Hereditary diffuse gastric cancer: laparoscopic surgical approach associated to rare mutattion of CDH1 gene

INTRODUCTION

Gastric cancer sets among the five most prevalent cancer in Brazil. For the year 2014, according to the National Cancer Institute (INCA), were expected 20,390 new cases with 13,328 deaths from the disease³.

Despite the identification of risk factors for the occurrence of neoplasia¹, approximately 80% of cases are sporadic and not associated with risk factors. Even less frequent, it is the hereditary cases and associated with mutation of the HRC 1 gene, determining the occurrence of Cancer Hereditary Diffuse Gastric Syndrome. It corresponds to 3% of cases of gastric cancer^{7, 10}.

Patients mutation CDH1 gene carriers have shown gastric cancer with more adverse prognosis, as the presence of signet ring cells, poorly differentiated tumors and diffuse histological pattern, making also important to identify families suffering from chromosomal gene changes and syndrome determinants to allow early diagnosis and preventive treatment^{7, 10}.

As for the surgical treatment of hereditary or not gastric cancer, laparoscopy has demonstrated oncologic results similar to laparotomy approach, and lower morbidity, with patients returning earlier to their activities⁴.

This study aims to report a case diagnosed clinically and genetically, with treatment done through laparoscopic radical gastrectomy.

CASE REPORT

Man with 33y was admitted in July 2012 at the General Surgery Service of the Hospital of the Military Police of Paraná, asymptomatic and without comorbidities, but with a family history of gastric cancer in reporting two first-degree relatives with a diagnosis of cancer, one of them younger than 50 years (Figure 1A). After the endoscopy (Figure 1B), was identified ulcerated lesion in the gastric body with positive pathology for adenocarcinoma with histological pattern of signet ring cells (Figure 1C).

Figure 1.

A) Heredogram showing three cases of gastric cancer in three generations of the same family; B) videoendoscopy demonstrating gastric ulcer; C) gastric adenocarcinoma (H & E)

Staging showed no metastatic or locally advanced disease. The patient underwent laparoscopic radical gastrectomy with derivation in Roux-en-Y and lymphadenectomy D2. The pathology of the surgical piece showed the presence of poorly differentiated adenocarcinoma, diffuse pattern, with cells in signet ring, free surgical margins and no lymph node compromised histologically in 29 dissected.

After the operation, according to guidelines of the International Gastric Cancer Linkage Consortium, was collected the blood and carried the mutation research of the HRC gene 1. It was analyzed by technique of polymerase chain reaction (PCR) with subsequent bidirectional sequencing of all coding exons and introns-exons junctions CDH1 gene. It was identified as heterozygous deletion of two pairs of bases 1763-1764 in the nucleotide, resulting in frameshift mutation at codon 588 (c.1763-176delTG; pVal588Glufs * 2) in CDH1 gene.

DISCUSSION

This syndrome affects individuals of the same family at young age^{7, 10}. It is defined by the presence of germline mutations of CDH1 gene, acquired by autosomal dominant, reaching penetration rates of up to 80% for both genders^{4, 7, 10}.

The CDH1 gene is located at 16p22.1 gene. It consists of 16 exons encoding a transmembrane protein called E-cadherin. It holds cells together in intra and extracellular domains that communicate with neighboring cells by other proteins called catetines⁴.

The genetic alterations detected in the CDH1 gene are mutations, frameshift mutations and deletions. Mutations are more related to the occurrence of hereditary diffuse gastric cancer syndrome, the codon 1003, located in exon 7 the most frequent site of changes. In the present study, a frameshift mutation was detected in codon 588, the first of its kind to be described in the literature. The real impact of this mutation on the phenotype is unknown^{6, 7}.

Clinical diagnostic criteria are established by the "International Gastric Cancer Linkage Consortium" that defines as the presence of two or more cases of diffuse gastric cancer in first or second degree relatives being one of them diagnosed before age 50, or three or more cases of diffuse gastric cancer diagnosed in first or second degree relatives, regardless of age^{7, 10}.

Once established the clinical and genetic diagnosis of the syndrome, it is important to extend the research to the direct family members, and women crawl them for lobular breast carcinoma. Other syndromes may be present at diagnosis, such as colorectal cancer not polypoid, Li-Fraumeni syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome and Cowden⁵.

Prognosis is dependent on early diagnosis and total gastrectomy indication even in the absence of invasive disease^{7, 9, 10}.

Total gastrectomy is the most efficient way to eliminate the risk of developing gastric cancer, including how to limit proximal surgical resection along the distal esophagus and eliminating any risk of residual mucosa tissue on cardia^{9, 10}.

Endoscopic surveillance of patients at risk is not the first choice, considering the high penetration rates of the gene, as well as the tendency to multifocality of neoplastic cells and sometimes more initial stages, and the neoplasia below the mucosa. The diffuse histological pattern also carries a worse prognosis due to higher frequency of histologically positive lymph nodes and peritoneal implants^{6, 9, 10}.

Only in patients who refuse surgical treatment is indicated follow-up with serial endoscopies, added to chromoscopy and immunohistochemistry in biopsies, targeting respectively the largest detection of early gastric cancer and signet ring cells⁶.

Norton et. al.⁸ demonstrated the occurrence of early gastric cancer associated with the syndrome, indicating early radical gastrectomy in six patients. In all surgical specimens had multifocal adenocarcinoma, invasive and histological pattern of signet ring.

Despite the risks of surgery, such as fistulas, infections, dehiscence and anesthetic complications may reach up to 22% of morbidity and mortality of 4%, the benefits of early operation are superior to endoscopic surveillance or the diagnosis of neoplasia in symptomatic patients. Laparoscopy becomes the major route of surgical approach, since the syndrome is prevalent in young patients and its early identification enables the provision of prophylactic operation in the absence of advanced disease, with faster surgical recovery and earlier return to daily activities^{2, 10}.