SALL4 Represents Fetal Gut Differentiation of Gastric Cancer, and is Diagnostically Useful in Distinguishing Hepatoid Gastric Carcinoma From Hepatocellular Carcinoma

Abstract

The novel stem cell marker SALL4 has been identified as a diagnostic marker of germ cell tumors, especially yolk sac tumors, in gonadal organs. To clarify the significance of SALL4 as an oncofetal protein, we investigated SALL4 expression by immunohistochemistry in non-neoplastic stomach and gastric carcinoma with particular emphasis on á-fetoprotein (AFP)-producing gastric carcinoma, as AFP-producing gastric carcinoma shares expression of AFP and glypican 3 (GPC3) with yolk sac tumors and hepatic neoplasms. A total of 338 gastric carcinomas, 60 hepatocellular carcinomas, and 48 cholangiocellular carcinomas were studied by immunohistochemistry on tissue microarrays. In addition, more detailed whole tissue section immunohistochemistry was performed on non-neoplastic gastric tissue from 5 adult and 8 fetal specimens, 6 hepatoblastomas, and 31 cases of AFP-producing gastric carcinomas. SALL4 expression was observed in the neofetal stomach in gestational week 9 and disappeared thereafter. It was also identified by tissue microarray study in a fraction of gastric carcinomas (51 of 338, 15%), associated with older age (P=0.0001), male sex (P=0.0033), intestinal-type histology (P=0.0001), and synchronous liver metastasis (P=0.0047). AFP and GPC3 were closely associated with SALL4 expression in gastric carcinoma (both, P<0.0001), and a full-section study indicated that SALL4 was positive in all 31 cases of AFP-producing gastric carcinoma with diffuse staining in 24 cases (78%). Diffuse SALL4 expression was observed in the histologic patterns of hepatoid (89%), glandular (57%), and clear cell (39%) AFP-producing gastric carcinoma. In addition, SALL4 expression was completely negative in hepatoblastoma (n=6) and hepatocellular carcinoma (n=60). SALL4 is an oncofetal protein similar to AFP and GPC3, but it represents fetal gut differentiation in gastric carcinoma. SALL4 is a sensitive marker for AFP-producing gastric carcinoma and is especially useful to distinguish hepatoid gastric carcinoma from hepatocellular carcinoma.

Immunohistochemistry in Undifferentiated Neoplasm/Tumor of Uncertain Origin

“…1,112,113 SALL4 and lin-28 homolog A (LIN28) are highly sensitive and specific markers for identifying a tumor of germ cell origin. [88][89][90][91][92][93][94][95]114,115 The markers for determinining many neoplasms are summarized in Table 3.…”

“…SALL4 and LIN28 are excellent screening markers for germ cell tumors, which are positive in nearly 100% of seminomas, embryonal carcinomas, and yolk sac tumors; 70% of choriocarcinomas; and 50% of teratomas. [88][89][90][91][92][93][94][95][96]114,115 D2-40 and CD117 are specific markers for seminoma; AFP and glypican-3 are specific markers for yolk sac tumors; SOX2, NANOG, and CD30 are relatively specific markers for embryonal carcinomas, although NANOG is also positive in seminomas and SOX2 may be positive in yolk sac tumors; and CD10 and b human chorionic gonadotropin (B-HCG) are specific markers for choriocarcinomas. The useful markers are summarized in Table 22.…”

“…[90][91][92][93][94] The reported sensitivity for seminomas, embryonal carcinomas, and yolk sac tumors is nearly 100%, which is also our experience, as shown in Table 11. Even though SALL4 is a highly specific marker for a broad spectrum of germ cell tumors, its expression has been reported in 89% of hepatoid gastric carcinomas, 95 58% of embryonal components of hepatoblastoma, 89 88% of malignant rhabdoid tumors, and 50% of Wilms tumors. 208,209 More recently, a unique punctate/ clumped nuclear staining pattern of SALL4 was observed in 30 of 32 HCCs (94%).…”

Esophageal Adenocarcinoma with Enteroblastic Differentiation Arising in Ectopic Gastric Mucosa in the Cervical Esophagus: a Case Report and Literature Review

“…Immunohistochemically, recent reports have demonstrated that AFP, glypican3 and SALL4 were sensitive markers for the enteroblastic type of tumor [16,[25][26][27]. In our patient, the tumor more strongly expressed SALL4 than AFP and glypican 3.…”

Alpha-fetoprotein producing Gastric carcinoma : A rare entity

“…SALL4 is a sensitive marker for AFP-producing gastric carcinoma and is especially useful to distinguish hepatoid gastric carcinoma from hepatocellular carcinoma. 12 Various reports have shown that AFP producing carcinoma of the stomach has a more aggressive behavior than the common gastric cancers in the form of higher incidence of vascular invasion, lymph node and liver metastasis. 13 Data regarding optimum therapy of AFPGC is sparse.…”