Deficient Mismatch Repair Proteins in Gastric Mixed Neuroendocrine Non-Neuroendocrine Neoplasm: A Rare Case Report

Abstract

Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare type of gastric carcinoma with controversial diagnosis and treatment. Recent data implies that deficiency mismatch repair proteins inducing microsatellite instability are considered one of the potential drivers of this disease. Hence, we report a stomach MiNEN with MMR protein loss. An admitted 60-year-old woman complained of epigastric pain. The pathological analysis of the gastro-endoscopic biopsy specimen revealed gastric adenocarcinoma. The radiological staging was cT3N1M0; therefore, she received D2 distal gastrectomy. Suspecting neuroendocrine component admix with adenocarcinoma part on the resected specimen microscopy, applying biomarkers including AE 1/3, synaptophysin, and chromogranin A to confirm the diagnosis of MiNEN. The neuroendocrine part was classified as neuroendocrine tumor grade 2 with Ki 67 at 16.5%. To further understand the molecular characterization of this disease, we evaluated mismatch protein expression by staining MLH1, MSH2, MSH6, and PMS2 antibodies. Interestingly, both components lost MLH1 and PMS2 proteins. Her radical surgery followed oxaliplatin/capecitabine adjuvant chemotherapy. The patient is still well after eight cycles of chemotherapy. dMMR gastric MiNENs and dMMR gastric cancer share many clinical and genetic characteristics. Further studies are necessary to survey the role of dMMR in the prognosis and treatment of this entity.

Keywords: Adjuvant chemotherapy; Gastric cancer; Gastric mixed neuroendocrine non-neuroendocrine neoplasm; Microsatellite instability; Mismatch repair protein.

Fig. 1.

Preoperative tests. a Gastroendoscopy shows a central ulcerated area surrounded by rough, protruding border. b Hematoxylin-eosin (H&E) stain (original magnification, ×10) of endoscopic biopsy specimen illustrates malignant cells arranged in irregular glandular structures. c, d Abdominal CT scan shows lesser curvature lesion of the stomach (red arrow) and enlarged regional lymph node (blue arrow).

Fig. 2.

H&E stains of resected specimen. a Two components without clear boundary (original magnification, ×4). b Moderately differentiated adenocarcinoma component (original magnification, ×40). c NET component (original magnification, ×40).

Fig. 3.

Immunohistochemistry stainings for resected specimen. Neuroendocrine constituent: positive with AE 1/3 (a), positive with synaptophysin (b), positive with chromogranin A (c), Ki 67 16.5% (d). Muscle invasive adenocarcinoma part: positive with AE 1/3 (e), negative with SP 11 (f), negative with chromogranin A (g), Ki 67 51% (h).

Fig. 4.

Immunohistochemistry stainings for MMR protein expression of resected tissue. Adenocarcinoma part: deficient expression of MLH1 (a), deficient expression of PMS2 (b), intact expression of MSH2 (c), intact expression of MSH6 (d). Neuroendocrine component: deficient expression of MLH1 (e), deficient expression of PMS2 (f), intact expression of MSH2 (g), intact expression of MSH6 (h). b, f Both imaging reveal background staining in the acceptable positive internal control.

Fig. 5.

Immunostainings (original magnification, ×10) for metastasis in regional lymph node. a Positive with AE 1/3. b Negative with chromogranin A. c Negative with synaptophysin.