Trefoil Factor 2 (TFF2) as a Surrogate Marker for Endocervical Gastric-type Carcinoma

Gastric-type carcinoma (GAS) is the most common human papilloma virus-independent endocervical adenocarcinoma (ECA), characterized by an aggressive behavior. Trefoil factor 2 (TFF2) is a mucin-associated peptide expressed in normal gastric but not endocervical glands. This study was carried out to investigate whether TFF2 could be a surrogate marker to separate GAS from other types of ECA. ECAs from 9 international institutions were reviewed for consensus histotype. Of them, expression of TFF2 was immunohistochemically examined compared with that of HIK1083, using whole sections of 50 ECAs (10 GASs and 40 non-GASs) and 179 ECAs (24 GASs and 155 non-GASs) with tissue microarrays (TMAs). TMAs were assessed to simulate assessment of immunohistochemical stains in small biopsies. Both markers were similarly scored, and any cytoplasmic/membranous staining of >5% of tumor cells was considered positive. Of 50 ECAs with whole sections, TFF2 was significantly more frequently expressed in GASs (8/10) compared with non-GASs (5/40) (P<0.01). In 179 ECAs with TMAs, TFF2 was also significantly more frequently expressed in GASs (7/24) compared with non-GASs (4/155) (P<0.01). There was no significant difference in specificity among the 2 markers. Double positivity for TFF2 and HIK1083 in ECAs was highly specific in separating GASs from non-GAS (P<0.01). A significantly smaller percentage of GASs were TFF2 positive in TMAs than in whole sections (P<0.01). Our results suggest that TFF2 is a promising marker, along with HIK1083, to confirm a diagnosis of GAS. This marker may be negative in small biopsies, indicating the necessity of using other exclusionary markers in combination with rigorous morphologic review and extensive sampling in resection specimens.