Locally advanced mismatch repair‐deficient gastroesophageal junction cancer: Diagnosis, treatment modifications, and monitoring

Abstract

CW is a Caucasian woman aged 70 years with history of asthma, sleep apnea (on continuous positive airway pressure), hypertension, and hyperlipidemia who presented to her primary care physician for her annual physical. She was otherwise well and specifically denied any gastrointestinal symptoms or unintentional weight loss. Per patient report and a review of outside records, she underwent a computed tomography (CT) scan of the chest without contrast for abnormal pulmonary physical examination findings. The CT scan revealed normal lung fields, but it was incidentally noted that she had thickening of the wall of the distal esophagus and the fundus of the stomach. Esophagogastroduodenoscopy was performed, which revealed a large, fungating, ulcerating mass within the gastric cardia extending proximally into the lower esophagus and distally into the gastric body (>3 cm in extension) along the lesser curvature. The pathology was consistent with a poorly differentiated adenocarcinoma. Biomarker status was not available, and the patient was referred to our institution for further management. She underwent additional staging with positron emission tomography (PET) imaging, which revealed a metabolically active mass extending from the lower one third of the esophagus inferiorly to involve the gastroesophageal junction (GEJ) and proximal stomach, with a maximum standardized uptake value (SUV) of 25.9 (Figure 1A). Several other enlarged regional lymph nodes were noted without metabolic activity. No metabolically active distant metastatic disease was noted. She underwent staging laparoscopy, which revealed no evidence of peritoneal disease. The tumor seemed to involve the cardia and the proximal body of the stomach. Two small, superficial nodules were noted on the surface of the liver, one of which was resected at that time (and was identified as a cavernous hemangioma on histopathologic assessment). Cytology of peritoneal washings revealed benign mesothelial cells. Finally, a staging endoscopic ultrasound was performed, which revealed a hypoechoic, noncircumferential mass in the lower esophagus, cardia, fundus, and 5 cm into the body of the stomach along the lesser curvature. There was sonographic evidence suggesting invasion into the serosa. Six malignant-appearing lymph nodes were observed in the paracardial region (level 16), the gastrohepatic ligament (level 18), the celiac region (level 20), and the perigastric region (Figure 2A–F). This was staged as T3 (Tumor 3) with N2 lymph node status (uT3N2) by endosonographic criteria. During this time, the patient started to experience intermitted dysphagia to solids but was able to maintain adequate nutritional intake orally with supplementation. On histopathologic evaluation, the GEJ tumor biopsy revealed poorly differentiated adenocarcinoma (Figure 3). Biomarker testing specifically for mismatch repair (MMR) proteins was requested. Immunohistochemical staining for MMR proteins showed loss of expression of postmeiotic segregation increased 2 (PMS2) and mutL homolog 1 (MLH1) in tumor cells, but intact mutS homolog 6 (MSH6) and MSH2, consistent with MMR deficiency (dMMR). At baseline, a cell-free DNA liquid biopsy test (Guardant360®; Guardant Health) was also performed. The highest variant allele frequency was 2.2%, with microsatellite instability high (MSI-H) detected (other genomic alterations noted on the cell-free DNA assay are listed in Table 1). Representative PET images that aided in assessing tumor response and treatment strategy. (A) PET image at baseline before starting treatment. (B) PET image showing modest response to FLOT chemotherapy (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel). (C) PET image showing robust response after four cycles of pembrolizumab. PET indicates- positron emission tomography; SUVmax- maximum standardized uptake value. Endoscopic and EUS images of the gastroesophageal tumor staged as uT3N2. (A) Endoscopic appearance of the tumor in the gastric card