Fetal gut cell-like differentiation in esophageal adenocarcinoma defines a rare tumor subtype with therapeutically relevant claudin-6 positivity and SWI/SNF gene alteration

Abstract

Esophageal adenocarcinoma (EAC) is one of the deadliest tumor entities worldwide, with a 5-year survival rate of less than 25%. Unlike other tumor entities, personalized therapy options are rare, partly due to the lack of knowledge about specific subgroups. In this publication, we demonstrate a subgroup of patients with EAC in a large screening cohort of 826 patients, characterized by specific morphological and immunohistochemical features. This subgroup represents approximately 0.7% (6/826) of the total cohort. Morphological features of this subgroup show a striking clear cytoplasm of the tumour cells and the parallel existence of rare growth patterns like yolk sac-like differentiation and enteroblastic differentiation. Immunohistochemistry reveals expression of the fetal gut cell-like proteins Sal-like protein 4 (SALL4), claudin-6, and glypican 3. Interestingly, we find a correlation with alterations of SWI/SNF-complex associated genes, which are supposed to serve as tumor suppressor genes in various tumour entities. Our results suggest a possible implication of rare tumour subtypes in the WHO classification for EACs according to the classification for gastric cancer. Furthermore, claudin-6 positive tumors have shown promising efficacy of CAR T cell therapy in the recently published BNT-211-01 trial (NCT04503278). This represents a personalized therapeutic option for this tumor subtype.

Keywords: Claudin-6; Clear cell adenocarcinoma; Esophageal adenocarcinoma; Fetal-gut; Glypican 3; SALL4; SMARCA2-loss.

Figure 1

HE-morphology of different tumor growth patterns (different growth patterns can co-exist within the same tumor): (a) enteroblastic, (b) papillary, (c) solid clear cell, (d) garland “yolk-sac”-like.

Figure 2

Immunohistochemistry in esophageal adenocarcinoma with expression of fetal-gut cell markers; (a) Claudin-6 expression on tumour cells, (b) glypican 3 expression on tumor cells, (c) SALL4 expression on the nucleus of the tumor cells, (d) CK7 loss of the tumour cells, (e) AFP expression on tumour cells (lymph node metastasis), (f) SMARCA2 loss of tumour cells (tumor nuclei in pale blue without expression of SMARCA2 protein and co-existing lymphocytes and other stroma cells within the tumor show preserved SMARCA2 expression).