Discordance in Claudin 18.2 Expression Between Primary and Metastatic Lesions in Patients With Gastric Cancer

Abstract

Purpose: Claudin 18.2 (CLDN18.2) has emerged as a promising therapeutic target for CLDN18.2-expressing gastric cancer (GC). We sought to examine the heterogeneity of CLDN18.2 expression between primary GC (PGC) and metastatic GC (MGC) using various scoring methods.

Materials and methods: We retrospectively analyzed data from 102 patients with pathologically confirmed paired primary and metastatic gastric or gastroesophageal junction adenocarcinomas. CLDN18.2 expression was evaluated through immunohistochemistry on formalin-fixed paraffin-embedded tissue samples. We assessed CLDN18.2 positivity using multiple scoring approaches, including the immunoreactivity score, H-score, and the percentage of tumor cells showing moderate-to-strong staining intensity. We analyzed the concordance rates between PGC and MGC and the association of CLDN18.2 positivity with clinicopathological features.

Results: CLDN18.2 positivity varied from 25% to 65% depending on the scoring method, with PGC consistently showing higher expression levels than MGC. Intratumoral heterogeneity was noted in 25.5% of PGCs and 19.6% of MGCs. Intertumoral heterogeneity, manifesting as discordance in CLDN18.2 positivity between PGC and MGC, was observed in about 20% of cases, with moderate agreement across scoring methods (κ=0.47 to 0.60). In PGC, higher CLDN18.2 positivity correlated with synchronous metastasis, presence of peritoneal metastasis, poorly differentiated grade, and biopsy specimens. In MGC, positivity was associated with synchronous metastasis, presence of peritoneal metastasis, and metastatic peritoneal tissues.

Conclusions: CLDN18.2 expression demonstrates significant heterogeneity between PGC and MGC, with a 20% discordance rate. Comprehensive tissue sampling and reassessment of CLDN18.2 status are crucial, especially before initiating CLDN18.2-targeted therapies.

Keywords: Claudin; Gastric cancer; Metastasis.

Fig. 1. Representative cases of intratumoral heterogeneous expression patterns of CLDN18.2 in a single tumor specimen. (A) A biopsy specimen of a primary gastric tumor showed strong membranous staining (3+ intensity) in some areas and no CLDN18.2 expression in others (original magnification, ×15; scale bar, 200 μm). (B) A gastrectomy specimen revealed strong CLDN18.2 expression (3+ intensity) in certain areas and very weak membranous staining (1+ intensity) in others (original magnification, ×5; scale bar, 400 μm). (C) A needle biopsy of a supraclavicular lymph node demonstrated areas of strong (3+ intensity), moderate (2+ intensity), and weak (1+ intensity) membranous staining (original magnification, ×15; scale bar, 200 μm). (D) A metastatic brain tumor from gastric cancer exhibited strong membranous staining (3+ intensity) in some areas and weak staining (1+ intensity) in others (original magnification, ×5; scale bar, 500 μm).

CLDN18.2 = claudin 18.2.

Fig. 2. CLDN18.2 expression in PGC and MGC according to scoring criteria. (A) IRS, (B) H-score, (C) percentage of tumor cells with staining intensity ≥2+, and (D) percentage of CLDN18.2-positivity according to scoring criteria.

CLDN18.2 = claudin 18.2; PGC = primary gastric cancer; MGC = metastatic gastric cancer; IRS = immunoreactivity score; ns = not significant. ^*P<0.05; ^***P<0.001.

Fig. 3. Concordance of CLDN18.2-positivity between PGC and MGC according to scoring criteria.

CLDN18.2 = claudin 18.2; IRS = immunoreactivity score; PGC = primary gastric cancer; MGC = metastatic gastric cancer.

Fig. 4. Representative cases with discordant CLDN18.2 positivity between the PGC and MGC. A gastrectomy specimen from one patient showed strong membranous staining (A; 100% of tumor cells with a staining intensity of 3+; original magnification, ×100; scale bar, 300 μm), while the resected specimen of a metastatic distant lymph node showed CLDN18.2 negativity (B; 0% of stained tumor cells; original magnification, ×100; scale bar, 300 μm). In another patient, a gastrectomy specimen showed very weak membranous staining (C; 5% of tumor cells with a staining intensity of 1+; original magnification, ×100; scale bar, 300 μm), while the resected specimen of a liver metastasis showed a strong CLDN18.2 expression (D; 90% of tumor cells with a staining intensity of 3+; original magnification, ×100; scale bar, 300 μm).

CLDN18.2 = claudin 18.2; PGC = primary gastric cancer; MGC = metastatic gastric cancer.

Fig. 5. Clinicopathological characteristics associated with CLDN18.2 positivity according to the scoring criteria.

CLDN18.2 = claudin 18.2; PGC = primary gastric cancer; MGC = metastatic gastric cancer; IRS = immunoreactivity score.