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S10120-015-0497-9.Pdf Gastric Cancer (2016) 19:498–507 DOI 10.1007/s10120-015-0497-9 ORIGINAL ARTICLE Clinicopathologic and immunohistochemical characteristics of gastric adenocarcinoma with enteroblastic differentiation: a study of 29 cases 1,2 2 3 1 Takashi Murakami • Takashi Yao • Hiroyuki Mitomi • Takashi Morimoto • 1 1 2 1 Hiroya Ueyama • Kenshi Matsumoto • Tsuyoshi Saito • Taro Osada • 1 1 Akihito Nagahara • Sumio Watanabe Received: 21 December 2014 / Accepted: 1 April 2015 / Published online: 18 April 2015 Ó The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2015 Abstract and SALL4). Glypican 3 was the most sensitive marker Background Gastric adenocarcinoma with enteroblastic (83 %) for GAED, followed by SALL4 (72 %) and AFP differentiation (GAED) has been recognized as a variant of (45 %), whereas no CGA was positive. Furthermore, the alpha-fetoprotein (AFP)-producing gastric carcinoma, rate of positive p53 staining was 59 % in GAED. Re- although its clinicopathologic and immunohistochemical garding the mucin phenotype, CD10 and CDX2 were dif- features have not been fully elucidated. fusely or focally expressed in all GAED cases. Invasive Methods To elucidate the clinicopathologic and im- areas with hepatoid or enteroblastic differentiation were munohistochemical features of GAED, we analyzed 29 negative for CD10 and CDX2. cases of GAED, including ten early and 19 advanced lesions, Conclusions Clinicopathologic features of GAED differ and compared these cases with 100 cases of conventional from those of CGA. GAED shows aggressive biological gastric adenocarcinoma (CGA). Immunohistochemistry for behavior, and is characteristically immunoreactive to AFP, AFP, glypican 3, SALL4, and p53 was performed, and the glypican 3, or SALL4. phenotypic expression of the tumors was evaluated by im- munostaining with antibodies against MUC5AC, MUC6, Keywords Gastric adenocarcinoma with enteroblastic MUC2, CD10, and caudal-type homeobox 2 (CDX2). differentiation Á Alpha-fetoptotein-producing gastric Results Lymphatic and venous invasion was more fre- carcinoma Á Glypican-3 Á SALL4 quent in GAED (76 and 72 %) than in CGA (41 and 31 %; P B 0.001). Lymph node metastasis was more frequently observed in GAED (69 %) than in CGA (38 %; Introduction P = 0.005), as were synchronous or metachronous liver metastases (GAED, 31 %; CGA, 6 %; P B 0.001). Im- Gastric adenocarcinoma with enteroblastic differentiation munohistochemically, all GAED were positive for at least (GAED), also known as clear cell gastric carcinoma, is a one of three enteroblastic linage markers (AFP, glypican 3, rare and not particularly well documented malignancy; previous reports have been either small series or a single case report [1, 2]. This type of tumor has been histo- & Takashi Murakami logically characterized as having a primitive intestine-like [email protected] structure, composed of cuboidal or columnar cells with 1 clear cytoplasm [1, 3, 4]. GAED has also been noted to Department of Gastroenterology, Juntendo University School produce alpha-fetoprotein (AFP) in the serum and within of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan the tumor [1, 2], and it is recognized as a variant of AFP- producing gastric carcinoma. However, the association 2 Department of Human Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, between GAED and AFP production remains unclear as Tokyo 113-8421, Japan some GAED cases may be AFP negative [2, 5]. 3 Department of Surgical and Molecular Pathology, Dokkyo Since the first case of AFP-producing gastric cancer Medical University School of Medicine, Tochigi, Japan with liver metastasis was reported in 1970 [6], many cases 123 Clinicopathologic and immunohistochemical characteristics of … 499 of this tumor type have been reported. In previous reports, pT1 tumors irrespective of lymph node or liver metastasis AFP-producing gastric cancer was associated with a poor as early lesions, and we defined the remaining tumors as prognosis, and advanced-stage disease usually presented advanced lesions. with liver metastases [7–10]. Histologically, typical AFP- producing gastric cancer shows a hepatoid pattern com- Immunohistochemistry posed of neoplastic cells with abundant eosinophilic cyto- plasm in solid nests [11], or a clear cell tubular pattern Serial tissue sections (4 mm thick) prepared from formalin- resembling fetal gut epithelium [1, 3, 4]. Diagnosis of AFP- fixed and paraffin-embedded tissues were subjected to producing gastric cancer is based on positive immunohis- immunohistochemistry. For immunohistochemical ex- tochemical staining of AFP; however, some hepatoid or amination, staining was performed using a Dako EnVision enteroblastic tumors are negative for AFP expression. kit with antibodies against AFP (rabbit polyclonal, 1:1000; Recent studies have demonstrated that glypican 3 and Dako, Glostrup, Denmark), glypican 3 (clone 1G12, 1:200; SALL4 are also oncofetal proteins indicative of hepatocyte BioMosaics, Burlington, VT, USA) SALL4 (clone 6E3, differentiation [4, 12–16]. Glypican 3, a cell-surface hep- 1:100; Abnova, Taipei, Taiwan), and p53 (clone DO-7, aran sulfate proteoglycan, is present in fetal liver and 1:100; Dako, Glostrup, Denmark). The phenotypic ex- hepatocellular carcinoma or hepatoblastoma [4, 12–14]. pression of the tumors was evaluated by immunostaining Immunohistochemically, glypican 3-positive areas nearly with antibodies against MUC5AC (NCL-MUC-5AC, always overlap with AFP-positive areas in AFP-producing 1:100; Novocastra, Newcastle-upon-Tyne, UK), MUC6 gastric cancer [13]. SALL4 is a member of the SALL gene (NCL-MUC-6, 1:100; Novocastra, Newcastle upon Tyne, family and acts as a zinc finger transcription factor. SALL4 UK), MUC2 (NCL-MUC-2, 1:100; Novocastra, Newcastle has an essential role in maintaining the self-renewal and upon Tyne, UK), CD10 (NCL-CD10-270, 1:100; Novo- pluripotency of embryonic stem cells [15, 16]. Accord- castra, Newcastle upon Tyne, UK), and caudal-type ingly, glypican 3 and SALL4 have been suggested to be homeobox 2 (CDX2; CDX2-88, 1:100; BioGenex, Fre- sensitive markers for AFP-producing gastric cancer and mont, CA, USA). Appropriate positive and negative con- related tumors. trols were used for each antibody. Thus, the aim of this study was to elucidate the AFP, glypican 3, or SALL4 staining was assessed ac- clinicopathologic and immunohistochemical features of cording to a previous description [15]. Cytoplasmic stain- GAED in association with the immunostaining of AFP, ing for AFP, and membrane and cytoplasmic staining for glypican 3, SALL4, and p53. glypican 3 were evaluated. Only nuclear staining was considered positive for SALL4. The scoring system was as follows: score 0, less than 1 % of tumor cells positive; Materials and methods score 1, 1–25 % of tumor cells positive; score 2, 26–50 % of tumor cells positive; score 3, 51–75 % of tumor cells Case selection positive; and score 4, more than 75 % of tumor cells positive. The final results were reported as negative We studied 29 patients with GAED who underwent en- (score 0) or positive (score 1, 2, 3, or 4). doscopic or surgical resection at Juntendo University The phenotypes were classified into four categories ac- Hospital, Tokyo, Japan, between January 2009 and March cording to the combination of the expression of CD10, 2014. These included 10 early and 19 advanced lesions. MUC2, MUC5AC, MUC6, and CDX2 [18]. Specimens The diagnosis of GAED was based on the criteria described positive for MUC5AC or MUC6 were defined as gastric by Matsunou et al. [1]: (1) columnar carcinoma cells grow type, those positive for MUC2, CD10, or CDX2 were de- primarily in tubulopapillary and glandular patterns; (2) fined as intestinal type, and those with both phenotypes carcinoma cells have clear cytoplasm and an oval nucleus were considered to be gastrointestinal type. In addition, situated on the basal side; (3) abundant glycogen granules, specimens with no CD10, MUC2, MUC5AC, or MUC6 but no mucin, are contained in the clear cytoplasm. expression were considered to be unclassified type. Ex- Sex, age, tumor location, tumor size, macroscopic ap- pression of p53 was recorded as positive if distinct and pearance, depth of invasion (pT stage), lymphatic or ve- strong nuclear staining was observed in more than10 % of nous invasion, lymph node metastasis, hepatic metastasis, tumor cells [19]. and outcome were evaluated in all patients. The pT stage The histology and immunohistochemical staining results was classified according to the seventh edition of the were evaluated by two observers (T.M. and T.Y.). When American Joint Committee on Cancer/Union for Interna- discrepancies arose, the cases were reviewed using a tional Cancer Control staging system [17]. We classified multiheaded microscope to achieve a consensus. 123 500 T. Murakami et al. Comparisons with conventional gastric Table 1 Clinicopathologic features of gastric adenocarcinoma adenocarcinoma studied Adenocarcinoma with Conventional We randomly selected 100 samples of conventional gastric enteroblastic differentiation adenocarcinoma adenocarcinoma (CGA) from our files of endoscopically or (n = 29) (n = 100) surgically resected specimens at our hospital between 2009 Sex and 2014. These lesions were histologically papillary Male 23 (79 %) 74 (74 %) adenocarcinomas, well to moderately differentiated tubular Female 6 (21 %) 26 (26 %) adenocarcinomas, and poorly differentiated adenocarcino- Age (years) 73.0 ± 7.5 70.6 ± 7.8 mas. We compared 29 GAED
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