Gastric carcinoma with osteoclast-like giant cells: a case report and review of the literature

Gastric carcinoma with osteoclast-like giant cells: a case report and review of the literature 1 first-author 1 1 1 1 2 2 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:qs_tong@hotmail.com †E-mail:qs_tong@hotmail.com qs_tong@hotmail.com Department of Pathology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China Department of Pathology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China Department of Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China Department of Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China Gastric carcinoma with osteoclast-like giant cells (OGCs) is an extremely rare tumor. So far, only six cases have been reported in the literature. Here we report an additional case of this tumor in a Chinese 78-year-old man presented with abdominal pain, vomiting, and hematemesis. Physical examination and gastroscopy revealed a tumor in the gastric antrum. The biopsy and pathological findings indicated a gastric adenocarcinoma with OGCs, which were present in both the tumor and the metastatic lymph nodes. Further immunohistochemical staining indicated that OGCs were reactive with CD68, CD45, and vimentin protein, but not with pancytokeratin, carcinoembryonic antigen, or epithelial membrane antigen, suggesting the monocytic/histiocytic derivation of these OGCs. In situ hybridization for Epstein-Barr virus showed no nuclear positivity in either adenocarcinoma or OGCs. Postoperative follow-up showed that the patient had survived for at least 6 months without recurrence. Further investigation is warranted to clearly define the prognostic significance of OGCs in gastric carcinoma. Gastric carcinoma Adenocarcinoma Osteoclast-like giant cell (OGC) INTRODUCTION 1 Benign multinucleated giant cells have been reported in neoplasms of various organs, such as the breast, pancreas, thyroid, liver, gallbladder and lung (Gjerdrum et al., 2001 2001 ; Tezuka et al., 2006 2006 ; Mehdi et al., 2007 2007 ; Ahaouche et al., 2005 2005 ; Akatsu et al., 2006 2006 ; Bocklage et al., 1998 1998 ). Because these giant cells present similar morphology with those in giant cell tumors of bones, they are named as osteoclast-like giant cells (OGCs) (Gjerdrum et al., 2001 2001 ). Recently, some authors have suggested that the OGCs originate from monocytes/histiocytes, and probably represent an unusual host response to the accompanying neoplasm (Al-Brahim and Salama, 2005 2005 ). However, the clinical importance of this phenomenon remains unclear, owing to the rarity of such cases. So far, only six cases of gastric carcinoma with OGCs have been reported (Baschinsky et al., 1999 1999 ; Stracca-Pansa et al., 1995 1995 ; Willems et al., 2005 2005 ). Although the significance of OGCs still remains unclear, these authors believed that gastric carcinoma with OGCs may represent a distinct pathological entity (Baschinsky et al., 1999 1999 ; Stracca-Pansa et al., 1995 1995 ; Willems et al., 2005 2005 ). Here, we report an additional case of gastric carcinoma with OGCs and review the literature. CASE REPORT 1 A 78-year-old male patient was admitted because of abdominal pain, vomiting, and hematemesis in the preceding 12-month period. There was no history of hematochezia, melena, clay-colored stools, jaundice, or hepatitis. Physical examination revealed mild tenderness in the epigastric and right upper quadrant regions of abdomen. A 6 cm×5 cm solid mass with obscure boundary was palpable in the middle abdomen around the navel. During the gastroscopical examination, an 8 cm×6 cm tumor mass was clearly observed in the antrum and posterior wall of the stomach. Since the mass biopsy indicated an adenocarcinoma, an exploratory laparotomy was undertaken for the patient with resection of the whole stomach. Postoperative follow-up showed that the patient had survived for at least 6 months without recurrence. Pathological findings 2 The initial gastroscopic biopsy showed that some tissue fragments of the initial gastroscopic biopsy contained necrosis of ulceration, whereas others contained infiltrating signet ring cell cancer. The OGCs were not identified under a microscope. The specimens of laparotomy included the whole stomach, and parts of the proximal duodenum and omentum. In the stomach body and antrum, a 10 cm×8 cm lump area was observed. There were 25 lymph nodes within the connective tissue around the stomach. Representative tumor specimens were collected, fixed in 0.1 g/ml neutral formalin, embedded in paraffin, sliced at thickness of 3~4 µm, and stained with hematoxylin and eosin. Under a microscopy, the peripheral tumor specimens showed a poorly differentiated adenocarcinoma with glandular spaces. The central part of ulceration was characterized by a poorly differentiated adenocarcinoma with focal signet ring cells. There was no prominent vascularity throughout the tumor. OGCs, small round lymphocytes and plasma cells were present at the periphery of tumor and sprinkled among the tumor cells (Fig. 1 1 ). The giant cells contained 3~20 regular and round nuclei with evenly dispersed chromatin. The tumor invaded into the muscular layer and through seromuscular layer. There was no carcinoma at the surgical resection margins. However, the gastric mucosa represented chronic gastritis and focal intestinal metaplasia. Metastatic adenocarcinoma was observed in 13 of the 25 lymph nodes. Within all of the metastatic lymph nodes, there were a lot of OGCs intermixed with the tumor cells. Immunohistochemical staining and in situ hybridization 2 To better define the nature of OGCs, immunohistochemical staining was applied. As shown in Fig. 2 2 , OGCs were immuno-reactive with antibodies against CD68 (Dako, Glostrup, Denmark), CD45 (Dako), and vimentin protein (Dako), but not reactive with antibodies against pancytokeratin (AE1/AE3; Dako), carcinoembryonic antigen (CEA; Dako), or epithelial membrane antigen (Dako). The tumor cells were reactive with pancytokeratin and CEA, but no reactive with CD68, CD45, vimentin protein, or epithelial membrane antigen. In addition, neither the adenocarcinoma nor OGCs were reactive with antibodies (Dako) against the muscle-specific actin (clone HHF-35), smooth muscle antigen, S-100 protein, and latent membrane protein (LMP) of the Epstein-Barr virus (EBV). Moreover, in situ hybridization showed no nuclear positivity of EBV in either the adenocarcinoma or OGCs. DISCUSSION 1 Extraskeletal tumors containing OGCs are frequently reported in the breast and pancreas (Krishnan and Longacre, 2006 2006 ; Molberg et al., 1998 1998 ). So far, only six cases of gastric carcinoma with OGCs have been reported in the literature (Baschinsky et al., 1999 1999 ; Stracca-Pansa et al., 1995 1995 ; Willems et al., 2005 2005 ). All these cases were poorly differentiated adenocarcinoma characterized by the presence of OGCs sprinkled among the tumor cells (Baschinsky et al., 1999 1999 ; Stracca-Pansa et al., 1995 1995 ; Willems et al., 2005 2005 ). Gastric carcinomas with OGCs should be distinguished from giant cell carcinomas, which have the following distinctive features. Firstly, they are composed of pleomorphic and undifferentiated giant cells with bizarre nuclei (Alasio et al., 2007 2007 ). Secondly, giant cell carcinomas show immunohistochemical evidences of epithelial characteristics (Alasio et al., 2007 2007 ). Thirdly, these tumors represent a transition between adenocarcinoma and giant cells since these components have the same origin (Alasio et al., 2007 2007 ). The OGCs found in our patient had none of these characteristics. Similar to the reported cases of gastric carcinoma with OGCs (Baschinsky et al., 1999 1999 ; Stracca-Pansa et al., 1995 1995 ; Willems et al., 2005 2005 ), the tumor invaded beyond the muscular layers in this case. There were 13 metastatic lymph nodes, and one of them was 3.5 cm in diameter. We suspected that the gastric carcinoma may represent a metastasis from other organs. However, we did not find any other mass during the exploratory laparotomy, which indicated a primary carcinoma of gastric origin. In addition, a previous report indicated that increased vascularity was associated with tumor with OGCs (Min and Gillies, 1996 1996 ); however, we did not find the abnormality of vascularity (such as hemorrhage) in this case. The nature and origin of OGCs still remain largely unknown. Some authors suggest that OGCs derive from epithelial, histiocytic, or mesenchymal metaplasia (Gjerdrum et al., 2001 2001 ; Tezuka et al., 2006 2006 ; Krishnan and Longacre, 2006 2006 ; Molberg et al., 1998 1998 ). Consistent with previous cases of gastric carcinoma, OGCs were present in both the tumor tissues and the metastasic lymph nodes in this case. These evidences suggest that OGCs may be one part of the systemic response to tumor, but not a local reaction to tumor tissue damage and invasion. In accordance with the previous reports (Baschinsky et al., 1999 1999 ; Stracca-Pansa et al., 1995 1995 ; Willems et al., 2005 2005 ), OGCs present in this case showed immunohistochemical evidence of monocytic/histiocytic origin, but not of epithelial derivation. The cancer cells were strongly and exclusively immuno-reactive with pancytokeratin, while the OGCs represented strong CD68 staining in cytoplasm. These findings indicate that OGCs are a specialized form of macrophage. The detailed mechanism of this peculiar reaction still remains speculative. The formation of OGCs may result from fusion of mononuclear histiocytes/macrophages, which were attracted to the tumor tissues by cancer cell-released growth or chemotactic factors (Newbould et al., 1992 1992 ). Further investigations are needed to confirm this hypothesis. Since the presence of a marked lymphocytic infiltrate in this case, the possibility of a lymphoepithelioma-like carcinoma (LELC), which can occur in the stomach, was raised. The LELCs are undifferentiated adenocarcinomas characterized by a strong lymphoid reaction and shortage of OGCs (Willems et al., 2005 2005 ). In a previous report, the EBV sequences were found in seven of eight gastric carcinomas with LELC morphology, which indicated a potential linkage between EBV and lymphoid infiltrate within tumors (Shibata et al., 1991 1991 ). In six reported cases of gastric carcinoma with OGCs (Baschinsky et al., 1999 1999 ; Stracca-Pansa et al., 1995 1995 ; Willems et al., 2005 2005 ), one case was immunohistochemical positive for LMP of the EBV (EBV-LMP) (Stracca-Pansa et al., 1995 1995 ), while another case showed intense nuclear positivity for EBV measured by in situ hybridization (Willems et al., 2005 2005 ). However, in this case, the immunohistochemical staining for EBV-LMP and in situ hybridization for EBV were non-reactive. Although the OGCs are a characteristic feature of tumors, its significance is unknown. Recently, some authors have suggested that gastric carcinoma with OGCs is associated with a more favorable prognosis (Baschinsky et al., 1999 1999 ). As shown in Table 1 1 , males appear to be affected in a higher rate than females. In these cases, the tumor was at an advanced stage with metastasis of lymph nodes. Postoperatively, the patient had survived for at least 6 months without evidence of recurrence. Follow-up data in the literature (Table 1 1 ) have shown that 50% of patients with gastric carcinoma containing OGCs were still alive after surgery, and that one patient was alive for 10 years (Stracca-Pansa et al., 1995 1995 ). However, further investigation is warranted to clearly define the prognostic significance of OGCs in gastric carcinoma. 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