Introduction
Primary gastric adenosquamous carcinoma (ASC) is a
rare, aggressive tumor, and accounts for less than 1% of gastric
carcinomas (1). Gastric ASC is
characterized histopathologically by the presence of adenocarcinoma
and squamous cell carcinoma (SCC) components within the same tumor
(1). Recently, the
clinicopathological characteristics of gastric ASC have been
analyzed (1). This type of tumor
mainly affects males (73.3%). In a previous study, half of tumors
were stage T4 and most patients (86.2%) had lymph node metastasis
(1). These results suggest that
gastric ASC has an aggressive clinical course compared with
conventional gastric adenocarcinoma. However, because of rarity of
the tumor, pathogenesis of this type of tumor remains unclear.
Gastric carcinoma with lymphoid stroma (GCLS) is a
distinct and relatively rare histopathological variant that is
characterized by prominent lymphoid infiltration within and around
the neoplastic cells, and is commonly associated with Epstein-Barr
virus (EBV) infection (2). It has
been reported that this type of tumor shows a relatively better
prognosis compared with conventional gastric adenocarcinoma
(2).
The association between ASC and GCLS has been poorly
understood, and only two reports of concomitant occurrence of ASC
and GCLS have been reported (3,4). In this
article, we described a case of simultaneous gastric ASC and GCLS,
and assessed the clinicopathological features of the previously
reported cases, as well as the present one, and the pathogenesis of
gastric ASC, including the association with EBV infection in
gastric ASC.
Case report
A 58-year-old Japanese male without significant past
history complained of loss of appetite. Gastric endoscopic
examination revealed a type 3 tumor in the antrum, and biopsy of
the lesion showed adenocarcinoma with squamous cell carcinoma (SCC)
component. Laparoscopic examination revealed disseminated lesions
in the peritoneum; thus, he underwent neoadjuvant chemotherapy (11
cycles of S-1 and oxaliplatin), followed by distal gastrectomy with
lymph node dissection. The post-operative course was uneventful,
and chemotherapy was added. The patient has been free from tumor
recurrence during 8 months of medical follow-up.
Formalin-fixed and paraffin-embedded specimens of
the resected tumor were processed for routine histological
examination and immunohistochemical and in situ
hybridization analyses. Immunohistochemical analyses were performed
using autostainers (XT System Benchmark, Roche Diagnostics, Basel,
Switzerland and link 48, DAKO Cytomation, Glostrup, Denmark). The
primary antibodies used were a rabbit monoclonal antibody against
caudal type homeobox 2 (cdx-2) (EPR2764Y, Roche), a mouse
monoclonal antibody against keratin 5/6 (D5/16 B4, DAKO), a mouse
monoclonal antibody against keratin 7 (OV-TL 12/30, DAKO), a mouse
monoclonal antibody against keratin 20 (Ks20.8, DAKO), and a mouse
monoclonal antibody against p40 (BC28, Roche). In situ
hybridization analysis was performed using autostainer (XT System
Benchmark, Roche Diagnostics, Basel).
Macroscopic examination of the resected specimen
revealed two discontinuous lesions in the antrum (Fig. 1A). The first lesion, an ASC, was
detected preoperatively by endoscopic examination. This type 3
tumor was composed of a mixture of SCC (approximately 75% of the
tumor) and poorly to moderately differentiated adenocarcinoma
(approximately 25%) (Fig. 1B). The
neoplastic cells of the SCC component had large round to oval
nuclei with small nucleoli and relatively rich eosinophilic
cytoplasm (Fig. 1B). Although
obvious keratinization was not detected, an intercellular bridge
was noted. This component was intermingled with adenocarcinoma
component, which formed irregular fused glands and had large round
to oval nuclei (Fig. 1B). The tumor
invaded into the serosa, and lymphovascular invasion was noted.
Immunohistochemically, the SCC component was diffusely positive for
p40, but the adenocarcinoma component was negative for p40
(Fig. 1C). Keratin 5/6 was expressed
only in the SCC component, and keratin 7 and 20, and cdx-2 were not
expressed in both components. In situ hybridization detected
no EBV-encoded RNA (EBER)-positive neoplastic cells in both
components. The lymph nodes contained metastatic ASC (with
intermingled SCC and adenocarcinoma components) (5/39).
 | Figure 1.Macroscopic, histopathological,
immunohistochemical and in situ hybridization findings of
the gastric tumors. (A) Macroscopic findings. Type 3 tumor (black,
lesion 1) and submucosal tumor-like type 1 tumor (red, lesion 2)
are closely located, but no continuity is present. (B)
Histopathological features of adenosquamous carcinoma (lesion 1).
Squamous cell carcinoma component is composed of solid nest or
trabecular proliferation of the neoplastic cells with relatively
rich eosinophilic cytoplasm and large round to oval nuclei. Focal
glandular formation is noted (arrows) (H&E; magnification,
×400). (C) Immunostain for p40 demonstrating positive reactivity in
the squamous cell carcinoma component. The neoplastic cells showing
glandular formation lacking p40 expression (arrow; magnification,
×400). (D) Gastric carcinoma with lymphoid stroma (lesion 2).
Diffuse proliferation of the neoplastic cells accompanying abundant
lymphocytic infiltration (H&E; magnification, ×200). (E) EBER
is detected in the neoplastic cells of the gastric carcinoma with
lymphoid stroma (magnification, ×200). EBER, Epstein-Barr virus
encoding RNA. |
The second lesion, a GCLS, was not preoperatively
detected by endoscopic examination (Fig.
1A). This submucosal tumor-like type 1 tumor was composed of
diffuse proliferation of the neoplastic cells containing large
round to oval nuclei with nucleoli accompanying dense lymphocytic
infiltration with lymphoid follicle formation (Fig. 1D). The tumor had invaded into the
muscularis propria, and lymphovascular invasion was noted.
Immunohistochemical analyses revealed that the neoplastic cells
were focally positive for cdx-2 and keratin 20, but negative for
p40, and keratin 5/6 and 7. EBER was detected in the neoplastic
cells by in situ hybridization (Fig. 1E). The lymph nodes contained
metastatic GCLS (5/39).
Accordingly, a diagnosis of double gastric cancers
composed of ASC (pT4a) and GCLS (pT2) was made. Moreover, both
tumors showed mild chemotherapeutic effect.
Discussion
We herein report the first documented case of double
gastric cancers composed of ASC and GCLS. The peculiar finding of
the present case was the presence of two discontinuous tumors
composed of ASC and GCLS.
Table I summarizes
the clinicopathological features of the two previously reported
cases of concomitant ASC and GCLS, as well as the present one. In
the case reported by Oya et al, the adenocarcinoma component
of the ASC was a GCLS (3). In the
other case reported by Kuroda et al, both GCLS and ASC were
present within the same tumor (the adenocarcinoma component of the
ASC was a conventional adenocarcinoma); thus, the authors suspected
two possibilities regarding the pathogenesis of the lesion: i)
collision of two distinct tumors, and ii) differentiation of
adenocarcinoma toward an EBV-related tumor and SCC (4). Although ASC and GCLS were close in
location in the present case, the pathogenetic relationship between
the two lesions is unclear.
 | Table I.Clinicopathological features of
gastric adenosquamous carcinoma with carcinoma with lymphoid
stroma. |
Table I.
Clinicopathological features of
gastric adenosquamous carcinoma with carcinoma with lymphoid
stroma.
| Factor | Age/sex | No. of the
lesions | Location | Size (mm) | p63/p40 | EBER | Prognosis | Authors, year | (Refs.) |
|---|
| Case 1 | 50's/male | 1 | Upper | 90×85 | Not done | SCC(−), GCLS (+) | AWD, 10 years | Oya et al,
2010 | (3) |
| Case 2 | 67/male | 1 | Upper | 60×50 | Ad(−), SCC (+), GCLS
(−) | Ad(−), SCC(−), GCLS
(+) | Not available | Kuroda et al,
2010 | (4) |
| Present case | 58/male | 2 | Lower | 35×25 (ASC) 45×36
(GCLS) | Ad(−), SCC (+), GCLS
(−) | Ad(−), SCC(−), GCLS
(+) | AWD, 8 months | – | – |
The pathogenesis of gastric ASC has been under
debate, and several hypotheses have been proposed: i) squamous
metaplastic transformation of adenocarcinoma, ii) oncogenic
transformation of metaplastic squamous cells, iii) collision of
concurrent adenocarcinoma and SCC, and iv) differentiation of stem
cells toward glandular and squamous cells (2). In the present case, the adenocarcinoma
and SCC components were intermingled, as they were in the
metastatic lymph nodes. Furthermore, it has been reported that
adenocarcinoma is the most frequent component of the metastatic
lymph nodes of patients with gastric ASC, followed by a combination
of both adenocarcinoma and SCC components (2). Therefore, the first hypothesis is the
most considerable.
It has been well recognized that the occurrence of
GCLS is associated with EBV in most cases. Although only limited
cases of ASC associated with EBV have been reported (5), the SCC components of the two previously
reported cases and the present case were not associated with EBV
infection. Therefore, additional studies are needed to clarify the
clinicopathological features and pathogenesis of gastric ASC,
including the association with GCLS.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
All data generated or analyzed during the present
study are included in this published article.
Authors' contributions
CM and MI were involved in the conception and design
of the study. HMiy, CM, MI, HMik, KI and KT were involved in the
acquisition and analysis of data. CM and MI drafted the manuscript
and constructed the figure. The final version of the manuscript has
been read and approved by all authors.
Ethics approval and consent to
participate
This study was conducted in accordance with the
Declaration of Helsinki.
Patient consent for publication
Patient consent was obtained according to our
hospital policy.
Competing interests
The authors declare that they have no competing
interests.
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