Makarious Kerolles1, Lindsey Oudijk2, Marie-Louise van Velthuysen2, Tessa van Dijk3, Wouter Koole4, Eskeatnaf Mulugeta5, Wouter de Herder1, Ernst-Jan Speel6, Johannes Hofland1
(1) Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.
(2) Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
(3) Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
(4) Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
(5) Department of Internal Medicine, Endocrine Tumor Laboratory, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.
(6) Department of Clinical Bioinformatics, Erasmus Medical Center, Rotterdam, The Netherlands.
Introduction
Secondary gastric neuroendocrine tumors (gNETs) arise in the setting of achlorhydria and hypergastrinemia due to chronic atrophic gastritis and are usually indolent. Germline ATP4A mutations, encoding the gastric H+/K+-ATPase, cause gNETs with achlorhydria and hypergastrinemia with diffuse parietal cell hyperplasia and a higher metastatic potential. Their transition from neuroendocrine cell hyperplasia to malignancy remains unexplained.
Aim
To assess histopathological features of ATP4A-associated gNETs and explore factors underlying their malignant transformation.Methods: A case report of a patient with metastasized gNETs. Additionally, Next-Generation Sequencing (NGS) of leucocytes and a lymph node metastasis was performed.
Results
A 29-year-old woman presented with hematemesis. Gastroscopy identified multiple lesions, histologically confirmed as gNETs. Gastrin was moderately elevated (182 ng/L, normal A, p.Tyr159*) and a missense variant (c.2889T>A, p.Asn963Lys) in the ATP4A gene and a heterozygous pathogenic nonsense variant of the DNA repair gene ATM (c.5932G>T, p.Glu1978Ter). The latter has been associated with absent ATM expression. NGS of a lymph node metastasis revealed no ATM second hit or loss of heterozygosity.
Conclusion
Germline ATP4A testing should be considered in young patients with multiple gNETs and parietal and neuroendocrine cell hyperplasia. Additional germline variants in cancer-predisposing genes might contribute to the malignant transformation and the higher metastatic potential of ATP4A-associated gNETs.