Gastric carcinoma with lymphoid stroma derived from hamartomatous inverted polyp with osteoclast-like giant cells: a case report

Abstract

Gastric carcinomas with lymphoid stroma (GCLS) are characterized by prominent stromal infiltration of lymphocyte and account for 1–4% of gastric cancers. Although, osteoclast-like giant cells (OGC) have been reported in some GCLS, OGCs in gastric tumors is exceedingly rare. A 60-year-old woman presented to our hospital after the finding of a positive fecal blood test during a routine medical check. Esophagogastroduodenoscopy revealed a Type 0-III + IIc tumor in the middle part of the gastric body. Biopsy revealed a poorly differentiated tumor and she was referred to our department. Early phase computed tomography showed thickening of the wall in the middle of the gastric body and enlargement of nearby lymph nodes. Laparoscopic total gastrectomy was performed. Pathological examination revealed a hamartomatous inverted polyp (HIP) in the submucosal layer with tub2-por1 tumor in the HIP. Prominent lymphocytic infiltration and OGCs were found around the tumor. Immunohistochemical analysis showed that the tumor cells were negative for EBER, MLH-1, and MSH2, 6. These findings suggest that this tumor was a non-microsatellite instability (MSI)-high GCLS without Epstein–Barr virus (EBV) infection. The patient’s postoperative course was uneventful and she was discharged 11 days after surgery. She remains well 3 years after surgery.

Introduction

Gastric carcinomas with lymphoid stroma (GCLS) were first reported in 1921 by MacCarty et al. [1]. According to the 2010 World Health Organization classification, GCLS are a rare histologic variant of gastric cancer (GC), accounting from 1 to 4% of all gastric carcinomas [2, 3]. Typical histopathologic features of GCLS include poorly developed tubular structures and prominent lymphoid infiltrates in non-desmoplastic stroma [4]. These tumors were therefore often misdiagnosed as undifferentiated-type adenocarcinoma when using previous Japanese criteria [4]. Patients with GCLS have a favorable prognosis with low rates of lymph node metastasis [3]. There is evidence of Epstein–Barr virus (EBV) infection from 82 to 93% of GCLS [5]. The molecular characteristics of GCLS and non-GCLS cancers differ.

Osteoclast-like giant cells (OGCs) are multinucleated giant cells that are found in neoplasms of various organs, such as the breast and pancreas [6]. These cells are called OGCs because their morphology is similar to that of giant cell tumors of bones. OGCs are rarely found in gastric cancers; more than half of GCs with OGCs are reportedly GCLS [7]. Little is known about these cells, including their origin, because they are very rare.

Hamartomatous inverted polyps (HIP) are characterized by submucosal growth of hypertrophic glands with cystic dilatation [8]. They are distinct from the other types of hamartomatous polyps which, in contrast to the endophytic nature of these polyps, have an exophytic configuration. Hamartomatous polyps with or without an endophytic configuration are found in less than 0.1% of gastric tumors [9].

We herein report a rare case of GCLS with OGC derived from an HIP.

Case report

A 60-year-old woman had a positive fecal blood test on routine medical examination and esophagogastroduodenoscopy (EGD) revealed a type 0-III + IIc tumor in the middle of the gastric body. Biopsy showed it was poorly differentiated. She was referred to our department for surgery. Her medical history included ovarian cancer surgery, atrophic gastritis with Helicobacter pylori infection that had not been eliminated, and reflux esophagitis. Laboratory tests showed carcinoembryonic antigen 5.3 ng/mL, carbohydrate antigen 19-9 < 1 U/mL, carbohydrate antigen 125 6 U/mL, CYFRA 1.0 ng/mL, and alpha fetoprotein 6 ng/mL. Esophagogastroduodenoscopy showed a III + IIc tumor in the middle of the gastric body (Fig. 1a). Early phase computed tomography (CT) showed thickening of the wall in the middle of the gastric body and enlargement of nearby lymph nodes (Fig. 1b). The preoperative diagnosis was GC (M post T2 (MP) N1 H0 P0 M0, Stage IIA). Laparoscopic total gastrectomy and D2 dissection was performed. Gross examination of the resected specimen showed the SMT-like tumor in the posterior wall of the middle part of the gastric body (Fig. 2a). The SMT-like tumor was surrounded the slightly depressed lesion. Microscopic examination showed an HIP in the submucosal (SM) layer and a tumor (tub2-por1) in that HIP (Fig. 2b). Microscopic examination of another section showed that the tumor in the HIP was covered by normal mucosa and the submucosal tumor pushed up this normal mucosa and, in addition, SMT-like lesion was surrounded by malignant mucosa (Fig. 2b). Immunohistochemical analysis revealed that the tumor cells expressed CK-AE but not EBER; no loss of MLH1, MSH2, or MSH6 was found (Fig. 3). The tumor was heavily infiltrated by CD8-positive lymphoid cells and surrounded by multinucleated giant cells that resembled bone osteoclasts. These atypical cells showed immunostaining with CD68 and macrophage marker but not CK-AE (Fig. 4). Only one metastatic lymph node was found in No.3 lymph node.

Fig. 1.

Esophagogastroduodenoscopy (EGD) and computed tomography (CT) findings a EGD image showing a III + IIc tumor in the middle of the gastric body (arrow) b Abdominal CT image showing early enhancement, thickening of the wall in the middle of the gastric body (arrow), and enlargement of nearby lymph nodes

Fig. 2.

Resected specimen and microscopic findings a Resected specimen showing a III + IIc tumor in the posterior part of the greater curvature of the stomach (arrow) b Photomicrograph showing an hamartomatous inverted polyp in the SM layer and tumors (tub2-por1) in the polyp. (left upper figure: × 20) (left lower and right figure: × 40) c Photomicrograph (another section) showing the tumor in the SM layer and the malignant lesion existed around the SMT-like tumor. (left figure: × 12.5, right figure: × 200)

Fig. 3.

Photomicrographs showing immunohistochemical staining of cancer cells a CK/AE, b EBER, c MLH1 (× 200) The tumor shows cytoplasmic expression of CK/AE but not EBER and no downregulation of MLH1 expression

Fig. 4.

Photomicrographs showing immunohistochemical staining of infiltrating lymphocytes and OGCs a Hematoxylin and eosin (HE), b CD8 (× 40) c HE (OGC) (× 200), d CK/AE, e CD68 (× 400) There is prominent infiltration by CD8-positive lymphocytes (a, b). OGCs are seen around the epithelium on HE staining (arrow) (c). Immuno-pathological staining shows expression of CK/AE and CD68 in OGCs (arrow) (d, e)

The final diagnosis was GCLS (EBV − and non-microsatellite instability (MSI)-high status) with OGCs derived from an HIP (T1b(SM), por1, v0, ly1a, N1, H0, P0, M0, Stage IB). The patient’s postoperative course was uneventful and she was discharged 11 days after surgery. She remains well 3 years after surgery.

Discussion

GCLS was proposed as a new type of gastric carcinoma by Watanabe et al. [10]. Typical histopathologic features of GCLS include prominent lymphoid infiltration in non-desmoplastic stroma and poorly developed tubular structures [4]. Gwang et al. reviewed 59 GCLS that were excised. Two of the patients with SM GCLS (4.0%) had lymph node metastases [4]. The 4.0% rate of lymph node metastasis for SM cancers with GCLS is much lower than the rate for those without GCLS (19.4%), including differentiated and undifferentiated tumors [4]. The immune cells that infiltrate the tumor and its stroma are referred to as tumor-infiltrating lymphocytes (TIL) and indicate an immune response against the tumor cells. Extensive tumor infiltration by TILs, especially CD8-positive T cells, is strongly associated with a favorable prognosis and good response to therapy [11–13]. In our case, more than half of the TILs were CD8-positive T cells, suggesting that the tumor’s activity was being strongly suppressed. Actually, although lymph node metastasis was found, she remains well 3 years after surgery with no signs of disease recurrence. The poorly developed tubular structures in GCLS can result in these atypical tumors being classified as undifferentiated-type adenocarcinomas. One Japanese paper reported that none of 14 such lesions were correctly diagnosed by preoperative biopsy as GCLS [14].

One component of the Cancer Genome Atlas project in 2014 was a comprehensive molecular evaluation of 295 primary GC. This molecular investigation resulted in identification of four major genomic subtypes of GC: EBV-infected tumors (9%), MSIs (22%), genomically stable tumors (20%), and chromosomally unstable tumors (50%) [15]. EBV positivity is reportedly found in 82–93% of GCLS [5]. The characteristics of non-EBV-infected GCLS have been previously investigated [16, 17]. Arai et al. reported that MSI-high GCs account for 43% of poorly differentiated adenocarcinomas and that GCLS can be identified in some MSI-high GCs [17], including some that are EBV-negative. Another group reported identifying 66.7% EBV + /microsatellite instability stable (MSS), 16.7% EBV − /MSI, and 16.7% EBV − /MSS GCs among 24 GCLS [16]. Only a few studies have reported MSI status. Further identification of the features of this rare subtype requires determining the MSI status of EBV-negative GCLS.

Thus, the nature and origin of OGCs and their effect on tumor prognosis remain uncertain. OGCs express CD45 and CD68, which are leukocyte and macrophage markers, respectively, but not cytokeratin, indicating that OGCs are a specialized form of macrophage [6]. Newbould et al. proposed that OGCs may result from fusion of mononuclear macrophages and histiocytes that have been attracted to a tumor by growth or chemotactic factors released by the cancer cells [18]. Ushiku et al. reviewed seven cases of GCs with OGCs and found that four of them were GCLS- and EBV-positive [7]. The above findings suggest that there may be crosstalk between infiltrated lymph nodes and OGCs and that this may affect the prognosis.

Diagnosis of HIPs without pathologic examination is difficult; these tumors may mimic ectopic pancreatic tissue on endoscopy and endosonography [8]. One of the features that suggest HIPs on endoscopic ultrasound imaging is hyperechoic lesions with hypoechoic spots [8]. Aoki et al. suggested that HIP without a stalk are classified as the “SMT type” because the tumor is inverted into the submucosal layer, whereas HIP with a stalk are classified as the “polyp type” [9]. About 20% of hamartomatous polyp are reportedly malignant [8]. Matsuoka et al. reviewed 30 HIPs with a stalk in Japan in 2015, and only one case was diagnosed as a GC originating in a HIP [19]. There is no consensus regarding the macroscopic finding of GC originating in the HIP because of its rarity. In our case, macroscopic finding showed SMT-like tumor surrounded by slightly depressed mucosa (type IIc). Microscopic examination showed a tumor cells in the epithelium of not only HIP part but also of non-HIP part surrounding the HIP. The malignant lesion in the non-HIP part around HIP lesion maybe looked like type IIc tumor. To the best of our knowledge, no case of GCLS derived from HIPs has previously been reported.

In conclusion, this is the first report of a case of GCLS (EBV − , non-MSI-high) with OGCs derived from HIP. The MSI status of all EBV-negative GCLS should be determined to assist evaluation of these lesions’ clinical characteristics and prognosis.

Abbreviations

CT

Computed tomography

EBV

Epstein–barr virus

EGD

Esophagogastroduodenoscopy

ESD

Endoscopic submucosal dissection

GC

Gastric cancer

GCLS

Gastric carcinoma with lymphoid stroma

HIP

Hamartomatous inverted polyp

MSI

Microsatellite instability

MSS

Microsatellite instability stable

OGC

Osteoclast-like giant cell

SM

Submucosal

TIL

Tumor-infiltrating lymphocyte

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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