Gastric adenocarcinoma with enteroblastic differentiation should be differentiated from hepatoid adenocarcinoma: A study with emphasis on clear cells and clinicopathologic spectrum

Background: In gastric cancer, clear cells are preferentially found in gastric adenocarcinoma with enteroblastic differentiation (GAED) and hepatoid adenocarcinoma (HAC). The distinction between GAED and HAC is difficult because of their rarity and histologic overlap. Methods: To elucidate identification of gastric adenocarcinoma with clear cells as GAED or HAC, survival analyses were performed in 28 GAED, 26 HAC, and 1107 conventional adenocarcinoma cases. Cells of origin were assessed by investigating the expression of oncofetal proteins (α-FP, glypican-3, SALL4), in addition to gastric (MUC5AC, MUC6), and intestinal (MUC2, CD10, CDX-2) cell markers. Results: Clinically, HAC showed frequent (57.5%) distant metastasis (mostly in the liver) at the time of diagnosis compared to GAED (P < 0.001). On pathology, all 28 GAED had a predominantly tubulopapillary growth pattern while 24 HAC displayed a predominantly hepatoid growth pattern. In survival analyses, patients with HAC had significantly shorter overall and recurrence-free survival (mean: 25 months, and 53 months, respectively) compared to those with GAED (mean: 107 months, and 118 months, respectively) (P < 0.001). HAC with clear cells showed diffuse and strong expression of all oncofetal proteins (α-FP, glypican-3, and SALL4), were highly positive for CDX-2, and were negative for CD10, MUC6, MUC5AC, and MUC2, suggesting an intestinal mucin phenotype and hepatoid features. In contrast, GAED showed focal expression of one or two oncofetal proteins and commonly expressed CD10, CDX-2, and MUC6 but not MUC2 and MUC5AC, suggesting both gastric antral/intestinal mucin phenotype and focal enteroblastic differentiation. SALL4 was diffusely and strongly positive in HAC, while it was heterogeneously expressed in GAED. Conclusions: In conclusion, although rare, HAC with clear cells should be differentiated from GAED based on the poor prognosis, diffuse and strong oncofetal protein expression, and intestinal mucin phenotype.