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Review Article
Linitis Plastica of The Stomach : A Review
Md. Mizanur Rahman1
ABSTRACT
Linitis plastica (LP) is a particular subtype of diffuse gastric cancer and is thought to have a separate
entity in respect with its biological behaviour, pathology, presentation and treatment outcome. The poor
prognosis of LP gastric cancer is due primarily to its advanced stage at diagnosis. The characteristic
histopathological feature of this entity is cellular spread to the submucosa and stroma with minimal
mucosal alterations accompanied by an excessive desmoplastic reaction. Despite recent research on
alternative therapies, surgical resection appears the only potentially curative approach. Patient selection
and multidisciplinary management are paramount when considering surgical resection in patients with
gastric LP. The operative approach in patients with LP has historically been questioned because of the
poor outcomes. The aim of this review is to highlight different dimension of linitis plastica stomach in
respect to its definition, classification, clinico-pathological characters, diagnostic approaches and
treatment outcome.
Correspondence to: Prof. Md. Mizanur Rahman, Professor
(Retd) of Surgical Oncology, National Institute of Cancer Research
and Hospital, Dhaka, Email address: mizannicrh@gmail.com
Received: 29 June 2018 Accepted: 30 June 2018
Background
Linitis plastica (LP) of the stomach is a long-known
condition, with initial reports oriented from sixteenth
and seventeenth century1. It was defined as a distinct
entity in 1859 by Dr. William Brinton, who described
it as a benign disease with peculiar characteristics:
the stomach was macroscopically thickened, with
inconsistent evidence of mucosal ulceration;
pathologically, it showed a prominent submucosal
hypertrophy due to an increase in the connective tissue
and prominent muscular hypertrophy2. Among all
morphological subtypes of the gastric cancer it needs
special consideration and discussion. Linitis plastica
is seen in 3–19% of all gastric adenocarcinomas3. It
is characterised by a rigidity of a major portion, or all
of the stomach, with the absence of a filling defect or
extensive ulceration. Gastric carcinoma is notorious
for its failure to cause early symptoms so that patients
do not present themselves for diagnosis until late in
the course of the disease. Because of the rich
lymphatic supply, the cancer rapidly disseminates
beyond the reach of surgical resection. Consequently,
the patients with symptoms generally have far-
advanced malignancy4,5 2.
The term ‘linitis plastica’ (LP)-Greek for linen cloth or
net was introduced by Brinton in 1858 on the basis of
macroscopic criteria. Up until 1943 it was unclear
whether linitis plastica, also called ‘leather bottle
stomach’, was an inflammatory or a neoplastic
disease, when Saphir described the macroscopic
morphology, the neoplastic nature, and the progression
with metastatic spread of this type of carcinoma6.
The term “linitis” was due to the presence of irregular
bands of filamentous tissue in the hypertrophic
submucosa, resembling fibres of linen. Clinically, this
disease was unavoidably fatal without treatment. Early
reports on the presence of cancerous cells in the
setting of LP were notable for the difficulty in identifying
malignancy. Malignant cells, when detected, were often
Journal of Surgical Sciences (2018) Vol. 22 (2) : 125-138
© 2012 Society of Surgeons of Bangladesh
described as few and scattered2. As a consequence,
for many years, it was controversial if the condition
was benign or malignant. Then in 1953 Dr. Arthur Stout
clarified the issue, proposing linitis plastica as a
specific type of gastric carcinoma characterized by
an excessive production of fibrous scar like tissue,
with areas in which only scattered cells were present.
He expressed doubts about the malignant nature of
the cells because of his previous authors’ failure to
find cancer cells2. Like many series of works in
Bangladesh, surgeons are sharing this dreadful
situation of the patients also. This literature review of
linitis plastica will focus on its current concept,
highlight the diagnostic challenges, its pathological,
clinical, prognostic implications, and the therapeutic
options available. Future perspectives for its
management are also addressed6.
Definition
In the intervening years, multiple classifications for
gastric carcinoma have been established, reflecting
the heterogeneity of this malignancy7,8. Each is based
on different macroscopic and microscopic aspects of
the tumour. LP had been associated with gastric
carcinoma (GC), but Stout’s classification did not take
hold, and LP was never included in any of the other
staging systems. In the following years, the definition
of LP was separated from the presence of fibrous
tissue, becoming more generalized and being
increasingly associated with diffuse carcinomas with
infiltration of the gastric wall, resulting in the stomach
having a stiffened appearance and a partial or complete
lack of distensibility9 ; occasionally, the term has also
been extended to include other conditions associated
with thickening of the stomach wall without any fibrous
component at all (i.e., lymphoma) 10.
Recent reports of LP lack a clear and standardized
codification. “Linitis plastica” is used interchangeably
with “Bormann type IV carcinoma,” “scirrhous
carcinoma,” “signet-ring cell carcinoma,” and “Lauren
diffuse carcinoma”11,12. However, it is not clear if these
terms correctly define this condition, as only some of
the tumours in each of these categories have the
features of LP.
Due to the lack of agreement on the clinical significance
of LP and the difficulty in attributing this condition to
the common classification systems, some authors
have proposed to abandon this definition13. Others,
nonetheless, still recognize LP a specific type of
gastric cancer with a distinct growth pattern and
biological behaviour, and advocate that the identification
of such a subset of gastric cancer patients could be
useful in risk stratification, in identifying a target for
therapeutic management, and in guiding future
research14,15.
Definition: postoperative or preoperative?
LP is, by the original definition, a scirrhous tumour
that spreads through the submucosal and muscular
layers of the stomach, with thickening of its wall and
loss of distensibility. The presence of poorly
differentiated, poorly cohesive, or SRCs is often
involved.
However, the original definition is based on autopsies
and surgical specimens, and it should be noted that
it may be difficult to obtain a reliable biopsy
documenting both the predominance of the stroma
and the cancerous cells in the preoperative setting.
Moreover, many of these patients, affected by
advanced disease, would not undergo gastrectomy;
therefore, analysis on postoperative surgical
specimens would not always be possible. In addition,
the increasingly common practice of administering
preoperative therapy in the form of systemic
chemotherapy or radiotherapy may hamper the
identification of the typical stromal reaction of LP, as
fibrosis is often a consequence of preoperative
therapy16.
Current classifications for gastric carcinoma and
their relations to LP
Gastric cancer (GC) has several classifications related
to its macroscopic and microscopic aspects. All are
commonly used, but none of them has been accepted
as the standard system. Hereby the most common
ones will be reviewed, addressing their overlap with
LP. Bormann classification: first proposed by Bormann
in 1926 2, this classification is most commonly used
in Eastern countries8,12. It is based on the
macroscopic, endoscopical/ endoluminal aspect of
the tumour and is most useful as a preoperative
assessment tool and a prognostic factor. Bormann
type IV tumours are described as diffuse and infiltrative
(“tumour without diffuse ulceration or raised margin,
the gastric wall is thickened and indurated, and the
margin is unclear”8. Both Bormann III and Bormann
IV tumours show an infiltrative pattern, and even
Bormann III tumours may show a consistent
desmoplastic reaction. At the same time, not every
Bormann IV tumour presents with the typical
Vol. 22, No. 2, July 2018 Journal of Surgical Sciences
126
demoplastic characteristics of LP 11. Therefore, LP is
often improperly defined as a Bormann IV tumour.
Cancer stromal volume classification: this microscopic
classification is part of the Japanese classification8.
It includes cancers with a medullary type (scanty
stroma), a scirrhous type (abundant stroma), and an
intermediate type. A similar system is utilized in the
World Health Organization (WHO) classification7,
although tumour stroma is less commonly categorized
by Western pathologists. In the Eastern setting, this
classification is more commonly applied; however,
there are few studies focusing on the clinico-
pathological aspects of tumours identified by the
scirrhous classification system. Scirrhous cancers,
in accordance with the original definitions of LP , are
strictly related to the LP phenotype, which presents
in its classical form only when the submucosa is
diffusely fibromatous2,17.
Lauren classification: this microscopic classification
divides gastric tumours into diffuse, intestinal, or mixed
and indeterminate types. Diffuse adenocarcinomas
are defined by their growth pattern as tumours
infiltrating the stroma as discohesive tumour cells
arranged singly and in small clusters. The intestinal
type is defined by its cytoarchitecture, and
characterized by cohesive cells which form gland-like
structures. Mixed tumours have both an intestinal and
diffuse component, while indeterminate types include
most of the undifferentiated tumours7,18,19.
Diffuse tumours account for 32–49% of GCs. There is
a significant correlation between the diffuse histotype,
the Bormann III and IV types, and the scirrhous stromal
category20.
WHO classification: The WHO classification is a
descriptive system which defines five main types of
gastric carcinoma: tubular, papillary, mucinous, poorly
cohesive (including signet-ring cell carcinomas and
other variants), and mixed adenocarcinomas. Lauren
diffuse carcinomas most often have a poorly cohesive
histotype. Signet-ring cell (SRC) carcinomas are
defined as tumours composed of cells containing
intracytoplasmic mucin and eccentrically placed
nucleus, in a proportion >50 %. They may form lace-
like glands or a microtrabecular pattern in the mucosa,
or extend to deeper layers with significant
desmoplastic reaction. Irrespective of the category,
SRCs may also be present in different tumours, as
poorly cohesive variants, mucinous tumours (defined
by extracellular mucin >50%), and mixed carcinomas
(defined by a clonal mixture of both glandular and poorly
cohesive aspects). Hereditary diffuse GC typically
presents as a diffuse gastric carcinoma containing
SRCs, and often with features of linitis plastica 7,21.
Histology
The most characteristic feature of LP is the
macroscopic thickening of the stomach wall, often
diffusely involving the entire stomach, which has been
described in detail since its early reports as an
impressive increase in the submucosal connective
tissue in the form of immature and mature stroma
with hypertrophy of the muscle layer and subserosal
thickening. These characteristics strictly resemble
those of scirrhous carcinoma, which, as mentioned
above, is a particular form of GC in which cancer cells
trigger a stromal reaction involving mature and
immature fibrosis (which are characterized,
respectively, by the presence of collagen I and III)22,23.
The scirrhous reaction is almost always triggered by
poorly cohesive neoplastic cells, often with signet-
ring morphology. More rarely, cases of schirrous
tumours accompanied by moderately differentiated
adenocarcinomas have been reported24,25.
Scirrhous tumours are characterized by a complex
interaction between cancer cells and cancer-
associated fibroblasts (CAFs), which may represent
up to 90% of the tumor and appear to have a primary
role in cancer progression. The origin of CAFs is under
investigation; these cells seem to be heterogeneous,
as they may be local fibroblasts, cells recruited from
the bone marrow, or pericytes which undergo
endothelial to mesenchymal transition22,26.
Secondary LP features may be found in other hollow
viscus or cystic organs, such as the bowel, bladder,
and ovaries27. Frequently, SRCs are detected in these
types of secondary lesions28. At the same time, even
secondary LP of the stomach has been described.
The most commonly reported cases of secondary LP
are those associated with metastatic invasive lobular
carcinoma of the breast, which presents with identical
radiologic and nearly identical histologic
characteristics to primary linitis plastica 29. Notably,
lobular breast carcinoma is also a feature of hereditary
diffuse GC30, and it often contains scattered SRCs29.
Subtypes:
In regards to the quality of the mucosal involvement,
two different subtypes of linitis plastica have been
described. In the first type, giant-fold or waffle-like,
Linitis Plastica of The Stomach: A Review Md. Mizanur Rahman et al
127
the mucosa demonstrates a characteristic
morphological change consisting of an enhancement
of the design of the folds, which remain flexible but
appear prominent and crossing one another. This effect
may be due to the relatively normal state of the mucosa
in comparison to the involvement and contraction of
the submucosal and muscular layers2, 11. The pattern
of waffle-like LP has been extensively described in
several Japanese studies, and in case reports of
patients refusing surgery and subsequently being
followed for years11,31. The first lesion generally
originates from the proximal or middle stomach, near
the great curve, as a type IIc (flat depressed) early
GC.
In the second type, the flat type, submucosal
involvement is paralleled by mucosal thickening or
atrophy 11. This type most commonly originates from
the antrum, near the lesser curvature, and then
extends to involve the antrum circumferentially. Flat
type LP development has not been extensively
studied. The difference between the characteristic
mucosal pattern in waffle-like LP and the mucosal
flattening and induration in flat type LP may be due to
diffusion of the neoplasm in a more superficial plane
(involving the lamina propria, the muscularis propria,
or the mucosa itself) in flat type. The tumour is thought
to originate near the pylorus, involve the antrum
circumferentially, and extend to the entire stomach5,9.
The flat type is commonly believed to be the most
common in Western settings11. However, even if the
original description by Brinton, most of the LP cases
were identified as originating from the distal stomach,
with hypertrophic mucosal folds, and a mixture of both
subtypes11. In 1990, a US study demonstrated that
up to 88% patients with scirrhous tumorus present
with the radiological features of thickened gastric folds.
Extension and macroscopic features
LP does not always present as complete involvement
of the stomach. It may appear in plaques which gives
the appearance of a segmental lack of distensibility.
Localized and diffuse forms of linitis were found in the
early reports of this condition, and subsequently being
followed for years11,31,32.
The first lesion generally originates from the proximal
or middle stomach, near the great curve, as a type IIc
(flat depressed) early GC. This condition may remain
stable for 2–5 years (slow-phase), until the lesion
progresses to advanced GC and ulcerates reaching
the submucosal layer. At this point, the ulcerative
lesion can persist or heal, while the submucosal
involvement, once a scirrhous reaction is initiated,
enters a fast-phase, involving the entire stomach (LP)
in about 1 year31,32.
Cell lines and their effects
Two new gastric cancer cell lines, designated OCUM-
8 and OCUM-11, which developed the characteristic
biology of scirrhous gastric carcinoma upon orthotopic
implantation in mice. Involvement of lymph nodes and
liver metastasis was also found in both orthotopic
models. Histologically, these orthotopic models
showed proliferation with extensive fibrosis, resembling
human scirrhous gastric cancer. Both cell lines were
derived from ascites of patients with scirrhous gastric
cancer. The growth of OCUM-8 and OCUM-11 cells
following the addition of KGF, FGF, and EGF was
increased significantly relative to untreated cells.An
increase in the number of attached and spreading cells
occurred following the addition of TGF-â1 in both cell
lines. OCUM-11 cells showed microsatellite instability.
Although subcutaneous scirrhous gastric cancer cells
show medullary growth, most in vivo studies of
scirrhous gastric cancer have used xenografted
tumours implanted subcutaneously33.
Genetic alterations
OCUM-8 cells had Loss of heterogygosity (LOH) at
the APC (D5S346) and c-met (D7S501) loci, and a
band shift (D3S1611) was found. OCUM-11 cells
showed 3 of 11 (27%) microsatellite loci, D2S123,
P53-Dinucl, and P53Penta, with a novel band shift,
and OCUM-11 cells had LOH at the APC (D5S346)
locus. OCUM-11 cells were defined as MSI-positive,
but no mutations were found in Fas antigen, BAX,
TGFâRII, IGFR II, hMSH3 and hMSH633.
Recent studies have revealed that genetic instability
is an important predisposition for human multistep
carcinogenesis.34) MSI was observed in 10 to 20% of
gastric carcinoma cases,) while the reported
prevalence of MSI in human scirrhous gastric
carcinoma has varied between studies, ranging from
5% to 75%.35 Although some colorectal cancer cell
lines have MSI status,36) few researchers have pursued
the establishment of MSI-positive gastric carcinoma
cell lines. OCUM-11 cells had MSI status, and
therefore might be useful for the study of the
characteristic features of MSI in scirrhous gastric
carcinoma. no frameshift mutation of the TGFâ-RII,
BAX, or hMSH3 genes was detected in OCUM-11
Vol. 22, No. 2, July 2018 Journal of Surgical Sciences
128
cells, whereas TGFâ-RII, BAX, and hMSH3 frameshift
mutations have been reported to be frequent in MSI
colon cancers.
In conclusion, two new scirrhous gastric cancer cell
lines was established, designated OCUM-8 and
OCUM-11, which have the characteristic biology of
scirrhous gastric carcinoma in situ. The two cell lines
may be useful for analyzing disease progression and
for developing novel therapeutic options33.
Cell adhesion and CDH1:
It is well settled that diffuse type cancer is composed
by non-cohesive cells (with or without signet ring
cells).It is now widely accepted that genetic and
epigenetic alterations in the host contribute to the
development of disease in combination with
environmental factors. Diffuse gastric cancer (DGC)
has a clear hereditary form and results from E-cadherin
deregulation upon genetic or epigenetic alterations37.
It comes as no surprise that genetic or epigenetic
alterations in E-cadherin leads to disturbed epithelial
cell-cell adhesion and structure, aberrant stromal
interactions, as well as altered cell migration and
signalling, with ultimate oncogenic potential38. Indeed,
functional loss of E-cadherin is a well-established
molecular event that occurs during tumour
progression, leading to increased invasion of cancer
cells to neighbouring tissues and to metastasis39.
More so, reduced expression of E-cadherin, mostly
due to decreased expression at mRNA and protein
levels, is regarded as indicative of poor outcome in a
variety of malignancies. In fact, only a minor proportion
of advanced carcinomas present CDH1 mutations.
CDH1 is however regarded as a classical tumour
suppressor gene in gastric carcinogenesis, being
involved in the initiation and progression of both
sporadic and hereditary forms of GC 40. Of relevance,
inherited germline mutations in CDH1 are a causative
feature of hereditary diffuse gastric cancer (HDGC),
awarding E-cadherin as the culprit for the development
of this cancer syndrome40.E-cadherin has been
awarded a key role during the development of cancer,
where coordinated cell-cell adhesion is required for
proper establishment of the body plan and integrity of
tissue differentiation. The recognition of E-cadherin
as a key molecule at the intersection of cell-cell
adhesion, cell morphology and polarity, and cell life
and death, has awarded E-cadherin a leading position
in cancer initiation and progression41.
Clinico-pathological characters
The clinical characteristics of Bormann type IV gastric
cancer include a high rate of incidence in young
females, delayed diagnosis and detection at an
advanced stage, peritoneal dissemination at the first
operation, many peritoneal recurrences after a curative
resection, low hepatic metastasis and a low curative
resection rate42,43.
Figure 1. CT Scan delineating stomach with liniits plastica, stomach wall is thickened throughout the length of
lesser and greater curvature.
Linitis Plastica of The Stomach: A Review Md. Mizanur Rahman et al
129
Epigastric pain combined with progressive dysphagia
to both liquids and solids and severe weight loss
constitute the most frequent clinical signs. Clinical
examination is usually unremarkable and biological
markers within normal limits. Rare relative
presentations include worsening symptoms of gastric
outlet obstruction, haematemesis, gastrointestinal
bleeding and perforation. Clinical manifestations of
pseudoachalasia secondary to massive invasion of
the gastric walls and the cardia are not infrequent 44.
Cases of gastric metastasis simulating LP-type
carcinoma from primary rectal lesion present with
signs of iron deficiency anemia, recent fecal
incontinence, lower colicky abdominal pain and
distension, bleeding, diarrhea or complete intestinal
obstruction due to gradual narrowing of the bowel
lumen. Rectal examination reveals a circumferential,
constricting, irregular mass without irritability, but
even then, establishing an accurate differential
diagnosis is difficult. A case of primary LP involving
the entire colon, ileum and appendix has also been
described 45.
Gastric LP is often detected at an advanced stage,
while metastases to the colon occur via contiguity
along mesenteric facial planes. Although a prominent
pattern of disease failure is peritoneal carcinomatosis,
some patients experience rapid disease progression
without signs of intra-peritoneal dissemination.
Peritoneal carcinomatosis was the commonest sign
of disease progression, while bone metastasis was
associated significantly with poor prognosis and lymph
node invasion. T4 and N3 histological status proved
independent prognostic determinants found in studies.
In addition, the increased number of metastatic nodes
(>16) was defined as an important risk factor for the
development of bone disease in comparison with
modest nodal involvement 46.
In LP patients, peritoneal carcinomatosis occurs as
a consequence of dissemination of free cancer cells
from the primary lesion. Furthermore, cytological
examination of peritoneal washing has been proposed
to estimate the possibility of intra-peritoneal
recurrence in curatively resected cases of LP-type
gastric carcinoma. This assessment has recently been
added to disease staging and its prognostic value has
been confirmed employing immunohistochemistry or
reverse transcriptase polymerase chain reaction (RT-
PCR). A newly established protocol for rapid,
quantitative detection of free cancer cells in peritoneal
washings using carcinoembryonic antigen (CEA)
mRNA as a neoplastic marker has also been
suggested47,48.
Linitis plastica: diagnostic challenges
Typical symptoms of LP are dyspepsia, nausea,
vomiting, and anorexia. Unfortunately, those symptoms
are not reliable for establishing a timely diagnosis, as
they usually present insidiously, and manifest only in
an advanced stage. Available diagnostic instruments
for this condition include endoscopy, endoscopic
ultrasound (EUS), upper gastrointestinal contrast
studies (UGI), computed tomography (CT) and 18-
fluorodeoxyglucose (18-FDG) positron emission
tomography (PET) scans, and magnetic resonance
imaging (MRI).
Endoscopy is considered the gold standard for the
diagnosis of GC. However, the peculiar spread pattern
of LP tumours involves primarily the submucosa and
muscularis propria of the stomach, while mucosal
involvement is inconstant and may present as
nonspecific gastritis or normal mucosa in up to 30%
of cases11. The flat type could be confused with
atrophic gastritis and suspected by endoscopy
sometimes only due to the lack of distension of the
Figure 2. Total Gastrectomy for linitis plastica
stomach
Vol. 22, No. 2, July 2018 Journal of Surgical Sciences
130
stomach wall. Waffle-like appearance of the mucosa
is more characteristic, even if biopsies have the same
low diagnostic yield. Due to their poorly cohesive
nature, cancer cells are often scattered between the
tumour stroma49 or even absent in some sections 50.
Indeed, studies show high rates of non-diagnostic
biopsies (30–36%)9,51. Sometimes, the delay in the
histologic diagnosis may represent a serious
challenge, especially when the clinical and
instrumental suspicion of LP is strong, as several
different diagnoses are possible in the presence of
hypertrophic mucosal folds and/or scarce distensibility
of the stomach (gastric lymphoma, Ménétrier disease,
granulomatous diseases and metastasis) and not all
of them are surgical19,11. Gastrectomy is a major
procedure with considerable morbidity and mortality,
and many clinicians would not perform resection until
cancer has been proven by biopsy.
Several endoscopic strategies to better diagnose this
disease have been proposed. EUS features include
submucosal and muscular thickening, and EUS fine-
needle aspiration allows reaching of the submucosal
layer11. Even with this strategy, however, negative
biopsies have been reported52. For this reason, EUS
is also not considered the gold standard in diagnosis
of LP.
Barium studies can be a useful diagnostic instrument,
as they could document the thickening of the mucosal
folds, and assess in real time the segmental or
complete lack of distensibility of the gastric wall. UGI
has been progressively discarded as a diagnostic
technique for gastric cancer diagnosis and staging;
nevertheless, given the low sensibility of conventional
endoscopy, it remains of valuable support in evaluating
this condition.
CT scan allows for comprehensive staging of the
tumour, and could give rise to reasonable suspicion
when identifying a stomach with thickened walls, which
presents with complete flattening of the mucosal folds
or thickened folds even after distension53. 18FDG PET,
by the contrary, may have scarce diagnostic
significance, as poorly differentiated, diffuse, mucinous,
and SRC carcinomas have all been reported to be low
in 18-FDG uptake 54.
MRI has been recently proposed as an alternative to
CT, due to its advantages in characterizing tissue
nature and obtaining soft tissue contrast, but the topic
is still controversial55,56.
Suspicion of linitis plastica should prompt
consideration for laparoscopy in staging. In
consideration of the well-known peritoneal tropism of
the disease, a diagnostic laparoscopy with peritoneal
washings is a good alternative.
A gold-standard diagnostic instrument for LP has yet
to be defined, the development of a diagnostic strategy
is difficult. Moreover, macroscopic and microscopic
assessments of the stomach are both required to
identify the condition. If the suspicion is strong, even
in the absence of a positive biopsy, the possible
diagnoses should be discussed with the patient, and
a diagnostic laparoscopy proposed to avoid deleterious
diagnostic delays.
Future diagnostic advancements may be obtained by
the use of blood-based biomarkers. In 2000, Ichikawa
et al. proposed a high level of trypsinogen as a simple
and specific marker to diagnose linitis plastica, but
this marker has not been further tested or introduced
in clinical practice. “Liquid biopsy” of circulating tumor
cells, cDNA, or miRNA may represent a future
perspective57,58 especially as genomic and epigenetic
characteristics of GC are better understood. EUS
allows the estimation of the invasion depth and extent
of lymph node metastasis and aids in determining
the TNM staging.4,5However, it is difficult to accurately
determine the extent of cancer cell infiltration using
EUS alone as thickened areas caused by fibrosis may
confound the findings59.
Linitis plastica: implications for therapy
As soon as the possibility of a curative treatment for
a patient with LP is assessed, other questions arise
in regards to the therapeutic management. Though
surgery is considered the best option of treatment it
is difficult to get a margin free status. For years, ample
resection margins (>5 cm) have been advocated to
avoid R1 resection in GC patients, and they are
considered the current standard for patients with
Bormann III and IV tumors, in accordance with the
Japanese Guidelines 60. This topic, however, is
extremely controversial. Indeed, a discrete number of
studies seem to have disproved the value of wide
resection margins, as long as a R0 resection is
obtained, while other studies have even been
questioning the role of R0 resection in advanced
stages. However, studies focusing on diffuse, SRC,
and especially on scirrhous tumours are lacking. Thus,
caution is needed when performing limited resections
in these subgroups. Given its high accuracy61, a frozen
Linitis Plastica of The Stomach: A Review Md. Mizanur Rahman et al
131
tissue biopsy should be routinely performed. If a frozen
tissue biopsy is not available, a margin of 5 cm currently
remains the gold standard. It should also be
considered that in scirrhous gastric cancers and LP
phenotypes a frozen tissue could be less reliable due
to the lack of tumour cellularity.
Recently, much attention has been given to the use
of preoperative hyperthermic intraperitoneal
chemotherapy (HIPEC) in GC, both for the prevention
of peritoneal disease and for its treatment, and a few
randomized investigations are ongoing62. Given the
strong peritoneal tropism of scirrhous and LP tumours,
in the near-future, HIPEC could come to the foreground
for the routine management of this subgroup of
patients.
Neoadjuvant therapy has many theoretical advantages.
Among them are the higher rate of treatment
compliance in comparison to postoperative therapy,
and the possibility of downstaging or downsizing the
tumour63. As LP tumours often present in an advanced
stage, neoadjuvant therapy may be of particular value
in improving local control and increasing the rate of
potentially curative gastrectomies.
Nevertheless, concerns remain when applying
conventional therapeutic agents. The use of
radiotherapy as an adjuvant treatment was
significantly less effective in diffuse tumours in both
the ARTIST trial and the 10-year update of the INT-
0116 trial. In vitro testing on the G-DIF gene-expressing
subtype demonstrated reduced sensitivity to 5-
fluorouracol and oxaliplatin in comparison to cisplatin.
In a 2004 survey, the use of cisplatin as intraperitoneal
preoperative lavage in patients with CY+ schirrous
tumorus gave no survival benefit in comparison to non-
operative management. HER-2 activating mutations
are rare between the GS, the MSS/EMT, and the
mesenchymal metabolic subtypes, so Trastuzumab
is rarely an option. Finally, in a retrospective French
study, patients with SRC tumours have been reported
to show scarce response to standard perioperative
chemotherapeutic regimens and poor survival64, due
to possible progression of the disease during
neoadjuvant therapy, and a phase III randomized
clinical trial is currently ongoing to assess the role of
perioperative versus adjuvant chemotherapy in this
subset 65.
Currently, targeted therapy is considered only for
certain GC subtypes, and almost all the
chemotherapeutic regimens are directed solely against
the cancerous cells. Scirrhous tumours, though, have
several distinct features that may be strictly related
to their aggressive biological behaviour. This strategy
may represent a real game-change in the context of a
multimodal therapeutic management, especially for
patients which are non-responders to conventional
therapy. In this regard TGF-B and FGF7 receptor
inhibitors66 created interest in association with
standard chemotherapy.
Development
The pre-stage of LP type GC
LP type GC was defined by Sugiyama et al.67 in 1980
as a lesion infiltrating twice as prolifically into the
submucosa compared with the mucosa, with no
primary localized mass formation. It was later divided
into three clinical stages:11 typical (defined as
submucosal infiltration of a tumour occupying more
than 1/4 of the total stomach with narrowing of the
gastric lumen), latent (defined as tumour invasion of
more than 1/4 of the total area without luminal
narrowing), and pre-LP (defined as cancer cells
invading less than 1/4 of the total area of the
submucosal infiltration and as the absence of luminal
stenosis)68.
Retrospective studies of LP type GCs
In 1980, Nakazawa et al69 identified two distinct
courses in the progression of LP type GCs: slow
progression (slow phase) and fast progression (fast
phase). Takeda et al70 retrospectively described 16
cases of LP type GCs. According to their results,
progression to LP type GC required 21 months if the
first lesion was ulcerative. If the presenting lesion was
a IIc lesion without ulceration, progression to LP type
GC also required a long time. In contrast, if only
localized mucosal edema was noted, LP type GC
developed in 12 to 21 months. Moreover, if the lesion
had giant mucosal folds, it quickly advanced to LP
type GC within 10 months.
Ohgushi et al71 described the progression of seven
LP type GCs in a retrospective study. Initially, the
primary tumours resembled IIc-like lesions in the
fundic gland area or transition zone. After formation of
the IIc lesions, the surrounding mucosa became
sclerotic, with a flat elevated appearance. Eventually,
the lesions became malignant ulcers and gradually
invaded the submucosal layer, even if the ulcers were
healed.
Vol. 22, No. 2, July 2018 Journal of Surgical Sciences
132
In 1992, Takizawa72 surveyed 245 patients with LP
type GCs over a 10-year period. The primary lesion
occurred in the fundic gland in all patients.
Pathologically, most lesions were diagnosed as
undifferentiated carcinomas, and lymphatic
metastasis was noted in more than 50% of the cases.
Observation pared with other types of advance GCs,
patients with LP of early gastric cancers (EGCs) with
IIc-like lesions revealed type GC were younger at
disease onset and more frequently that these lesions
progressed to pre-stage LP type GC73.
Prognosis:
Among the limited studies, according to the findings
it was seen that the diffuse type gastric cancer has
an extremely bad overall prognosis. The median
survival was only 8 months, five year survival 8%.
Among the prognostic factors the diagnostic
laparoscopy turned out to be a very safe procedure
for the diagnosis of the local tumour spread, lymph
node status, distant metastases, and the histological
proof of peritoneal implants. In 60% of investigated
patients peritoneal seeding could only be diagnosed
at the time of laparoscopy74.The tumor marker CA
19-9 (cut-off value of 45u/l), the immunocytochemical
detection of FPT has turned out to be an independent
additional strong prognostic factor.
Peritoneal carcinomatosis is generally assumed to
occur as a result of shedding from tumour cells from
the serosal surface of the primary tumour or via the
lymphatic drainage system75. Lymphoreticular organs,
called milkey spots, occur throughout the greater
omentum and may represent the barrier to peritoneal
seeding. The present data suggest that the release of
tumour cells from lymphatic capillaries plays an
important role in peritoneal dissemination. A significant
survival advantage for patients with linitis plastica can
only be achieved after complete resection76. Even
patients with a multivisceral resection had a significant
survival benefit77.
For potentially resectable LP patients (i.e., stage I-
III), 5-year DSS was 0 per cent for no treatment and
for radiation therapy alone, 18 per cent for both and
surgery and radiation, and 20 per cent for surgery
alone(P < 0.001). LP is a marker of poor survival in
patients with GA. However, surgical resection provides
the best oncologic outcomes in these patients with a
20 per cent 5-year DSS in patients with loco-regional
disease78.
Role of Surgery:
The overall poor prognosis of LP gastric cancer has
led some authors to conclude that LP is not a surgical
disease, and many oncology providers remain biased
against surgical resection for gastric LP5. Aranha et
al. compared 13 unresectable patients with gastric
LP with 13 patients with resected gastric LP and noted
no difference in OS (6.6 vs. 7.2 months), leading them
to conclude that gastrectomy for LP is never curative
and may only palliate 20 % of LP patients79. It should
be noted that more than half of their resected patients
had liver, peritoneal, or adjacent organ involvement,
and improved survival was reported in resected patients
with limited locoregional disease (13.6 months). In
another earlier clinical series, Hamy et al. reported a
50 % 1-year survival in 86 patients with LP80. However,
5-year survival was 10 %, supporting their conclusion
that while overall prognosis is poor, in the absence of
alternative effective therapies, surgical resection
remains the only means of improved survival or
potential cure. Other authors at the time proposed
left upper abdominal evisceration for LP (including
stomach, spleen, distal pancreas, transverse colon,
left adrenal, gallbladder with associated
lymphadenectomy) citing significantly improved
locoregional recurrence and survival81.
Whereas outcomes in these earlier studies were
discouraging, more recent focus has identified several
prognostic factors that could be used to select patients
who benefit from surgical treatment. Complete surgical
resection (R0) has consistently been associated with
improved survival in LP patients82.
It was also seen that many LP patients will not benefit
from surgery due to peritoneal dissemination or locally
advanced disease that precludes complete resection.
Our data suggest that LP patients who achieve optimal
surgical resection, inclusive of a total gastrectomy
and extensive lymphadenectomy, can expect long-
term survival rates similar to stage III non-LP optimally
resected patients. Frozen sections have a high
negative predictive value in LP cases and provide
surgeons the opportunity to salvage incomplete
microscopic resections by identifying positive margins
intraoperatively. Despite the stigmata and bias against
surgical intervention, there are subgroups of LP patient
who can achieve acceptable survival, and as such,
surgical resection should remain part of the
multimodality approach for gastric cancer patients with
LP. So it is speculated that updated staging systems
Linitis Plastica of The Stomach: A Review Md. Mizanur Rahman et al
133
should differentiate between LP and non-LP gastric
cancer, whereas treatment guidelines should consider
early stages of LP as advanced stage and treat them
accordingly82.
Therapeutic strategy
Although multivariate analysis has shown that curative
resection is a significant prognostic factor for the
survival of patients with this group of patients like SGC,
only about 20% of the patients with SGC benefit from
total gastrectomy83. Radical operations such as en
bloc total gastrectomy, which includes the pancreatic
body and tail, spleen, gallbladder, transverse colon
and the left adrenal gland, have been previously
performed. However, such extensive surgery did not
result in a distinct survival benefit. Because the 5-
year overall survival rate of patients with SGC at stages
II and III after curative surgery remains low; additional
effective treatments are necessary to improve patient
survival. Although other treatments such as
chemotherapy, radiotherapy, hyperthermia, hormonal
therapy or immunotherapy have been attempted, their
anti-tumour effects have been insufficient in improving
the prognosis of patients with LP84. Accordingly, novel
therapy based on the characteristic biological
behaviour is necessary.
Although a targeted therapy for patients with HER2-
positive advanced GC have reached satisfactory
clinical results, a new targeting therapy for SGC has
not been defined. Preclinical studies have
demonstrated the efficacy of targeted therapy for
advanced GC. Some FGFR2 inhibitors such as
tyrosine kinase inhibitor and monoclonal antibodies
have decreased the proliferation of SGC cells by
inhibiting FGFR2 signalling in vitro and in vivo. Study
proved that combined administration of S1 and FGFR2
inhibitor decreases cell proliferation in SGC more
effectively than S1 alone85,86.
Conclusion:
In conclusion primary LP is to be differentiated from
other variety of gastric cancer both in its preoperative
and peroperative steps by its schirrous appearance.
LP is different by its fatal outcome and biological
behaviour. Diagnosis is also very challenging.
Sometimes surgeons fail to come to a conclusion by
traditional diagnostic tools. Outcome of surgery is still
debatable. So decision making for palliative or radical
surgery for the best outcome is under the jurisdiction
of the surgeon. Though there are options and study
on systemic therapy a concrete approval is yet to
arrive. The recent accumulation of information provides
a deeper understanding of the molecular biology
underlying its characteristics which can facilitate the
development of treatment strategies.
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