percentage of patients with pNⴙ perigastric stations was higher in BIM– (p ⴝ 0.001). The BIM–/GIM– patients had a number of abdominal metastatic lymph nodes higher than did the BIM–/GIMⴙ patients (p ⴝ 0.0001). Conclusions. According to the presence or absence of BIM and GIM in the esophagus and cardia, adenocarcinoma correspond to three different patterns of lymphatic metastasization, which may reflect different biologic and carcinogenetic pathways. (Ann Thorac Surg 2013;95:1147–53) © 2013 by The Society of Thoracic Surgeons

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of TNM and thus further investigation on tumor biology should be performed [5], and that different types of tumor arise in the esophagus, the gastroesophageal junction, and the stomach [6]. To investigate the biologic behavior of esophageal and cardia adenocarcinoma, we compared the immunoprofiles of a series of esophageal and cardia adenocarcinoma cases to the profiles of gastric antrum cancer [7]. As the cancerous overgrowth may destroy or hide the surrounding areas of intestinal metaplasia [8], we investigated also morphology and immunohistochemistry of the intact mucosa of the gastric corpus and antrum to search for new reliable diagnostic indicators [7]. Three different immunoprofiles were identified that could allegedly correspond to a Barrett’s esophagitis–like type, a gastric cancer–like type, and a third undefined type; these groups were also different for the presence or absence of Barrett’s intestinal metaplasia (BIM) and gastric intesti-

lassification and staging systems of adenocarcinoma of the esophagus and cardia are controversial. The classification proposed by Siewert and colleagues [1], based on topographic criteria, has been extensively adopted in the past for clinical and research purposes, but it has never been adopted for staging [2]. Recently, the 7th American Joint Committee on Cancer (AJCC) TNM classification [3] has included in the esophagus chapter adenocarcinoma of the esophagus and cardia, previously split into the esophagus and stomach chapters [2], again on the basis of topographic criteria [4]. However, this new authoritative regulation also has raised substantial controversies [5, 6]. It has been argued that Siewert types II and III should be included again in the stomach chapter Accepted for publication Dec 28, 2012. Address correspondence to Dr Mattioli, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via G. Massarenti 9, 40138 Bologna, Italy; e-mail: [email protected].

© 2013 by The Society of Thoracic Surgeons Published by Elsevier Inc

0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2012.12.040

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Esophagogastric Metaplasia Relates to Nodal Metastases in Adenocarcinoma of Esophagus and Cardia

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Fig 1. (A) Resection (black line) and lymphadenectomy (black dotted line) levels for patients receiving transabdominal proximal gastrectomy and right transthoracic esophagectomy with cervical or chest dome esophagogastric anastomosis and (B) for patients receiving transabdominal total gastrectomy and right transthoracic esophagectomy at the azygos vein.

nal metaplasia (GIM) [7]. As the literature documents, different patterns of metastatic spread by means of the lymph nodes exist in adenocarcinoma of the esophagus and cardia [5, 6, 9]; thus to further investigate the biology of esophageal and cardia adenocarcinoma, we analyzed the lymph node metastasis patterns in a case series of consecutive adenocarcinomas of the esophagus and cardia undergoing surgical resection, grouped according to the presence or the absence of BIM and GIM.

Material and Methods Patient’s data were collected according to a prospective study protocol established in 1980 [10] and modified in 2001 when sampling of the gastric corpus and antrum mucosa was added [7]. In the present study, we considered surgical cases up to December 2010 that fully adhered to the adjourned protocol [7]. Patients were operated on at the Sant’Orsola-Malpighi University Hospital until 2003 and successively at the Maria Cecilia Hospital; cases that were reported in our previous study [7] were included in the present series. The preoperative workup included collection of the medical history and symptoms in a dedicated questionnaire, upper gastrointestinal tract endoscopy with multiple biopsies of the tumor and the surrounding mucosa and of the fundic and antral mucosa (at least three samples per area), and chest and upper abdomen computed tomography (CT), positron emission tomography (PET), or CT-PET scan. Endoscopic ultrasound was selectively performed to verify T and N status when doubtful at CT-PET scans. Surgery was indicated for T1 through T3, N0 through N1, and M0 tumors

according to the 6th edition AJCC TNM classification system [2]. The pathology reports were produced according to the TNM 6th edition [2]. Reports were restaged according to the 7th edition AJCC TNM classification system [3] for the present study. Neoadjuvant treatment was not performed in any patient included in the study. Patients in which the presence of BIM around the tumor was histologically demonstrated by preoperative endoscopy (BIM⫹) underwent subtotal esophagectomy and proximal gastrectomy with a left cervical or intrathoracic esophagogastric anastomosis; the other patients (BIM–) underwent total gastrectomy and esophageal resection at the level of the azygos vein with a Roux esophagojejunostomy [10]. A right anterolateral thoracotomy and an upper midline laparotomy (eventually, a left cervicotomy in BIM⫹ patients) were performed. One or more frozen sections of the esophageal resection margin were routinely examined intraoperatively by the pathologist before performing the esophagovisceral anastomosis. Lymphadenectomy included stations 2R, 3, 4R, 7 through 9, and 15 through 20 (TNM 7th edition nomenclature) [3], the greater curvature (excluding cases treated with proximal gastrectomy), and the pancreatic and pyloric nodes (Fig 1). All the visible nodes for each station were resected in all cases. The follow-up (FU) protocol was based on clinical assessment, CA-19 and carcinoembryonic antigen (CEA) serum markers, abdominal ultrasound, chest radiographs at 6 months, clinical assessment, laboratory tests, upper gastrointestinal tract endoscopy, and chest and upper abdomen CT, PET, or CT-PET scan at 12 months. Time of FU was calculated since surgery to the last FU.

Causes of death were assessed by telephone or from the Health Information System of the Italian National Health Service. The cancer-specific survival rate was calculated (in months) from the date of surgery to the time of death owing to recurrent disease. Adjuvant multimodality therapy was mainly administered in case of disease recurrence. The institutional review board of the University of Bologna and the ethics committee of the IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (CEAV/IRST) approved using for research purposes the database from the Division of Thoracic Surgery.

Pathology Analysis Intraoperatively the surgeon labeled the resected nodes using the TNM nomenclature. Fragments of nodes were not included in the count. A trained pathologist collected and counted the resected nodes per N station. Surgical specimens were fixed with 10% buffered formalin. Multiple longitudinal sections (5 mm thick) were taken from the tumor and from the surrounding epithelium [10]. On preoperative endoscopy or on the surgical specimen, the stomach was sampled in the prepyloric area, in the angulus, twice in the lesser and twice in the greater curve and once in the fundus [7, 11]. Fourmicrometer sections were cut and stained with hematoxylin and eosin, periodic acid-Schiff, diastase– periodic acid-Schiff, and the Alcian blue periodic acidSchiff technique at pH 2.5. A Barrett’s esophagus diagnosis was defined by the presence of columnar glandular epithelium with mucinous goblet cells [12]. In the stomach, the presence and activity of gastritis and gastric gland atrophy and the presence of intestinal metaplasia were classified according to the updated Sydney system [13]. The histologic grading of the tumor was classified as “well differentiated” (G1), “moderately differentiated” (G2), “poorly differentiated” (G3), and “undifferentiated (G4) [3].

Statistical Analysis Age, tumor size, number of dissected lymph nodes, and FU duration are expressed as median and interquartile ranges (IQR). The differences between the BIM⫹ and BIM– cases were assessed using the Mann-Whitney U test for continuous variables and the Kruskal-Wallis H test for unpaired data as appropriate. The associations between the clinicopathologic characteristics and the two resection techniques were analyzed with a contingency table. Statistical significance was evaluated using the ␹2 test or Fisher’s exact test as appropriate. Cancer-specific survival rates were compared using the Kaplan-Meier method and the log-rank test. No Bonferroni correction was performed. A probability value of less than 0.05 was considered to be significant. The statistical analyses were performed using the SPSS 13.0 software package (SPSS Inc, Chicago, IL).

Results The BIM⫹ (54 patients) and BIM– (140 patients) groups did not differ significantly by median age at the time of

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the operation, respectively 66 years (IQR, 56 to 73 years) and 66 years (IQR, 58.5 to 70.5 years) (p ⫽ 0.67) and by male to female ratio (8/1 versus 4/1, respectively; p ⫽ 0.27). In the BIM⫹ group, mortality (5 of 54; 9%) was attributable to mediastinitis, heart failure, acute myocardial infarction, pulmonary embolism, and chronic renal failure; in the BIM– group, mortality (4 of 140; 3%) was attributable to mediastinitis after anastomotic leak in 3 patients and to peritonitis after dehiscence of the jejunostomy in 1 patient (p ⫽ 0.16). Major complications occurred in 9% of the patients (5 of 54) in the BIM⫹ group (anastomotic leaks at the neck in all cases) and in 5% (7 of 140) of patients in the BIM– group (anastomotic leaks in 6 patients and necrosis of the jejunal loop in 1 patient; p ⫽ 0.47). No complications related to lymphadenectomy were noted. The R0 resection rate was 100% (54 of 54) in the BIM⫹ group and 97% (136 of 140) in the BIM– group (p ⫽ 0.46), in which submucosal microscopic involvement of the esophageal margin (R1) was diagnosed in 4 patients, 2 of whom were younger than 40 years. In all cases the tumor was G4. We resected 6,010 lymph nodes: 1,515 lymph nodes were recovered in the BIM⫹ group, with a median of 29 per case (IQR, 15 to 36.5), and 4,495 lymph nodes were recovered in the BIM– group, with a median of 30 per case (IQR, 20 to 40). The distribution of thoracic and abdominal lymph nodal metastasis stations in the BIM⫹ and BIM– groups is displayed in Table 1. Considering the number of patients with nodal involvement, the thoracic stations were metastasized mainly by BIM⫹ tumors (16.4% BIM⫹ patients versus 4.2% BIM– patients; p ⫽ 0.001), whereas the lesser and greater gastric curvatures were metastasized predominately by BIM– tumors (63.5% BIM– patients versus 16.7% BIM⫹ patients; p ⫽ 0.0001). In the BIM⫹ and BIM– groups, the number of positive and negative nodes is not different for pT1 (p ⫽ 0.41), pT2 (p ⫽ 0.95), and pT4 (p ⫽ 0.07); however, it is different for pT3 (p ⫽ 0.03). There are no differences in positive and negative nodes for any stage between the BIM⫹ and BIM– groups. The distribution of pathologic stages (7th TNM edition) within the BIM⫹ and BIM– tumors is summarized in Tables 2 and 3. In the BIM⫹ group, 96% (52 of 54) of the patients were GIM– and 4% (2 of 54, all G4 tumors) were GIM⫹. In the BIM– group, 64% (90 of 140) of the patients were GIM– and 36% (50 of 140) were GIM⫹ (p ⫽ 0.001). Excluding the BIM⫹/GIM⫹ combination (2 patients, 1%), three major populations were accordingly identified: BIM⫹/GIM– (52 patients, 26.8%), BIM–/GIM– (90 patients, 46.4%), and BIM–/GIM⫹ (50 patients, 25.8%). Typical gastroesophageal reflux symptoms were recorded in 46 of 54 (85.2%) patients in the BIM⫹ group and in 10 of 140 (7.1%) patients in the BIM– group (p ⫽ 0.0001); in the BIM–/GIM⫹ and BIM–/GIM– groups, gastroesophageal reflux symptoms were respectively recorded in 5 of 50 (10%) patients and in 5 of 90 (5.5%) patients (p ⫽ 0.327). The distribution of tumor grade (G) by the presence (⫹) or absence (–) of BIM and GIM is shown in Table 4.

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Table 1. The pN Metastasis Patterns in the Presence and Absence of Barrett’s Intestinal Metaplasia Tumors by Nodal Stations BIM⫹ Group (n ⫽ 54)

BIM– Group (n ⫽ 140)

Nodal Station

No.

Median (IQR)

⫹

%

No.

Lesser curvature Paracardiac Greater curvature Pancreatic and pyloric Spleen Celiac trunk Hepatic artery TNM stations 8, 9 TNM station 7 TNM stations 2–4

174 148 ... 15 10 123 86 547 167 245

3 (2–11) 2.5 (0–6) ... 0 (0–3) 0 (0–2) 2.5 (1–6.25) 1.5 (0–3) 9 (4–15) 3.5 (1.25–7) 5 (2–10.5)

42 27 ... 0 2 3 1 90 5 5

24.1 18.2

1348 643 684 104 88 223 233 420 373 379

BIM ⫽ Barrett’s intestinal metaplasia;

0 20.0 2.4 1.2 16.4 3.0 2.0

Table 2. Distribution of Pathologic Stages Within Cases According to the Presence of Barrett’s Intestinal Metaplasia

TNM 7th Edition pT1 pT2 pT3 pT4a pN0 pN1 pN2 pN3 Stage Stage Stage Stage Stage Stage Stage Stage

Ia Ib IIa IIb IIIa IIIb IIIc IV

⫹

%

p Value

0.08 0.27 ... 0.78 0.46 0.60 0.75 0.01 0.24 0.34

467 218 93 31 5 21 10 24 2 0

34.7 33.9 13.6 29.8 5.7 9.4 4.3 5.7 0.5 0

0.005 0.001 ... 0.01 0.3 0.01 0.17 0.001 0.05 0.01

recurrence sites were significantly different for the BIM⫹ and BIM– patients, with preferential mediastinal spreading observed in the BIM⫹ patients (44% versus 17%; p ⫽ 0.05) and preferential aortic spreading observed in the BIM– patients (22% versus 0%; p ⫽ 0.05). The cancer-specific survival analysis according to the 7th edition TNM staging system found 5-year survival rates of 91% for stage IA, 73% for stage IB, 65% for stage IIB, 50% for stage IIIA, and less than 25% for stages IIIB, IIIC, and IV (Fig 2). No significant differences in cancerspecific survival emerged within the BIM⫹ and BIM– groups, both of which had 5-year survival rates of 42% (p ⫽ 0.679 by log-rank Mantel-Cox test; Fig 3A). The Table 3. Distribution of Pathologic Stages Within Cases Without Barrett’s Intestinal Metaplasia According to the Presence of Gastric Intestinal Metaplasia BIM–/GIM⫹ Group (n ⫽ 50)

BIM– Group (n ⫽ 140)

No.

%

No.

%

p Value

17 6 21 10 27 9 14 4 13 5 1 11 4 5 14 1

31 11 39 19 50 17 26 7 24 9 2 21 7 9 26 2

4 21 71 44 41 37 19 43 4 11 2 18 33 18 43 11

3 15 51 31 29 26 14 31 3 8 1 13 24 13 30 8

0.00001 0.48 0.13 0.07 0.006 0.15 0.04 0.0006 0.0001 0.75 0.83 0.18 0.01 0.48 0.51 0.11

BIM ⫽ Barrett’s intestinal metaplasia.

8 (5–11.25) 4.5 (0.75–13) 6 (3–11.25) 0.5 (0–2.75) 0.5 (0–4) 1.5 (0–3.75) 1.5 (0–2) 3.5 (3–6) 2.5 (0.25–4) 3 (1.5–6.5)

p Value

IQR ⫽ interquartile range.

Table 5 shows the distribution of pN metastases in the BIM– group by the presence or absence of GIM. No differences were recorded in BIM–/GIM⫹ versus BIM–/GIM– patients according to pT, pN, and stage (Table 3). One hundred percent of patients surviving the surgery were followed up. Median FU was 24.5 months (IQR, 14 to 52.2 months) for the BIM⫹ group and 29 months (IQR, 13.5 to 63 months) for the BIM– group (p ⫽ 0.27). Forty-three patients died of causes unrelated to cancer: 9 in BIM⫹ group and 34 in BIM- group. Of the 74 patients in whom the relapse site was assessed, 10 (13%) had local recurrence at the anastomotic level, and 34 (46%) had distant recurrences in multiple organs; there were no significant differences within either group. The nodal

BIM⫹ Group (n ⫽ 54)

Median (IQR)

TNM 7th Edition pT1 pT2 pT3 pT4a pN0 pN1 pN2 pN3 Stage Stage Stage Stage Stage Stage Stage Stage

Ia Ib IIa IIb IIIa IIIb IIIc IV

BIM–/GIM– Group (n ⫽ 90)

No.

%

No.

%

p Value

3 8 24 15 16 13 6 15 3 4 0 10 8 4 18 3

6 16 48 30 32 26 12 30 6 8 0 20 16 8 36 6

1 13 47 29 25 24 13 28 1 7 2 8 25 14 25 8

1 15 52 32 28 27 14 31 1 8 2 9 28 15 28 9

0.09 0.61 0.90 0.78 0.59 0.93 0.68 0.89 0.09 0.96 0.75 0.05 0.11 0.20 0.31 0.54

BIM ⫽ Barrett’s intestinal metaplasia; metaplasia.

GIM ⫽ gastric intestinal

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Table 4. Distribution of Tumor Grades by the Presence (⫹) or Absence (–) of Barrett’s Intestinal Metaplasia and Gastric Intestinal Metaplasia Grade

BIM⫹

BIM–

p Value

1 2 3 4 Total

13 (24%) 13 (24%) 26 (48%) 2 (4%) 54

27 (19%) 36 (26%) 72 (51%) 5 (4%) 140

0.56 0.91 0.68 0.96

a

BIM⫹/GIM– group versus BIM⫹/GIM⫹ group.

BIM ⫽ Barrett’s intestinal metaplasia;

BIM⫹/GIM– Group

BIM⫹/GIM⫹ Group

13 (25%) 13 (25%) 26 (50%) 0 52

0 0 0 2 2

b

p Valuea 0.001

BIM–/GIM⫹ Group

BIM–/GIM– Group

10 (20%) 17 (34%) 23 (46%) 0 50

17 (19%) 19 (21%) 49 (54%) 5 (6%) 90

p Valueb 0.67 0.24 0.62 ...

BIM⫹/GIM– group versus BIM⫹/GIM⫹ group versus BIM–/GIM⫹ group.

GIM ⫽ gastric intestinal metaplasia.

two [7]. We speculated that the preoperative assessment of BIM and GIM in the esophagus and stomach of patients affected by adenocarcinoma of the esophagus and cardia could become a more reliable categorization method [7] than the topographic ones [1, 4] for tailoring surgical resection [1, 6, 10]. In the present series of 194 cases, the three major populations identified according to the presence and absence of BIM and GIM [7] were statistically different according to the thoracic and abdominal lymph node station metastases distribution. The BIM⫹/GIM– tumors spread to the thoracic stations, whereas the lesser and greater gastric curvature tumors were metastasized by BIM–/GIM– and BIM–/GIM⫹ tumors. The percentages of nodes colonized by metastases in the cardiac, lesser curvature, greater curvature, and pyloric stations were significantly greater in the BIM–/ GIM– group than in the BIM–/GIM⫹ group; metastases at the gastric greater curvature station were detected in 22% and 4.7% of the cases in these subgroups, respectively. These findings from a larger population strongly confirm the distribution we have previously reported for our pilot study (25%, 50%, and 25%) [7]. The present study supports the theory of different biologic patterns and possibly of different carcinogenetic pathways within the adenocarcinomas of the esophagus and cardia. Two of the groups we identified probably correspond to the Barrett’s esophagitis–like pattern

survival rates were lower in the BIM–/GIM– patients (a 5-year survival rate of 36%), higher in the BIM–/GIM⫹ patients (a 5-year survival rate of 53%), and intermediate in the BIM⫹/GIM– patients (a 5-year survival rate of 43%); differences among groups were not significant (Fig 3B).

Comment Research on carcinogenesis and biology of adenocarcinoma of the esophagus and cardia is justified by the necessity to solve crucial controversies on classification, staging, surgical therapy, and, last but not least, dietarychemo prevention, surveillance, and early diagnosis programs. Several studies have suggested that there may be epidemiologic, clinical, immunohistochemical, and molecular differences among gastroesophageal junction adenocarcinomas, depending on whether they are predominantly esophageal or gastric in location [1, 14 –18]. In a previous publication based on the assessment of cytokeratins 7 and 20 in the tumor and in esophageal and gastric mucosa and the presence or absence of BIM and GIM, we determined that the esophageal and cardia adenocarcinoma family is composed of three entities: (1) a Barrett’s esophagitis–type pattern, (2) a gastric cancer–like pattern, and (3) a third entity that is distinct from the other

Table 5. Distribution of pN Metastases in Absence of Barrett’s Intestinal Metaplasia Group (140 patients) by the Presence (⫹) or Absence (–) of Gastric Intestinal Metaplasia BIM–/GIM⫹ Group (n ⫽ 50)

BIM–/GIM– Group (n ⫽ 90)

Nodal Station

No.

⫹

%

No.

⫹

%

p Value

Lesser curvature Paracardiac Greater curvature Pancreatic and pyloric Spleen Celiac trunk Hepatic artery TNM stations 8, 9 TNM station 7 TNM stations 2–4

453 141 334 61 34 84 65 115 125 175

93 25 16 7 3 3 3 7 2 0

20.5 17.7 4.7 11.4 8.8 3.5 4.6 6 1.6 0

895 502 350 43 54 139 168 305 248 204

374 193 77 24 2 18 7 17 0 0

41.8 38.4 22 55.8 3.8 12.9 4.4 5 0 0

0.0001 0.0001 0.0001 0.0001 0.31 0.02 0.95 0.83 0.21 ...

BIM ⫽ Barrett’s intestinal metaplasia;

GIM ⫽ gastric intestinal metaplasia.

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Fig 2. Cumulative cancer-specific survival analysis grouped by tumor stage according to the 7th edition TNM staging system.

(BIM⫹/GIM–) and the gastric cancer–like pattern (BIM–/ GIM⫹). The third group, BIM–/GIM– adenocarcinoma, is difficult to put into a category. As it was postulated by others [8], in these cases the rapid overgrowth of the tumor could have destroyed the surrounding BIM. Moreover, the literature suggests that adenocarcinoma of the lower esophagus and cardia may originate from a metaplastic esophageal columnar epithelium without goblet cells [19]. The pathogenesis of conversion from squamous to columnar epithelium in the esophagus is largely unknown [20]. Molecular alterations in non– goblet epithelium support the controversial concept that metaplastic esophageal columnar epithelium without goblet cells has neoplastic potential [21]. A significant risk of dysplasia or adenocarcinoma in patients with esophageal non– goblet columnar epithelium has been demonstrated in the long term [19, 22, 23]. A recent study suggests that neoplastic changes in the esophagus occur more frequently in association with non– goblet epithelium com-

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pared with columnar epithelium with goblet cells [24]. The present case series supports this observation. The BIM⫹/GIM– and the BIM–/GIM– subgroups identified with our study may correspond to the goblet cell–positive and goblet cell–negative epithelium. The BIM⫹/GIM– group and the BIM–/GIM⫹ group grossly correspond to type I and III of the Siewert classification, respectively [1]. In the BIM–/GIM– group, which is the larger (46.4%) of our case series, a third type of adenocarcinoma different for carcinogenesis and biology may coexist. In the group BIM–/GIM–, reflux symptoms were recorded in 5.5% with respect to 85% of the BIM⫹ group. These clinical data reinforce the idea that in the BIM–/GIM– patients a pathogenetic line different than gastroesophageal reflux disease leading to Barrett’s metaplasia leading to adenocarcinoma may be present [7]. The data obtained with this study raise further questions and speculation. In the present series, there were significantly fewer stage IA cases in the BIM– than in the BIM⫹ group and significantly more stage IIIA and IV cases in the BIM– than in the BIM⫹ group. However, the survival curves were almost identical. This outcome may reflect the different surgical approach (total gastrectomy) that has been tailored for BIM– patients, a group that includes patients with a higher stage and, for the GIM– tumors, a more aggressive disease with respect to the BIM⫹/GIM– group (gastric pull up). Notably, in the more aggressive BIM–/GIM– group, metastases were detected at the greater curvature region in 22% of cases. The rate of cancer-specific survival according to tumor stage of the whole case series has shown encouraging results: a 5-year survival of 91% has been reported for stage IA, 73% for stage IB, 65% for stage IIB, 50% for stage IIIA, and less than 25% for stages IIIB, IIIC, and IV. This study has three evident limitations. It does represent a single-center experience. The surgical information deposited in the literature on this topic is empiric; this not a justification, but it is an evident limitation of the present study. The decision to manage Siewert I and Siewert II and III tumors differently originates from experiences shared essentially by a few European groups. Moreover,

Fig 3. (A) Cumulative cancer-specific survival in presence (black line, 54 patients) and absence (gray line, 140 patients) of Barrett’s intestinal metaplasia groups (log-rank Mantel-Cox p ⫽ 0.679). (B) Cumulative cancer-specific survival by the presence or absence of Barrett’s intestinal metaplasia (BIM) and gastric intestinal metaplasia (GIM). BIM⫹/GIM– group, black line (52 patients); BIM–/GIM⫹ group, light gray line (50 patients); and BIM–/GIM– group, dark gray line (90 patients). Log-rank (Mantel-Cox), p ⫽ 0.460, BIM⫹/GIM– versus BIM–/GIM–; p ⫽ 0.846, BIM⫹/GIM– versus BIM–/GIM⫹; p ⫽ 0.289, BIM–/GIM– versus BIM–/GIM⫹.

our data are referred to as the Italian population. Ethnic, genetic, environmental, and dietary factors may play a role in the etiopathogenetic pathways [25]. Whether the meticulous lymphadenectomy, the tailored surgery (gastric pull up or total gastrectomy), or the association of both surgical steps improves the quality of surgery remains to be defined. We grouped patients and treated them according to the presence or the absence of BIM around the tumor and of GIM in the gastric mucosa, assessed preoperatively. This approach seems to overcome some of the biases of the topographic classification. The present study strongly indicates the need for further research on the biologic and surgical sides possibly by Asian, North American, and European multicenter research programs. If the existence of different pathogenetic pathways will be confirmed, surveillance and early diagnosis programs also will probably require some adjustments.

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