Review

Complete Mesogastric Excisions Involving Anatomically Based

Concepts and Embryological-Based Surgeries: Current
Knowledge and Future Challenges
Sergii Girnyi 1 , Marcin Ekman 1 , Luigi Marano 2, * , Franco Roviello 2 and Karol Połom 1

1 Department of Surgical Oncology, Medical University of Gdansk, 80-070 Gdansk, Poland;

[email protected] (S.G.); [email protected] (M.E.); [email protected] (K.P.)
2 Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences,
University of Siena, 53100 Siena, Italy; [email protected]
* Correspondence: [email protected]

Abstract: Surgeries for gastrointestinal tract malignancies are based on the paradigm that we should
remove the tumour together with its lymphatic drainage in one block. This concept was initially
proposed in rectal surgery and called a total mesorectal excision. This procedure gained much interest
and has improved oncological results in rectal cancer surgery. The same idea for mesogastric and
complete mesogastric excisions was proposed but, because of the complexity of the gastric mesentery,
it has not become a standard technique. In this review, we analysed anatomical and embryological
factors, proposed technical aspects of this operation and incorporated the available initial results of
this concept. We also discussed analogies to other gastrointestinal organs, as well as challenges to
this concept.






Keywords: mesogastrium; embryological planes; anatomical dissection; gastric cancer
Citation: Girnyi, S.; Ekman, M.;
Marano, L.; Roviello, F.; Połom, K.
Complete Mesogastric Excisions
Involving Anatomically Based
1. Introduction
Concepts and Embryological-Based
Surgeries: Current Knowledge and Gastric cancer is the fourth leading cause of death in worldwide cancer-associated
Future Challenges. Curr. Oncol. 2021, deaths [1]. It is often diagnosed in the advanced stage. Treatment of patients with advanced
28, 4929–4937. https://doi.org/ gastric cancer still has poor prognoses [2]. Currently, the primary treatment for locally
10.3390/curroncol28060413 advanced gastric cancer is surgery. The standard surgical treatment for advanced gastric
cancer worldwide is a gastrectomy with a D2 lymphadenectomy [3–5]. Rohatgi et al.
Received: 13 October 2021 have shown that despite radical surgical treatment, disease recurrence is observed in
Accepted: 19 November 2021 approximately 60% of patients [6].
Published: 22 November 2021 The primary aim of gastrointestinal cancer surgery is an en block resection of the
tumour together with its complex lymphovascular drainage that follows an organ’s specific
Publisher’s Note: MDPI stays neutral mesenteric layers [7]. The concept of an en block resection of the untouched fascia covering
with regard to jurisdictional claims in the mesenteric tissue mimicking an envelope is the basis for complete meso-excisions.
published maps and institutional affil- Heald et al. proposed a revolution in rectal surgery by implementing a total mesorectal
iations.
excision [8]. This procedure involves a sharp dissection following embryological planes
with intact mesorectal fascia that covers not only the tumour but also lymphatic vessels
and regional lymph nodes. Following this idea, the local recurrence rate in conventional
surgery, which was as high as 33%, dropped after the implementation of TME to 10% [9].
Copyright: © 2021 by the authors. A similar idea was proposed by Hochenberger et al. for colon cancer [10]. A complete
Licensee MDPI, Basel, Switzerland. mesocolic excision with a dissection of the mesocolic planes together with vascular ligation
This article is an open access article led to an improved short survival rate in a German group and in a Danish population-based
distributed under the terms and study [11]. The idea of applying mesentery-based surgeries for a number of other organs
conditions of the Creative Commons became popular and was subsequently proposed. A meso-oesophageal resection of the
Attribution (CC BY) license (https://
thoracic oesophagus was proposed by Matsubara et al., while Cuesta et al. presented a
creativecommons.org/licenses/by/
minimally invasive meso-oesophageal model [12,13].
4.0/).

Curr. Oncol. 2021, 28, 4929–4937. https://doi.org/10.3390/curroncol28060413 https://www.mdpi.com/journal/curroncol

Curr. Oncol. 2021, 28 4930

The idea of the mesopancreas was presented by Adham and Singhirunnusorn, and a
recent study presented robotic mesopancreatic resections on 289 patients [14]. In all, with
an increasing number of centres implementing this idea together with clinical data into
daily practices, this technique has already shown huge potential in this area [14,15].
The idea of meso-excision was also proposed in gastric cancer resections.
Gastric cancer has four main routes of metastasis. These include a direct invasion of
the tumour, lymphatic metastases, hematogenous metastases and peritoneal metastases.
In 2012, Xie et al. hypothesized there may be a fifth pathway for the spread of gastric
cancer cells called the metastasis V route [16]. This pathway differs from the other four
classical metastatic pathways and cannot be removed by a standard D2 gastrectomy.
Isolated tumour cells and small tumour nodules situated in the mesogastrium in adipose
connective tissue have no direct link to the primary tumour or to lymphatic or vascular
vessels. They proposed a third principle of radical gastrectomy, which is a complete
mesogastrium excision (CME) [16]. As a new concept, this hypothesis needs further
evidence, with preclinical as well as clinical studies, to become well established. In 2015,
Xie et al. demonstrated the existence of the gastric mesentery and its structure. A model
of the relationship between the stomach and the gastric mesentery surrounded by the
proper fascia was then proposed. Previously unknown at that time, there are actually six
anatomical structures formed between the embryological stage and the mature adult, and
they consist of adipose tissue, lymph nodes and vessels. These help to fix the stomach to the
posterior abdominal wall and were discovered and identified histologically. A CME using
the Table Model technique and a tri-junction access was applied on a group of 105 patients
to improve the conceptualization of gastric mesenteries [17]. The CME can also be called a
systemic mesogastric excision or perigastic mesogastrium excision [18–20]. The CME was
proposed by Xie et al.; however, a simple mesentery-based surgery that was the key to
success in colorectal surgery is not that easy to implement during a gastrectomy because of
various anatomical restrictions.
We need to point out here that, as with every new hypothesis, we need more evidence
and detailed technical aspects of operation followed by CME principles to show that en
block resection might be not enough in terms of oncological outcome. The primary and
preliminary aspects of this new technique are presented and discussed.

2. Mesogastrium
Due to the complexity of its structure, the mesogastrium is an anatomically unclassi-
fied structure. During embryological development, the tubular stomach and duodenum
are connected to the posterior abdominal wall by a continuous mesentery. This mesentery
consists of a double layer of peritoneum that surrounds the vessels, nerves and lymphatic
pathways. As it grows and unfolds, the stomach begins to expand and twist to the left,
clockwise around its longitudinal axis. At the same time, the pancreas, which is also a
mesenteric component, arises from primitive buds in the duodenal wall. It then grows into
the mesoduodenum and spleen, which is formed at the end of the first month of life, in
the dorsal mesentery of the stomach, near its greater curvature, which is when it begins to
enlarge [21,22].
During embryological development, both the stomach and duodenum are suspended
by dorsal and ventral mesenteries from the parietal wall. During a 90-degree clockwise
rotation along its longitudinal axis, the expansion of the dorsal mesogastrium into the
upper abdomen occurs and is responsible for the formation of the omental bursa, which is
fixed to the retroperitoneum. At the same time, there is a 270-degree counter-clockwise
rotation of the primary midgut loop. The axis of rotation is the superior mesenteric artery.
The transverse mesocolon moves closer to the dorsal mesogastrium. Both structures, the
mesoduodenum and transverse mesocolon, are covered by the greater omentum, creating
a derivative of the dorsal mesogastrium [23]. The creation of the mesopancreas is also
an important part of the development of embryological planes and is important during
mesogastric procedures in mesentery-based surgery for gastric neoplasms [23,24].
 omentum, creating a derivative of the dorsal mesogastrium [23]. The creation of the mes-
opancreas is also an important part of the development of embryological planes and is
Curr. Oncol. 2021, 28 important during mesogastric procedures in mesentery-based surgery for gastric neo- 4931
plasms [23,24].
Xie et al. suggested that the mesentery of the stomach separates in three places into
the greater mesentery and smaller mesentery of the stomach, the mesentery of the greater
Xie et al. suggested that the mesentery of the stomach separates in three places into
or lesser
the greatercurvature
mesentery of and
the stomach and the pancreatic
smaller mesentery mesentery.
of the stomach, In the course
the mesentery of theof greater
further
embryological development, the mesentery of the stomach is divided
or lesser curvature of the stomach and the pancreatic mesentery. In the course of further into six independent
areas. To date,development,
embryological no boundaries thehave been defined
mesentery betweenisthe
of the stomach perigastric
divided into sixadipose tissue
independent
and the connective soft tissue. In 2015, Xie et al. reported the
areas. To date, no boundaries have been defined between the perigastric adipose tissue existence and described the
anatomical
and structuresoft
the connective of tissue.
the gastric mesentery.
In 2015, Xie et al.They divided
reported thethe mesogastrium
existence into the
and described
the anatomical structure of the gastric mesentery. They divided the mesogastrium right
following six segments: the left and right gastroepiploic mesenteries, the left and into
gastric
the mesenteries,
following the posterior
six segments: gastric
the left andmesenteries (PGM) and
right gastroepiploic the short gastric
mesenteries, mesen-
the left and
teries.gastric
right We presented
mesenteries,an ideathe of the Table
posterior Model
gastric in Figure (PGM)
mesenteries 1. Each and segment has its
the short own
gastric
artery. They We
mesenteries. alsopresented
showed that an ideathe structure
of the Table ofModel
each ofinthe six mesogastrium
Figure 1. Each segment segments
has its ownvar-
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artery. They also to showed
their length
that theandstructure
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of each theetsixal.mesogastrium
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cancer recurrence
according depends
to their length andoncomplexity
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Jie et al. hypothesized that the[18].
riskColorectal
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cancer recurrences
recurrence depends are more
on the frequent
length in sections of
and complexity with
thelonger
mesentery and [18].
moreColorectal
complex mesen-cancer
teries, such as the hepatic and splenic flexures and the sigmoid
recurrences are more frequent in sections with longer and more complex mesenteries, colon, than in the remain-
such
ingthe
as parts of the
hepatic andcolon [25].flexures
splenic The possibleand the mechanisms
sigmoid colon, of thethan
metastasis V route have
in the remaining parts been
of
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key discussed
points of in thisa
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et al.; briefly, stomach and connective
will describe and adipose
the key points of thistissues
concept of[16].
the mes-
The
entery of
surface arethe
covered
stomach byand
a layer of deep
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adipose Within
tissues this space,
of the tumourare
mesentery nodules
coveredmay by
aspread beyond
layer of the classic
deep fascia. Withinwaythis of metastasis.
space, tumour In advanced
nodules may gastric cancer,
spread after athe
beyond muscular
classic
layerofinvasion,
way metastasis.cancerIn cells may drop
advanced gastricinto this envelope.
cancer, The migration
after a muscular of cancer cancer
layer invasion, cells in
this space
cells is attracted
may drop into thisby some cytokines,
envelope. e.g., vistafin
The migration of cancer or DAB2IP [26–28].
cells in this spaceThis concept
is attracted
by
hassome
beencytokines,
evaluated e.g., vistafin or DAB2IP
on cross-sectional analyses [26–28].
of theThis concept has[29].
mesogastrium been Inevaluated
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cross-sectional
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gastricof cancer,
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metastasis V[29]. was In a group
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found a mean
with advanced
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Not only waswerefound at a mean of
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from the gastric wall. Not only were the prognoses of the patients
senting metastasis V significantly worse, but this factor was also associated with other presenting metastasis V
significantly worse, but this factor was also associated with
poor prognostic factors, such as tumour invasion depth and the involvement of severalother poor prognostic factors,
such as tumour
metastatic lymph invasion
nodes. depth and the involvement of several metastatic lymph nodes.

Figure 1. Table Model for complete mesogastric excision.

2.1. Mesogastrium: Translation of the Idea from the Mesocolon

Shinohara et al. have shown similarities between the mesogastrium and mesocolon
based on their series of patients [24]. In a group of 157 mesosigmoid specimens, they
Curr. Oncol. 2021, 28 4932

reported similarities in the allocation of lymph nodes in three sectors of the mesocolon.
These mainly included the peri-organ, the intermediate and a root in comparison with
mesogastric lymph node stations 1–6; the second sector, including stations 7, 8 and 10–12;
and the last third in sector 9. The number of lymph nodes by sectors decreases as per the
convergence and represents 36.5 for the stomach, 18 and 4 for the abovementioned sectors
and 16, 7 and 4 for the analogous sectors in the mesocolon. A lower proportion in the main
nodes originating in the mesogastrium might be associated with the shorter length of the
celiac trunk when compared with the inferior mesenteric artery.

2.2. Mesogastric Excision

In each segment of the mesogastric Table Model, various structures are situated,
and different lengths and complexities are found between the segments [30]. There is a
difference in length between the lesser and greater curvature mesenteries, with a much
shorter length at the lesser mesentery and the upper part of the stomach; however, both
shorter mesenteries are much more complex. A D1 + lymphadenectomy, according to
Kumamoto et al., should be performed following the rules of a systemic mesogastric
excision [19]. This group divided the D1 + lymphadenectomy for gastric cancer into four
parts. The first part (the greater curvature segment) starts with a division of the greater
omentum to open the bursa 3 cm from the gastroepiploic vessels up to the spleen. The
left gastroepiploic vessels are then ligated at their roots. In case of a total gastrectomy, the
additional dissection of the short gastric arteries up to the left cardia is performed. The
second part (infrapyloric segment) of the dissection is between the mesoduodenum and
greater omentum as well as the transverse colon. Infrapyloric lymph nodes are separated
from the pancreas by following the intramesenteric dissectible layers. The third part
(suprapancreatic and lesser curvature) starts with a dissection of the lesser curvature
from the hepatoduodenal ligament up to the right cardia. The tissue with lymph nodes is
separated from the intramesenteric dissectible layers. At this point, the tissues are separated
from the arteries, including the proper hepatic, common hepatic and splenic arteries, and
from the pancreas. Part four consists of a ligation of the right and left gastric vessels at their
roots. In a total gastrectomy, we enlarge the dissection of lymph node stations 12a and 11d
with what seems to be a simple extension of the narrowed part of the mesogastrium [19].
Similar steps in a laparoscopic D2 lymphadenectomy using the CME concept have been
presented by Cao et al.; however, they started by lifting the stomach upward and in a
cephalic direction by the assist [31]. The suprapancreatic mesogastrium, which consists of
the left gastric mesentery (LGM), the right gastric mesentery (RGM) and the PGM, is then
exposed. Opening the serosal layer and identifying the retrogastric space starts with the
exposition of the LGM. Then, a tissue separation of the gastroduodenal artery (GDA) from
the duodenal side is performed exposing the RGM. Afterwards, the LGM mobilization and
the removal of tissue at the common hepatic artery (CHA) are performed. This manoeuvre
helps in finding the root of the left gastric artery that is also ligated at its origin. Dissection
and ligation of the RGM is performed along the CHA and portal vein. The superior border
of the splenic vessels is then cleaned from the adjacent tissues. The anterior lobe of the PGM
is then lifted to find and ligate the posterior gastric vessels. The mesogastric Table Model.

3. Recurrence of GC after a D2 Gastrectomy

Surgical treatment with peri-operative chemotherapy is currently the only available
method of treating advanced gastric cancer according to the current standards. The gold
standard of radical surgical treatment of advanced gastric cancer is a total gastrectomy with
a D2 lymphadenectomy. Unfortunately, a recurrence of the disease after radical surgery
has been frequently reported [32–37]. The main causes of relapse are the potential spread
of cancer cells during surgery or a minimal amount of cancer cells that have been left
behind. Earlier studies have shown that cancer nodules in the mesogastrium can be as
high as 8% [38]. Spolverato et al. stated that the recurrence rate of advanced gastric cancer
is approximately 30–45% [39]. Rohatgi et al. have shown that, despite radical surgical
Curr. Oncol. 2021, 28 4933

treatment, disease recession was observed in approximately 60% of patients with advanced
gastric cancer [6]. Likewise, Dickson et al. declared that, after radical surgery, 75–80% of
patients had disease recurrence after two years [37]. Extra-nodal metastasis of cancer cells
in adipose tissue was found in almost 40% of patients after a gastrectomy for T4a gastric
cancer [40]. Broken dissected vessels during a gastric cancer lymphadenectomy may be
responsible for cancer cell spillage into the peritoneal cavity [41].

4. Gastrectomy D2 + CME
A modification of the standard D2 gastrectomy to perform a CME was proposed by
Xie et al. with a procedure appropriately named the Table Model [17]. We presented a
modified scoring of the mesogastrium—amended proposition by Xie et al. [17] in Table 1.

Table 1. Scoring of modified mesogastrium—modified proposition by Xie et al. of analysing the quality of CME by scoring
different parameters by surgical, pathological and embryo-anatomical factors. With “6” being the highest mark while “0”
indicated the poorest sample.
Scoring of Mesogastrium

Surgery and Histopatological

“Tri-Junction” “Pumpkin-Like Surface” “Little Square” Root Ligation Bleeding Amount Lymph Nodes of Mesogastrium
Scoring of Mesogastrium

0 point Failed to find Failed to expose Failed to expose Failed to reach the root part of blood vessels >40 mL Organ + Lymphatic stations 1–6

0.5 point Not obvious Not obvious Not obvious Not quite satisfied 20–40 mL Lymphatic stations 1–6 + 7, 8, 10–12

1 point Very obvious Very obvious Very obvious Quite satisfied <20 mL Lymphatic stations 1–8, 10–12 + 9

After standard gastrectomy with a D2 lymphadenectomy, the recurrence rate during

the five years after the gastrectomy may be as high as 38%. Hypothetically, free cancer cells
spill into the operation area and peritoneal cavity, which may be responsible for the cancer
recurrence [42]. Xie et al. examined two groups of patients who had undergone either the
classical D2 or D2 + CME laparoscopic distal gastrectomies. In particular, they looked at
the intraoperative peritoneal washing before and after the operation and identified CEA
levels to show the presence of gastric cancer cells [43]. From the group with a low CEA
expression before the operation, they found that after the resection, 32% of CEA expression
was in the peritoneal fluid and 15% was from the D2 + CME procedure. Additionally, in
the group of patients with a low CEA expression, the DFS in the D2 + CME group was
significantly better than in the D2 gastrectomy group. They postulated that cancer cells
found in the peritoneum came from lymphatic vessels or from the serosal surface when it
is involved in the cancer process. However, this hypothesis cannot support the situation
when free cancer cells found in the peritoneal cavity also occur in tumours without a serosal
invasion or without lymph node involvement [44,45]. The possible presence of cancer
cells in the mesogastrium with no direct connection with the original tumour may be a
possible explanation for intraperitoneal recurrence after a traditional gastrectomy with a
D2 lymphadenectomy.
Short-term results after a laparoscopic D2 lymphadenectomy with CME on a group
of 54 patients not only presented the feasibility of this procedure but also resulted in
reduced blood loss, a good number of retrieved lymph nodes and improved short-term
surgical outcomes [18]. Short-term outcomes in a randomized clinical trial on D2 + CME
by Xie et al. suggested that this procedure, in comparison with the standard D2 dissection,
exhibits a reduction in blood loss, more lymph nodes being able to be dissected and earlier
postoperative flatus. Moreover, even as postoperative complications were comparable
between the two groups, the severity was significantly lower in the D2 + CME group.
A review of the available six studies on complete mesogastric excisions on 518 patients
showed that the mean number of resected lymph nodes was 36.7 ± 10 [46]. The mean
operative time was 240.7 ± 10.1 min, with a morbidity rate of 6% and a median blood loss
of 50.2 ± 39.6 mL. The length of stay was 10.7 ± 0.7 days. These studies all came from
China and Japan [18–20,31,47,48].
Curr. Oncol. 2021, 28 4934

5. Challenges
5.1. Resection of the Pancreas
It has been shown, based on molecular and embryological points of view, that the
pancreas is a separate mesenteric component arising from the duodenum. This process
is controlled by the pdx1 and ptf1a genes [21,49]. It has been shown that a pancreas-
preserving total gastrectomy is not related with a higher recurrence rate and that lymphatic
vessels do not pass through the pancreatic tissue. An adequate D2 lymphadenectomy
close to the pancreatic tissue seems to be the optimal choice for radical procedures in the
mesogastrium. Moreover, sparing the pancreatic tissue may be associated with a reduction
in possible complications.

5.2. Omentum and Peritoneal Lining of the Pancreas and Transverse Mesocolon
All the above-mentioned structures have been shown to be places where lymphatic
channels link with the stomach. Additionally, these regions are well-recognized places
of possible cancer cell implantation [50]. The idea of an omento-bursectomy has been
a standard in Japanese gastrectomies since 1950. This radical approach was revisited
after a phase III clinical trial (JCOG1001) showing that a bursectomy in resectable cT3/4a
gastric cancer did not improve survival over a non-bursectomy [51]. Current Japanese
guidelines still recommend an omentectomy in cT3/4 gastric cancer; however, its necessity
is also under debate. Several studies have shown no difference in survival rates between
an omentectomy and no omentectomy [52–54]. In a recent systematic review, Marano
et al. reported no statistically significant prognostic difference in terms of overall survival
between the bursectomy versus non-bursectomy groups [55]. Conversely, the resection
of the bursa omentalis was associated with better overall survival than non-bursectomy
surgery in serosa-positive gastric cancer patients.
It is important to say that, from embryonic anatomy, both the greater and lesser
omentum are not authentic parts of the mesogastrium. They do not meet two main
attributes of the mesogastrium, which include being located along the edge of the organ
and encompassing some of the main blood vessels that connect them to the main organ.
This is why, in the step-by-step resections previously mentioned, the omentum should be
divided 3 cm from the edge of the gastroepiploic vessels. These are important parts of the
mesogastric concept, and future analyses should also identify these aspects to show the
hypothesis of the mesogastrium.

5.3. Tailored Lymphadenectomy

An extended lymphadenectomy in colon cancer cases and a complete mesocolic exci-
sion has been adopted in many centres [10]. The extent of the lymphadenectomy following
the idea of the mesocolon changes according to the position of the colon cancer. For a hep-
atic flexure or proximal transverse colon cancer, not only the lymph nodes of the mesentery
but also the right gastroepiploic artery may need to be dissected for a complete peripancre-
atic lymph node dissection. Some have even advocated for the dissection of the nodes at
least 10 cm from the right gastroepiploic vessels together with the subpyloric station and
lymph nodes above the pancreatic head [56]. For cancer situated in the distal transverse
colon as well as in the splenic flexure, additional lymph nodes from the inferior pancreas
and along the left gastroepiploic artery should be dissected [55]. As reported in Perrakis
et al., the transverse colon together with both flexures should have infrapancreatic lymph
nodes as well as lymph nodes along the gastroepiploic arcade as regional lymph node
stations [57]. This same idea should be debated in cases of gastric cancer and a mesogastric
excision. A standard D2 lymphadenectomy is based on the JCOG9501 randomized trial
that compared D2 with D2 plus a para-aortic lymphadenectomy. For tumours located in the
lower third of the stomach for a D2 lymphadenectomy, stations number 13 (retropancreatic)
and 14v along the superior mesenteric vein are a part of the lymphadenectomy [42]. Based
on series of papers from the Italian Gastric Cancer Research Group (GIRCG), which include
being located along the edge of the organ and encompassing some of the main blood
Curr. Oncol. 2021, 28 4935

vessels that connect them to the main organ [58–61], special attention should also be paid to
the complete removal of infrapyloric lymph nodes (station 6) as seen in distal third gastric
cancers with station number 6 involvement. Furthermore, even in early forms, a resection
of station number 14v is advised by some authors [62]. Interestingly, we have also pro-
posed the possibility of a tailored lymphadenectomy, not only according to the tumour
position and Lauren histotype but also based on the molecular classification of the gastric
cancer [60]. The possible role of implementing these factors in a tailored lymphadenectomy
in cases with mesogastric excisions needs to be evaluated.

6. Conclusions
Mesogastric excisions are still a technique that needs closer attention and further
scientific evidence. From a technical point of view, the technique may be feasibly imple-
mented in all types of operations with a curative intent. Additionally, not only classical
open approaches but also laparoscopic approaches have been documented. Benefits of this
technique from the literature seem to be possible; however, we need to wait for overall
survival benefit studies. The same history was a part of the discussion concerning total
mesorectal and mesocolic excisions, and today, both techniques are routine operations in
many hospitals worldwide. Future studies are needed, and ongoing clinical trials may pro-
vide the first answers regarding the direction that the story concerning the mesogastrium
will follow.

Author Contributions: Study concept and design: S.G., M.E., L.M., F.R. and K.P.; acquisition of data:
S.G., M.E., L.M. and K.P.; study supervision: F.R. and K.P. All authors have read and agreed to the
published version of the manuscript.
Funding: The authors received no financial support for the research, authorship and/or publication
of this article.
Conflicts of Interest: The authors declare no potential conflict of interest with respect to the research,
authorship, and/or publication of this article.

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