ACRT Journal

Introduction

Clear cell adenocarcinoma (CCA) is a rare variant of gastric adenocarcinoma [1-4]. CCAs are usually found in the kidney; however, they have also been reported in the digestive tract and even in gastric cancer [1-4]. To date, only a few cases of gastric CCA have been reported [1-4]. Macroscopically, CCA often presents as a bulging or polypoid mass at the gastroesophageal junction [3]. In particular, CCA is more commonly seen in papillary adenocarcinoma (PA) in elderly patients [2]. Tubules and papillae are lined by clear cells, which represent the clear cytoplasm of the tumour [2]. In addition, this type of gastric adenocarcinoma has a poor prognosis, compared with conventional gastric adenocarcinomas [1]. Although differentiation of gastric CCA from metastatic renal CCA in the stomach contributes to accurate diagnosis and appropriate treatment [1-4], molecular identification of gastric CCA is important from not only a pathological but also clinical aspect. Here, we describe a rare case of gastric CCA including the pathological findings and molecular alterations.

Clinical Report Clinical Summary

A 63-year-old man with no clinical symptoms presented to the Department of Gastroenterology, Southern Tohoku General Hospital (Japan) for endoscopic examination. Endoscopic examination of the upper gastrointestinal tract revealed a depressed lesion with an irregular surface in the lesser curvature of the middle gastric body. The lesion was suspected to be early gastric cancer due to the endoscopic findings. Thus, the region was biopsied for definitive histological diagnosis, and the biopsy identified PA. Computed tomography did not show massive lymph node swelling around the stomach, suggesting no lymph node metastasis. In addition, laboratory data including tumour marker (AFP, CEA, and CA19-9) levels were within normal ranges. Although submucosal invasion was suspected based on the endoscopic findings, endoscopic submucosal dissection (ESD) was selected due to patient preference. A serum antibody test for Helicobacter pylori was performed. The antibody test was negative at the time of consultation.

Pathological findings in the resected stomach specimen

Macroscopically, a depressed lesion measuring 14 × 29 mm was observed in the resected specimen (Figure 1a). Histologically, the ESD specimen consisted of two components, PA and CCA, characterized by marked cytoplasmic clear cell changes in the depressed lesion (Figure 1b). The neoplastic glands had invaded into the submucosa, which was devoid of lymphatic and vascular invasion. The mucosal lesion comprised irregularly branched papillary neoplastic glands with high nuclear pleomorphism and mitotic activity (Figure 1c). The lesion was histologically diagnosed as PA (Figure 1d). In the submucosal lesion, the carcinoma was composed of polygonal tumour cells with marked clear cytoplasm and small round-like nuclei occasionally with obscure nucleoli and low mitotic activity (Figure 1e, f). The tumour cells showed mainly tubular structures (Figure 1e). A transitional area between the two components was clearly observed (Figure 1f and 1h). In addition, tumor necrosis and hemorrhage were not seen in either component. Although the Periodic acid–Schiff (PAS) reaction was focally positive in the PA component, it was negative in the CCA component. In addition, the PAS reaction was not digested in PA component. Thus, glycogen had not accumulated in the tumour cytoplasm. Alcian Blue staining was negative in both components. Finally, atrophic gastric mucosa with intestinal metaplasia was observed in the background mucosa of the lesion. Based on the pathological findings of the ESD specimen, we performed gastrectomy. No residual cancer tissue was identified in the resected specimens of the stomach. In addition, lymph node metastasis was not detected.

Molecular examination

Immunohistochemical staining of the tumour cells was performed using the Leica BOND system. Expression of MUC2, MUC5AC, and MUC6 was positive in both components (Figure 2a–f). In addition, expression of CD10 was focally positive (along the brush border) in both components. Therefore, the tumor was considered to exhibit the gastric and intestinal phenotypes (mixed phenotype) in both components (Figure 2g, h). According to the findings, the clear cell change was caused by accumulation of gastric and intestinal mucins. Adipophilin was not expressed in either component, suggesting that the clear cell change was not caused by fat deposits. Intranuclear expression of CDX2 was diffuse in the PA component and lower in the CCA component (Figure 2i, j). The ki-67 proliferation index was 76.8% and 4.80% in the PA and CCA components, respectively (Figure 2k, l). Overexpression of p53 was found in both components (Figure 2m, n). No intranuclear accumulation of β-catenin or expression of AFP, SAL4, or glypican-3 was detected in either component. Finally, expression of MLH1/PMS2 was also observed in both components. The immunohistochemical results are shown in Table 1. Multiple mutations in cancer-related genes were examined to determine the mutation profile of the tumor cells using a customized gene panel containing 28 genes (APC, BRAF, TP53, CDKN2A, MET, ATM, MLH-1, PMS2, HRAS, AXIN2, BAX, DCC, MSH2, POLE, RNF43, PTEN, EPCAM, MSH6, BUB1B, RHOA, KRAS, NRAS, SMAD4, CDK4, PIK3CA, STK11, TGFBR2, and EGFR) (Next Generation Sequencing; Illumina). Although no mutation was found in the other 27 genes, TP53 mutation was found in both components (P152L (cCg>cTg) exon 5, missense).

Figure 1: Macroscopic and histological features of gastric clear cell adenocarcinoma. a. A depressed lesion with an irregular surface located at the lesser curvature of the middle gastric body. b. Histological loupe finding of the lesion. The red, blue, and yellow squares indicate an intramucosal lesion, a submucosal lesion, and both lesions, respectively. c. Low-power view of papillary adenocarcinoma involved mainly in the intramucosal region. d. High-power view of clear cell adenocarcinoma that had invaded into the submucosal layer. e. Intermediate-power view of clear cell adenocarcinoma. f. High-power view of clear cell adenocarcinoma. g. Transitional area between the papillary adenocarcinoma and clear cell adenocarcinoma components. h. High-power view of the transitional area.

Figure 2: Immunohistochemical expression in the present case. a. MUC2 in papillary adenocarcinoma. b. MUC2 in clear cell adenocarcinoma. c. MUC5AC in papillary adenocarcinoma. d. MUC5AC in clear cell adenocarcinoma. e. MUC6 in papillary adenocarcinoma. f. MUC6 in clear cell adenocarcinoma. g. CD10 in papillary adenocarcinoma. h. CD10 in clear cell adenocarcinoma. i. CDX2 in papillary adenocarcinoma. j. CDX2 in clear cell adenocarcinoma. k. Ki-67 in papillary adenocarcinoma. l. Ki-67 in clear cell adenocarcinoma. m. p53 overexpression in papillary adenocarcinoma. n. p53 overexpression in clear cell adenocarcinoma.

Table 1: Immunohistochemical findings of the present case.