Total gastrectomy versus upper pole gastrectomy for the surgical therapy of Siewert type II adenocarcinoma of the esophagus: pathology may drive the choice
Original Article

Total gastrectomy versus upper pole gastrectomy for the surgical therapy of Siewert type II adenocarcinoma of the esophagus: pathology may drive the choice

Marialuisa Lugaresi1,2*, Benedetta Mattioli2, Niccolò Daddi1, Vladimiro Pilotti2, Luca Ferruzzi2, GianDomenico Raulli3, Deborah Malvi4*, Antonietta D’Errico4*, Roberto Fiocca5*, Sandro Mattioli1,2*

1Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; 2Division of Thoracic Surgery, Maria Cecilia Hospital, GVM Care & Research Group, Via Corriera 1, 48033 Cotignola (RA), Italy; 3AUSL Area Vasta Romagna, Viale V. Randi, 5, 48121 Ravenna, Italy; 4Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; 5Department of Surgical and Diagnostic Sciences (DISC), University of Genova and IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy

Contributions: (I) Conception and design: S Mattioli; (II) Administrative support: M Lugaresi; (III) Provision of study materials or patients: V Pilotti, L Ferruzzi; (IV) Collection and assembly of data: A D’Errico, R Fiocca, D Malvi, G Raulli, B Mattioli, N Daddi; (V) Data analysis and interpretation: M Lugaresi; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

*The Esophageal Adenocarcinoma Study Group Europe (EACSGE) (EACSGE-University of Bologna, Amsterdam University, University of Genova, University of Helsinki, IRST-IRCCS Meldola Oncology Institute).

Correspondence to: Prof. Sandro Mattioli. Department of Medical and Surgical Sciences (DIMEC) Alma Mater Studiorum, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy. Email:

Background: Whether to adopt total or upper pole gastrectomy for the. surgical therapy of Siewert type II adenocarcinoma is controversial. We investigated patterns of greater curvature nodal metastases and cancer ascending progression into the esophagus, which are key points for the choice.

Methods: A total of 154 patients who underwent primary trans-thoracic esophageal resection, laparotomic total gastrectomy, thoracic-abdominal lymphadenectomy were categorized according to the Lauren’s classification and the presence/absence of intestinal metaplasia in the esophagus and stomach. Gastric greater curvature, pyloric metastases and the esophageal resection margin status were linked with pathology categories, recurrence, cancer-specific survival.

Results: Pathological stages were IA–IIA in 11%, IIB in 12.4%, IIIA–IV in 76.6% of patients. 59% were intestinal-type, 41% were diffuse-type, 1.3% were Barrett’s-type, 65% were cardiopyloric-type, and 33.7% were gastric-type adenocarcinomas. Greater gastric curvature nodal metastases were detected in 22% of stage IIIa–IV, 47% of intestinal-type and in 53% diffuse-type patients. The number of metastatic nodes at station 4 was higher in cardiopyloric-like than in gastric-like adenocarcinoma (P<0.0001). The 5-year cancer-specific survival of the 154 cases was 40.5%, 59.4% for intestinal-type and 0% for diffuse-type adenocarcinoma. Five-year cancer-specific survival in the absence/presence of greater gastric curvature metastases were 48.7% and 14.9%, respectively. For the intestinal type, they were 67.4% and 27.9%. Histological subtype was an independent prognostic factor.

Conclusions: Primary trans-thoracic esophageal resection + total gastrectomy + extended thoracic and abdominal lymphadenectomy is justified for intestinal type but not for diffuse type Siewert type II adenocarcinoma.

Trial Registration: ID: NCT03416101.

Keywords: Esophagus; global surgery; oncology

Received: 22 April 2020; Accepted: 24 June 2020; Published: 25 June 2021.

doi: 10.21037/aoe-2020-13


The surgical treatment for Siewert type II adenocarcinoma of the esophagus (1) is still debated. Siewert, with others, indicated total gastrectomy due to the high frequency of perigastric and greater curvature nodal metastases (2-4).

On the basis of new data on the frequency of metastases at the gastric greater curvature (5-12), quite lower than those previously reported (2-4) (Table S1), it was concluded that the resection of the lower esophagus and the upper pole of the stomach could be as effective as total gastrectomy with regard to survival (7,10,11), eventually in association with neoadjuvant therapy (8,9,13). Recent papers support again the choice of total gastrectomy (14,15). The controversy may be produced by the Siewert’s classification, which is not precise enough to discriminate between type II and III cases (14-17), by the different modalities of lymphadenectomy performed (18) and of the pathological specimen work-up (19-22).

In 2007 to overcome biases of the Siewert classification, we adopted a new pathologic classification based on the presence/absence of intestinal metaplasia in the esophagus and/or stomach that discriminates cases in Barrett’s, cardio-pyloric and gastric types (23). Since, we started a prospective study protocol aimed to investigate biology and results of surgical therapy for esophageal adenocarcinoma. For the primary treatment of Siewert type II, we adopted the total gastrectomy associated with the esophageal resection at the azygos vein level through right thoracotomy, with an extended thoracic and abdominal (D2) lymphadenectomy; we had previously demonstrated that this technique provided a radical resection especially suited for poorly differentiated carcinoma (24). The intraoperative nodes retrieval and mapping, the pathology work-up of the surgical specimen, were aimed to investigate the oral and aboral intra mural cancer diffusion and modalities of nodal metastases spreading (24). We completed the pathology work-up with the adoption of Lauren’s classification (25), which is relevant from a prognostic, epidemiological, and pathogenic perspective for esophageal adenocarcinoma (26-30).

We indicated primary surgery for tumours up to T4 (diaphragm), N1 (peritumoural stations), with the exclusion of bulky metastases. By the time we maintained this line: at periodic analysis our results (21,22,24) were similar to those reported by others (31,32) and were competitive with survivals obtained with neoadjuvant therapy followed by surgical resection (33,34).

In the present study we considered cases classified type II according to Siewert’s, who were primarily operated upon between 2007 and 2017. We investigated the frequency of chest/abdominal nodal metastases with a particular focus on gastric greater curvature stations, the recurrence patterns, the submucosal orad cancer diffusion into the esophagus, 5-year survival according to these data and the Lauren’s classification. We present the following article in accordance with the STROBE reporting checklist (available at:


Preoperative diagnosis and clinical staging

The preoperative work-up included upper gastrointestinal tract endoscopy with multiple tumours’ and surrounding mucosa biopsies, barium swallow, thoracic and abdominal CT, PET or CT-PET. Tumours were staged according to the AJCC/UICC TNM 8th edition (35).

Surgical technique

The surgical technique we adopted (21,22,24) is extensively described in Supplementary 1 and Figure S1. Briefly, a midline or transverse laparotomy and a muscle-sparing lateral-anterior right thoracotomy were performed. The esophagus was resected at the level of the azygos vein arch, and a frozen section of the resection margin was routinely performed to achieve a proximal clean resection margin (24). The surgical specimen was comprehensive of distal esophagus, stomach and omentum. The digestive tract continuity was established with Roux-en-Y esophagojejunostomy.

Lymphadenectomy was extended to the thoracic stations R 2–4, 7–8–9, numbered according to Mountain’s classification (36) (Supplementary 2 and Figure S2), to the abdominal stations 1–12, numbered according to the Japanese Research Society for Gastric Cancer (JRSGC) 1998 classification (37) (Supplementary 2 and Figure S2).

Nodes were removed en bloc with the adjacent fat/connective tissue to achieve total lymphadenectomy (22). The surgical team labelled each lymph node when it was removed from the peripheral stations; lymph node fragments were excluded to avoid N over-count.

Mortality at 90 days and morbidity were extracted from the database.


The pathologic work-up of the surgical specimen (21,22,24) is illustrated in detail in Supplementary 3 and Figure S3. Based on the presence (+) or absence (−) of Barrett’s intestinal metaplasia (BIM) and intestinal metaplasia in the stomach (GIM), cases were categorized as Barrett’s-like type (BIM+/GIM−), cardiopyloric-like type (BIM−/GIM−), or gastric-like type (BIM−/GIM+) (21,23).

Adenocarcinoma was classified according to Lauren as intestinal, mixed, or diffuse type (25). Lymphovascular invasion was defined as absent or present (35), perineural diffusion and the ratio of the number of metastatic lymph nodes to the total number of nodes yielded (LNR) (22) were determined. Tumour grade (G) was grouped as 1+2 and 3+4.

Follow-up and survival

After surgery, patients were followed up twice per year (clinical assessment, serum oncologic markers, at each follow-up, upper gastrointestinal tract endoscopy, chest/abdominal CT, PET, or CT-PET, once per year). Site(s), relapse modalities, and date and cause of death were registered. Cancer-specific survival (in months), calculated from the date of surgery to the date of death due to documented recurrent disease, was adopted instead of overall survival, as it may better indicate the course of a specific disease and the effects of therapy (38).

Adjuvant therapy

In the absence of general contraindications, adjuvant chemotherapy and radiation therapy were administered according to guidelines (39,40) in cases of pN+, R1 surgery, lympho-vascular invasion or after documented recurrence.

Ethics committee approval

The local institutional review board of the IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (CEAV/IRST) approved the use of the database maintained by the Division of Thoracic Surgery for research purposes (No L3P1223). The study was conducted in accordance with the Declaration of Helsinki (as revised in Edinburgh 2000).

Statistical analysis

Data are represented as median and interquartile range (IQR) for continuous variables and as n (%) for categorical variables. The χ2 test or Fisher’s test (expected number less than 5) and the Mann-Whitney test were used to analyse categorical and continuous variables. Cancer-specific survival analyses were performed using the Kaplan-Meier method and the log-rank test. Univariable and multivariable (forward stepwise conditional method) Cox regression analyses were performed to estimate the effects of clinical and pathological parameters on cancer-specific survival. Multivariable logistic regression analysis was performed to identify the predictors of lymph node metastases in the greater gastric curvature. P values <0.05 were considered significant. Data were analysed using SPSS (version 15.0) (SPSS Inc., Chicago, IL, USA).


All 154 Siewert type II cases operated upon primarily in the considered period were suitable for the study. Six patients died within 90 postoperative days (6/154, 3.8%) for mediastinitis due to anastomotic fistula in 5 patients and peritonitis after dehiscence of the Roux jejunal anastomosis in 1 patient. Major morbidity included intrathoracic anastomotic leakage in 3 patients, necrosis of the jejunal loop in 2 patients, and torsion of the jejunal loop in 1 patient (6/154 patients, 3.8%). The R0 resection rate was 97.4% (150/154). Four cases showed submucosal microscopic involvement of the esophageal resection margin (R1, 2.6%). Two were of the diffuse type and two of the signet ring cells type; two patients were younger than 40 years. Sex, age, histology, grading and pathologic (p) staging data are displayed in Table 1.

Table 1
Table 1 Distribution of demographic parameters and pTNM staging (AJCC 8th edition) in 154 Siewert type II adenocarcinomas according to Lauren’s histological classification
Full table

A total of 4,825 nodes were yielded (median 30.5, interquartile range per patient 22–38; minimum, 8 nodes; maximum, 61 nodes).

The clinical N staging parameter was under-estimated in 47% of cases with respect to pathological N stage, which was 2 or 3 instead of 0 or 1. Overall, 91 (59%) were adenocarcinomas of the intestinal type, 10 were mixed type (6.5%) and 53 (34.5%) were diffuse type. Mixed type cases were included in the diffuse type (diffuse + mixed 41%) for analysis. Statistically significant differences between the intestinal and diffuse histological subtypes pNodes (P<0.0001), p staging (P<0.0001) and LNR (P<0.0001) were calculated. Of 154 cases, 120 (78%) were negative for metastases at the greater curvature/pyloric lymphatic nodes, while 34 cases (22%) were positive. Of 34 cases, 24 had metastases at station 4sa (15.6%), 9 at station 4sb (5.8%), and 1 at station 4d (0.6%). Nineteen of 34 patients were positive also at station 6 (12.3%). In Table 2, cases that were negative (group 1) and positive (group 2) for greater gastric curvature and pyloric lymph node metastases are distributed according to histological intestinal/diffuse subtype, grading (G), staging parameters, LNR, lymph-vascular invasion, perineural invasion, the percentage of metastases at the thoracic and abdominal lymphatic stations and the categorization of cases according to the presence/absence of BIM and GIM.

Table 2
Table 2 Distribution of Group 1 patients (120 cases) and Group 2 patients (34 cases) that were positive for gastric curvature and pyloric lymph nodes metastases according to histological subtype (Lauren’s classification). The distribution of lymph node metastases in the thoracic and abdominal lymphatic stations is shown at the bottom of the table
Full table

Statistically significant differences were found between groups 1 and 2 for grading (P=0.048), pT (P=0.015), pN (P<0.0001), p staging (P<0.0001), and LNR (P<0.0001) (Table 2). The median LNR (Figure 1) was higher in group 2 because both the number of positive lymph nodes (numerator) and the number of yielded lymph nodes (denominator) were greater than in group 1 (P<0.0001 and P=0.001, respectively). Logistic regression analysis identified the LNR as the only predictor of lymph node metastases in the greater curvature of the stomach (P=0.003; OR =1.045, 95% CI: 1.016–1.078). Within both groups, statistically significant differences between the intestinal and diffuse histological subtypes were found for pN, p staging, and LNR (Table 2). Siewert type II category was cardiopyloric-type in 100/154, 65% (BIM−/GIM−); gastric-type in 52/154, 33.7% (BIM−/GIM+); and Barrett’s-type in 2/154, 1.3% (BIM+/GIM−). Statistically significant differences with regards to age between gastric-like (median 67.5, IQR: 60.5–72.2 years) and cardiopyloric-like (median 63, IQR: 57.2–69 years) types were found (P=0.023). No significant differences between two types with regards to sex, histology (intestinal and diffuse type), grading, pT, pN, pM, p staging, and LNR were detected. In Table 3, cases are distributed according to BIM/GIM and the Lauren’s classification classes. The number of cases for each sub-group, with and without gastric greater curvature and pyloric nodal metastases, the number of lymph nodes harvested and the number of lymph nodes positive for metastases at the greater curvature stations are reported.

Figure 1 Box-plot representation of the values of the lymph node ratios (the ratio of the number of metastatic lymph nodes to the total number of nodes yielded) in Group 1 (median .06; IQR: 0–0.22) and Group 2 (median 0.30; IQR: 0.10–0.38) patients (P<0.0001).
Table 3
Table 3 Gastric greater curvature lymph nodes metastases (station 4 sa, sb, d, see text)
Full table

Of 148 patients who survived surgery, cancer recurred in 87 (58.7%) [27/88 (30.6%) intestinal type; 60/60 (100%) diffuse type]. Recurrence occurred at one site in 67 patients (liver, 21; lumbar-aortic nodes, 14; anastomotic level, 10; mediastinum, 10; lung, 6; brain, 5; cervical nodes, 1) and at multiple sites in 9 patients (liver and lumbar-aortic nodes, 4; bones and peritoneal area, 2; bones and anastomotic level, 2, anastomotic level and lumbar-aortic nodes, 1); peritoneal or pleura carcinosis was observed in 11 patients. The sites and modalities of recurrence were equal between the histological subtypes. Kaplan-Meier cancer-specific survival curves for the whole series and according to histology are shown in Figure 2 (5-year survival for all cases: 40.5%; for intestinal and diffuse type cases: 59.4% and 0%, respectively; P<0.0001). Univariable Cox regression analysis showed that G (P<0.0001), pT (P=0.005), pN (P<0.0001), p staging (P<0.0001), lymphovascular invasion (P<0.0001), perineural diffusion (P<0.0001), Lauren’s histology (P<0.0001), and LNR (P=0.001) significantly correlated with cancer-specific survival. Multivariable Cox regression analysis identified Lauren’s histology (P<0.0001; HR 2.9, 95% CI: 1.6–5.4) and lymphovascular invasion (P=0.028; HR 2.7, 95% CI: 1.1–6.6) as independent prognostic factors that significantly influenced cancer-specific survival.

Figure 2 Kaplan-Meier cancer-specific survival curves for the whole series (A) and for the patients with the intestinal and diffuse histological types (P<0.0001) (B).

Figure 3 shows cancer-specific survival curves for the intestinal and diffuse histological types in patients without (Group 1) and with (Group 2) greater gastric curvature/pyloric metastases (intestinal type Group 1 vs. Group 2, P=0.038; diffuse type Group 1 vs. Group 2, P=0.158). Patients without greater gastric curvature/pyloric metastases had significantly longer cancer-specific survival regardless of histological subtype.

Figure 3 Patients positive (Group 1) and negative (Group 2) for greater gastric curvature metastases. (A) Kaplan-Meier cancer-specific survival curves for patients with the intestinal histological type in Group 1 and Group 2 (P=0.038). (B) Kaplan-Meier cancer-specific survival curves for patients with the diffuse histological type in Group 1 and Group 2 (P=0.158).


In the past, it was generally presumed that station 4 metastases were more frequent in Siewert type III than in type II (1,2,10,11); station 4 high metastases rates were related to the higher percentage of cases of type III erroneously classified as type II (2,41,42).

In this series, in cardiopyloric-like type cases, metastases at the greater curvature region were detected in 20.4% of lymph nodes harvested, while in the gastric-like type, they occurred in 4.8% (P<0.0001); according to Lauren (25), cases were 59% intestinal type and 41% diffuse + mixed type. Histology, pTNM, and LNR parameters showed that the diffuse type is clearly more aggressive than the intestinal type. Lauren’s histological subtype was an independent prognostic factor.

Greater curvature and pyloric lymph node metastases were detected in 34 of 154 cases (22%), in stage IIIa–IV only, 47% in intestinal-type and 53% in diffuse-type. Four of 154 cases (2.59%) had positive esophageal resection margins at the azygos vein level. Two cases were of the diffuse type, and 2 were of the signet ring cell type (a 37-year-old man “a posteriori” resulted to have a CDH1 hereditary disease).

In 154 cases, the 5-year cancer-specific survival was 40.5%, with 59.4% for intestinal type and 0% for diffuse type. According to the absence/presence of gastric greater curvature metastases, the 5-year cancer-specific survival rates were 48.7% vs. 14.9%, respectively; for intestinal type, they were 67.4% vs. 27.9%, and for diffuse type, it was 0% independently from the nodal status.

For “esophageal adenocarcinoma”, pathology may: (I) discriminate cases originated from Barrett’s, cardio-pyloric and gastric mucosa, which have different patterns of nodal metastases and aggressiveness (21,22); (II) offer interesting biological/prognostic indications.

With total gastrectomy, D2 abdominal lymphadenectomy, transthoracic resection of the esophagus and of mediastinal nodal stations, we achieved 5-year cancer specific survival in 59.4% for intestinal type adenocarcinomas, of whom 64.8% were 3a–4 stage. With the same operation, none of the diffuse type cases survived over 3 years.

Greater curvature lymph nodes metastases were present in p stages III and IV only, mostly close to short gastric vessels (station 4a): these metastases possibly occurred in aggressive tumours (cardiopyloric and diffuse types), or in intestinal type cases that were diagnosed late. These data suggest that the resection of gastric greater curvature nodal stations is effective in cases of intestinal type adenocarcinoma, but not for the diffuse type.

For diffuse type adenocarcinoma, which includes signet ring cell carcinoma, in our opinion neoadjuvant therapy should be mandatory, eventually with new drug combinations (43). The same concept, to trim the extension of the surgical resection according to the aggressiveness of cancer, is probably valid for sizing the esophageal resection.

In case of intestinal type adenocarcinoma, it is not necessary to resect the esophagus at the azygos vein level; the higher the level of the esophageal-jejunal anastomosis, the higher the risk of jejunal loop ischemia-dependent complications, as demonstrated by the mortality-morbidity data displayed in this series.

In conclusion, the present study indicates that total gastrectomy associated with extended abdominal and thoracic station lymphadenectomy, with resection of the esophagus 5 centimetres above the tumour’s macroscopic upper margin (44,45), may be the right choice for intestinal type adenocarcinoma as an alternative to neoadjuvant therapy followed by the Ivor Lewis operation.

This proposal needs to be verified and confirmed by retrospective pathology analyses of data collected with cooperative studies comparing the efficacies of different surgery/chemo-radiotherapy sequences (15,39) and with new research protocols. The treatment’s modalities for diffuse type adenocarcinoma are also worth extensive investigation.


Funding: None.


Provenance and Peer Review: This article was commissioned by the Guest Editor (Riccardo Rosati) for the series “Current issues on GEJ adenocarcinoma” published in Annals of Esophagus. The article has undergone external peer review.

Reporting Checklist: The authors have completed the STROBE reporting checklist, available at

Data Sharing Statement: Available at

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at: The series “Current issues on GEJ adenocarcinoma” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The local institutional review board of the IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (CEAV/IRST) approved the use of the database maintained by the Division of Thoracic Surgery for research purposes (No L3P1223). The study was conducted in accordance with the Declaration of Helsinki (as revised in Edinburgh 2000).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See:


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doi: 10.21037/aoe-2020-13
Cite this article as: Lugaresi M, Mattioli B, Daddi N, Pilotti V, Ferruzzi L, Raulli G, Malvi D, D’Errico A, Fiocca R, Mattioli S. Total gastrectomy versus upper pole gastrectomy for the surgical therapy of Siewert type II adenocarcinoma of the esophagus: pathology may drive the choice. Ann Esophagus 2021;4:15.