Glypican 3‐expressing gastric carcinoma: Distinct subgroup unifying hepatoid, clear‐cell, and α‐fetoprotein‐producing gastric carcinomas

Abstract

Gypican-3 (GPC3) has been recognized as an oncofetal protein in hepatic neoplasms and yolk sac tumors. To characterize a distinct subgroup of gastric carcinoma (GC) expressing GPC3 (GPC3-GC), primary and metastatic GC tissues were evaluated by immunohistochemistry with special focus on their related entities: hepatoid, clear-cell, and afetoprotein-producing GC. GPC3-GC was defined as focal GPC3-GC when 10-49% of neoplastic cells were positive, and as diffuse GPC3-GC when more than 50% of cells were positive. Among 926 GC cases, 101 (11%) were GPC3-GC, of which 45 were diffuse and 56 were focal GPC3-GC. Specific histological patterns, such as the hepatoid and clearcell patterns, were frequently observed in diffuse GPC3-GC (38 and 49%, respectively) and in focal GPC3-GC (4 and 25%, respectively), whereas these patterns were extremely rare in GPC3-negative GC. Immunoreactive a-fetoprotein was only identified in GPC3-GC (38% of diffuse and 14% of focal GPC3-GC). Both diffuse and focal GPC3-GC showed nodal metastasis more frequently (67 and 55%, respectively) than GPC3-negative GC (34%), and the diffuse GPC3-GC had significantly more T2-4 and M1 stage cases. GPC3 immunostaining was present in 57 out of 61 nodal metastases (93%) and in all four liver metastases examined. Importantly, diffuse GPC3 expression was observed in the liver metastasis, even if the primary tumor was focal GPC3-GC. GPC3-GC is a distinctive group of GC, which unifies hepatoid, clear-cell, and a-fetoprotein-producing GC. GPC3 is expected to be a target of forthcoming immunotherapy for a patient bearing this specific type of GC. (Cancer Sci 2009; 100: 626-632) G ypican-3 is a cell-surface heparan sulfate proteoglycan that is linked to the extracytoplasmic cell-surface membrane by a glycosylphosphatidylinositol anchor.(1) Heparan sulfate proteoglycans are known to interact with growth factors through heparan sulfate chains and thereby serve as coreceptors for heparin-binding growth factors. Recently, GPC3 has been recognized as an oncofetal protein in the fetal liver and neoplasms of hepatocellular lineage, that is, hepatoblastoma and HCC.(2) Similar to α-fetoprotein, GPC3 is expressed in yolk sac tumors of the testis as well.(3,4) Immunohistochemistry for GPC3 labels much more neoplastic cells than that of AFP in testicular yolk sac tumors, although GPC3 is occasionally expressed in other types of germ cell tumors. The parallel expression pattern of GPC3 and AFP has been further demonstrated in our comparative study of GPC3, AFP, hepatocyte antigen, and protein-induced vitamin K absence or antagonist II in AFP-producing GC. Gastric carcinoma is the fourth most common malignancy worldwide, with approximately 870 000 new cases occurring yearly, and mortality due to GC is the second highest following lung carcinoma.(6) To overcome this carcinoma, it is important to identify its distinct subgroups with characteristic marker phenotypes. AFP-producing GC is such an example, and is characterized by an elevated serum AFP level in cancer-bearing patients. ...

α-Fetoprotein–producing gastric carcinoma and combined hepatocellular and cholangiocarcinoma show similar morphology but different histogenesis with respect to SALL4 expression

“…The liver and stomach are derived embryologically from the foregut; therefore, it is possible that hepatoid GC might relate to the foregut cells, which are able to differentiate into fetal gut and also hepatic stem cells. Molecules associated with immature hepatocytes, such as AFP and GPC3, were detected in hepatoid and nonhepatoid elements in this and previous reports [2][3][4][5][6]. However, there had been no reports concerning the expression of SALL4 in human fetal liver, which was undetectable in our immunohistochemical study.…”

“…Therefore, AFPproducing GC, especially of the hepatoid type, may mimic combined hepatocellular-cholangiocarcinoma (HC-CC) in which HCC and adenocarcinoma are mixed in a single tumor. Distinguishing between the 2 entities on the basis of immunostaining is difficult because HepPar1 and glypican 3 (GPC3) are frequently expressed in HCC and are sensitive markers of AFP-producing GC [2][3][4][5][6].…”

Differential expression of glypican-3 (GPC3) in lung squamous cell carcinoma and lung adenocarcinoma and its clinical significance

“…Previous studies have demonstrated that GPC3 expression is downregulated in gastric (Ushiku et al, 2009), breast (Xiang et al, 2001), and lung cancers (Kim et al, 2003), but is upregulated in liver cancer and melanoma (Komori et al, 2010). The present study demonstrated that the overall expression rate of GPC3 protein in lung cancer was 45%.…”

Practical Points in Gastric Pathology

“…39 Clear cell changes have been reported in 74% (17 of 23) of AFPproducing GCs 40 and in 36% (36 of 101) of glypican-3-expressing GCs. 41 Recently, our large cohort study 39 revealed clear cell changes in 8.5% (65 of 762) of GCs; these patients showed worse prognoses. Furthermore, in our cohort, GCs with clear cell changes were associated with a younger age, antral location, and increased aggressiveness, and they were also demonstrated to be an independent prognostic factor as compared to GCs without these changes.…”