To the Editor: Pediatric gastric adenocarcinoma (GAC) is very rare, accounting for 0.05% of all pediatric malignancies 1. In children, it is speculated to occur in patients with inherited susceptibility to diffuse gastric cancer 2. Signet-ring cell carcinoma (SRCC) of the stomach is a rare variant of gastric cancer and is exceedingly uncommon in children 3, 4. To the best of our knowledge, our patient represents the first case of gastroesophageal junction (GEJ) SRCC in a child. Here, we describe the clinical, pathological, and genetic characteristics of a very unusual case of SRCC of the GEJ in a 9-year-old female with no detectable underlying genetic predisposition. A 9-year-old female presented with 1 month of progressive dysphagia to solids and liquids, intractable emesis, and marked cachexia. Imaging studies revealed a markedly dilated esophagus and an ill-defined mass at the GEJ. Esophagogastroduodenoscopy (EGD) demonstrated severe Candida esophagitis with significant narrowing at the GEJ (Figure 1). Histologic examination of the tumor showed a poorly differentiated SRCC consisting of discohesive cells with signet-ring cell morphology in 90%, characterized by central optically clear cytoplasmic mucin with eccentrically located nuclei. By immunostains, the tumor cells were positive for cytokeratin and p53 and negative for HER2/neu. Clinical sequencing of CDH1, APC, and TP53 was negative. Mismatch repair immunohistochemistry showed retained expression of MLH1, MSH2, MSH6, and PMS2, indicating a low likelihood of Lynch syndrome or MSI-high status. The tumor PD-L1 proportion or combined positive score (CPS) was low (5%), while Claudin 18.2 (CLDN18.2) immunostaining was strongly positive in approximately 75% of viable tumor cells with 3+ staining, suggesting potential responsiveness to claudin-targeted therapies. Subsequent lung biopsy established metastatic SRCC consistent with Stage IV GEJ SRCC. Whole-exome sequencing was therefore applied to capture the majority of protein-coding regions for the identification of single-nucleotide variants, small insertions/deletions, and copy number abnormalities in the patient's germline as well as the primary tumor. The sample was sequenced to a mean depth of coverage of greater than 120×, and no pathogenic abnormalities were identified. Germline testing with a multi-cancer predisposition panel did not identify any pathogenic variants. Given the absence of pediatric-specific GEJ adenocarcinoma protocols, treatment was modeled on adult data, particularly the CheckMate 649 regimen of modified FOLFOX6 (mFOLFOX6) plus nivolumab for advanced HER2-negative gastric and GEJ adenocarcinoma 5. After initiation of mFOLFOX6 plus nivolumab, interim positron emission tomography and computed tomography (PET-CT) demonstrated marked reduction in FDG-avid mass-like thickening at the GEJ, resolution of mesenteric lesions, and near-resolution of prior right lung nodularity, consistent with an early radiologic response. Because of strong CLDN18.2 expression, the team investigated the potential use of the monoclonal antibody zolbetuximab based on the promising results established in the SPOTLIGHT trial that improved progression-free survival and overall survival when it was combined with mFOLFOX 6. However, the combination of zolbetuximab + mFOLFOX + nivolumab is still under clinical trials, with no results yet established (ILUSTRO trial), and, due to possible severe gastrointestinal toxicity with zolbetuximab, this therapy was held. In addition, we investigated the potential use of early-phase CLDN18.2-targeted CAR T-cell therapies that have demonstrated encouraging antitumor activity in heavily pretreated adults 7, 8. However, access to these agents was limited for this child, given that relevant CAR T-cell protocols were either closed or did not include pediatric solid tumor cohorts 7. Following Cycle 5 of mFOLFOX6 plus nivolumab, the patient developed escalating respiratory compromise with multifocal pulmonary consolidations, systemic candidemia, and radiographic findings consistent with aspiration pneumonia in the setting of profound esophageal dysfunction. Despite broad-spectrum antibacterial and antifungal therapy, high-flow oxygen, and intensive pulmonary hygiene, imaging studies continued to show worsening multifocal lung consolidations with near-complete opacification of the right lung, raising concern for a combination of progressive metastatic disease, recurrent aspiration, and chemotherapy-induced pneumonitis. Given the lack of curative options, cumulative treatment toxicity, and progressive respiratory failure, the family elected for comfort care, and the patient succumbed to disease progression 4 months after diagnosis. Pediatric gastric carcinoma is extremely rare, and it is unclear if it carries the same biological characteristics as its adult counterpart. Gastric cancer in children occurs mostly in genetically predisposed patients. Hereditary diffuse gastric cancer is a disease with autosomal dominant inheritance in which gastric cancer develops at a young age 2. Germline truncating mutations in the E-cadherin (CDH1) gene have been found in families with hereditary diffuse gastric cancer. This case is unique in many aspects. First, it illustrates an exceedingly rare occurrence of GEJ SRCC in a child with no germline predisposition. Second, the initial robust response to an adult-tailored regimen suggests that adult gastric cancer treatment approaches may provide meaningful, although temporary, disease control in children 3, 9. Despite this, achieving remission in metastatic cancer remains a significant challenge 3. Third, the strong CLDN18.2 expression in this pediatric tumor underscores the emerging importance of molecular phenotyping to identify candidates for novel targeted therapies, particularly as claudin-directed antibody cellular therapy moves into later-phase trials. This case adds to the sparse pediatric literature on GEJ SRCC. These findings reinforce the need for ongoing efforts in genomic characterization and development of pediatric-accessible targeted trials for ultra-rare gastric tumors. The authors declare no conflicts of interest. Consent was obtained from the patient's legal guardian for the publication of this case report.
Bakkar et al. (Thu,) studied this question.