Gastric Adenocarcinoma With Signet Ring Cell: A Case Report of a 10-year-old Girl.

Gastric cancer is an extremely rare diagnosis in children and adolescents. Representing 5% of neoplasia’s in childhood. Gastric adenocarcinoma has a prevalence of below 0.05% of all childhood cancers. The objective of this clinical case report is to describe the clinical presentation of this rare cancer in children, including it as a differential diagnosis, and to look for genetic causes in order to perform genetic counseling. with revealed a slim appearance, and upper Esophagogastroduodenoscopy revealed report described a poorly differentiated, diffuse pattern of signet ring cells, with positive immunohistochemical studies for the expression of MLH1, MSH6; PMS2. H. pylori was negative. Because this cancer presented during childhood, CDH1 gene was analyzed, however no ndings of pathologic variants, point mutations, or duplications or deletions were found. The patient underwent hospice care and died 7 months after the initial diagnosis.


Introduction
Gastric cancer is an extremely rare diagnosis in children and adolescents. Representing 5% of neoplasia's in childhood, lymphomas and sarcomas being the most frequent. Gastric adenocarcinoma has a prevalence of below 0.05% of all childhood cancers (1,2). Gastric adenocarcinoma with signet ring cells speci cally does not have a precise reported incidence in children (3,4).
Development of gastric adenocarcinoma in children are theorized by three main ways: de novo, secondary to a polyposis syndrome, or secondary to gastric lymphoma treatment (4,5). In adult patients, the main risk factors are clearly described, such as diet, tobacco, and Helicobacter pylori (H. pylori) infection. However, in children these risk factors are still unknown and studies that correlate the possible etiology and other risk factors are lacking (6,7). Recently, H. pylori infection in children has been reported to be associated with cancer due to an ongoing chronic in ammation in the gastric mucosa that eventually generates gastric atrophy, especially at the gastric antrum (2,8). The strongest associations for the development of gastric cancer in children are gene mutations that have been reported. There are variants described in genes such as CDH1, KRAS, TP53, APC, MLH1, and ERBB2 (9).
To our knowledge, there are relatively few pediatric cases of gastric adenocarcinoma with signet ring cells reported. This case report aims to describe the clinical presentation of this rare cancer in children, including it as a differential diagnosis, and to look for genetic causes in order to perform genetic counseling.

Case Report
A 10 year old female patient, who presented to the emergency department with 2 months of epigastric pain, vomit with undigested food, and 11 kg weight loss. Previously treated with proton pump inhibitors (PPIs), however without improvement of symptoms. Physical exam revealed a slim appearance, and a rm, painful, palpable mass in the upper abdomen. Cardiopulmonary system and extremities were normal without neurological de cits. Initial laboratory tests showed anemia, and normal hepatic and renal studies.
Thoracic and abdominal CT scan reported concentric wall thickening of the body and gastric antrum, with adjacent enlarged lymph nodes. Esophagogastroduodenoscopy revealed a mass with neoplastic appearance, pyloric antrum with subepithelial in ltrative phenomenon, and critical stenosis of the pylorus. Biopsy report described a poorly differentiated, diffuse pattern of signet ring cells, with positive immunohistochemical studies for the expression of MLH1, MSH6; PMS2 ( Fig. 1). H. pylori was negative. These results con rmed the diagnosis of gastric adenocarcinoma with signet ring cells.
The patient underwent a staging laparoscopy with evidence of neoplastic seeding in the peritoneum, peritoneal uid, and left diaphragm. Peritoneal immunohistochemical studies were positive for cytokeratin that indicated metastatic involvement. Because this cancer presented during childhood, CDH1 gene was analyzed, however no ndings of pathologic variants, point mutations, or duplications or deletions were found.
In a joint decision, Pediatrics, adult oncology, pediatric surgery, and palliative care decided that the patient would receive treatment with cisplatin and 5-uororacil with palliative intention, additionally parenteral nutrition support. By the end of the third cycle of chemotherapy, the mass reduced in size with improvement of symptoms and better food tolerance. Before the fth cycle, control CT showed a new concentric thickening of the gastric wall associated with peritoneal carcinomatosis, ascites, collapse of small bowel loops and partial distention of the colon. Despite progression of the disease, the patient continued on chemotherapy because of the improvement in symptoms and quality of life. The patient underwent hospice care and died 7 months after the initial diagnosis.

Discussion
The majority of gastric tumors during childhood are benign. Gastric adenocarcinoma is a rare diagnosis in pediatric patients. Currently, there are few reports of children with this cancer. In 1999, Sasaki H et al. Bonilla-Lanza et al. Reported a case of a 17 year old patient with gastric adenocarcinoma with signet ring cells, who initially presented with epigastric tenderness, vomit and weight loss and later development of ascites and peritoneal carcinomatosis. Undergoing palliative treatment (13). In all previously reported cases, upper abdominal pain was the leading symptom at initial presentation. Peritoneal carcinomatosis was a late clinical presentation, common in all the cases mentioned. The age range for initial symptoms was between 8 and 20 years. The majority of the biopsy reports described gastric adenocarcinoma.
The genetic causes of gastric cancer have been studied in the last decades. CDH1 gene, which codi es for E-cadherin, a transmembrane glycoprotein that is related to cellular adhesion has been previously related with diffuse gastric cancer with signet ring cells (14,15). CDH1 loss of function mutations generate an increase in cellular proliferation rate and are related with gastric cancer but with breast, colorectal, thyroid, and ovarian cancer as well (16). Huntsman Et al. studied CDH1 gene mutations in two families that had the index case below 25 years of age with gastric cancer. They reported some family members who were pathologic mutation carriers, 5 of them underwent total gastrectomy with biopsy result of signet ring cells malignant cells (17).
The majority of cancer that develops is associated with a pathology variant in CDH1 gene which has an early onset in patients below 40 years, 30 to 50% of those cases are point mutations, and 5% are deletions or duplications (18). Other studies have reported an association with MAP3K6 and CTNNA1 genes and germinal mutations, but currently there is not a solid correlation as to CHD1 gene, which makes these genes poorly used in clinical practice.
In regard to the patient in our case, there was no family or personal history as a risk factor and because of the early onset of symptoms, de novo disease was suspected, and genetic studies were performed. CDH1 sequencing was performed without any pathologic variants reported. Gene sequencing for APC, KRAS, TP53, MLH1, and ERBB1 were not performed because it would not change the course of action and genetic counseling (8,19,20).
In a Colombian population study, APC, KRAS, TP53 were analyzed by gene sequencing in 59 patients between 12 and 94 years of age with gastric and colon cancer, they reported that APC gene (15.3%) was the most common affected gene, followed by KRAS (10.1%) and TP53 (5.1%). They did not include CDH1 gene. Which increased the importance to developing studies that included CDH1 and with focus on the pediatric population.

Conclusion
The rarity of gastric adenocarcinoma with signet ring cells in pediatric patients makes early diagnosis di cult to make with treatment options limited to the pediatric population due to rarity, and worse prognosis. Knowledge of this disease in children could help physicians to identify atypical clinical manifestations and warning signs in order to have this as a differential diagnosis. Currently, genetic studies are essential to guide the treatment plan and to make genetic counseling to the patient and family members.

Declarations
Acknowledgements: The authors would like to thank Pathology Department of Universidad de Antioquia in Medellin, Colombia.
Funding: No funding was received.
Con ict of interest: The authors have no con ict of interest to disclose.
Ethics approval: All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Case report was approved by the Hospital Universitario San Vicente de Paul Ethic Board Committee. No. 25-2019.
Consent to participate and for publication: Informed consent was obtained from the patient mother for this case report.
Availability of data and material: Not applicable.