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International Journal of Case Reports and Images, Vol. 10, 2019. ISSN: 0976-3198

Int J Case Rep Images 2019;10:101031Z01VD2019. www.ijcasereportsandimages.com

Devezas et al. 1

CASE REPORT PEER REVIEWED | OPEN ACCESS

A case of a male BRCA2 mutation carrier with gastric adenocarcinoma with signet ring cells

Vítor Devezas, Silvestre Carneiro, Laura Elisabete Barbosa, José A Barbosa

ABSTRACT

Introduction: BRCA1 and BRCA2 are tumor suppressor genes with an autosomal dominant inheritance. Germline mutations of BRCA2 have more impact on men than on women. An increased risk of cancer of breast, prostate, pancreas, uveal melanoma, as well as gastric and esophageal cancer is associated with BRCA2 mutations. Case Report: We present a case of a middle-aged male, who was on follow-up because of a BRCA2 mutation and a familial history of many neoplasia. During the follow-up, the patient presented nonspecific symptoms of gastric malaise. The upper endoscopy revealed an ulcerated lesion at the incisura angularis, which on pathologic report revealed an adenocarcinoma with signet ring cells. Conclusion: There is growing evidence that BRCA2 mutations increase the risk of gastric cancer, especially in men. Surveillance

Vítor Devezas1, Silvestre Carneiro2, Laura Elisabete Barbosa3, José A. Barbosa4

Affiliations: 1Resident, Department of General Surgery, Centro Hospitalar Universitário de São João, Oporto, Portugal; 2Chief of Surgery, Director of Central Operation Room, Department of General Surgery, Centro Hospitalar Universitário de São João, Oporto, Portugal; 3Graduated Assistent of Surgery, Di-rector of General Surgery, Department of General Surgery, Centro Hospitalar Universitário de São João, Oporto, Portu-gal; 4Chief of Surgery, Responsible of the Esophageal and Gastric Surgery Unit, Department of General Surgery, Centro Hospitalar Universitário de São João, Oporto, Portugal.Corresponding Author: Vítor Bruno dos Santos Devezas, UAG Cirurgia – Serviço de Cirurgia Geral. Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal; Email: [email protected]

Received: 13 April 2019Accepted: 28 May 2019Published: 02 July 2019

endoscopic programs directed to families with these mutations should be considered to diagnose early-stage gastric cancer.

Keywords: BRCA2, Carcinoma, Endoscopy, Gastrectomy, Genes, Signet ring cell, Stomach neoplasms

How to cite this article

Devezas V, Carneiro S, Barbosa LE, Barbosa JA. A case of a male BRCA2 mutation carrier with gastric adenocarcinoma with signet ring cells. Int J Case Rep Images 2019;10:101031Z01VD2019.

Article ID: 101031Z01VD2019

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doi: 10.5348/101031Z01VD2019CR

INTRODUCTION

Germline mutations of BRCA genes (BRCA1 and BRCA2) are major risk factors for breast and ovarian cancer in women [1]. BRCA1 and BRCA2 are tumor suppressor genes and have an autosomal dominant inheritance. Those mutations have two major expressions. Mutations of the BRCA1 type represent a concern among the women, while the BRCA2 type relates with an increased risk among men. Male BRCA mutation carriers additionally have an increased risk for breast cancer (cumulative age-adjusted risk 5.8%) [1], as well as prostate, pancreas, uveal melanoma, but also gastric and esophageal cancer [2, 3].

We present a case report, when we reviewed the demographic, surgical, postoperative, and histological data of the patient submitted to gastric surgery at our institution.



Devezas et al. 2

CASE REPORT

A 43-year-old male patient was on a follow-up in the outpatient oncogenetics clinic because of a BRCA2 mutation carrier. His medical history included a lumbar surgical instrumentation 23 years ago, and the diagnosis of epilepsy and depression. He was on clonazepam and fluvoxamine on a daily basis. He was a light smoker. He had a familial history of cancer (Figure 1): breast cancer in his mother and two sisters (both at 33-year-old and one of them an index case for diagnosis of BRCA2 gene mutation), a brother with nasopharynx cancer is 19 years old, two aunts and father diagnosed with gastric cancer at age 48 and breast cancer at 47-year-old, and two cousins with breast and gastric cancers.

After two years of follow-up he started with nonspecific epigastric discomfort. An upper gastrointestinal endoscopy (UGE) was performed that depicted an ulcerated lesion at the incisura angularis. Biopsy revealed an adenocarcinoma with signet ring cells and the patient was referred for treatment.

Thoraco-abdominal-pelvic computed tomography (CT) scan did not show abnormal findings or distant metastasis (Figure 2).

According to our protocol, the patient was submitted to laparoscopic total gastrectomy with D2 lymphadenectomy. He was discharged on the sixth postoperative day with no complications.

Pathologic examination of the surgical specimen revealed adenocarcinoma with signet ring cells, without involvement of the 34 resected lymph nodes. There was no histological evidence of venous, lymphatic, or perineural permeation. Pathologic staging was pT1N0 (Stage IA – pT1N0M0) [4].

The patient was scheduled for regular follow-up. Due to the age, family history of gastric cancer and the presence of adenocarcinoma with signet ring cells, we proceeded to the search for the E-cadherin mutation (CDH1) which was negative.

DISCUSSION

The BRCA1 gene was the first identified susceptibility gene for breast cancer followed by the report of BRCA2, shortly afterward [5]. The BRCA1 and BRCA2 genes are involved in pathways important for DNA damage recognition, double-strand break repair, checkpoint control, transcription regulation, and chromatin remodeling. Mutation of these genes may increase the proliferation of cancer cells, because cells lacking BRCA are highly prone to DNA damage and marked genetic instability. In other words, BRCA1 and BRCA2 are tumor suppressor genes. These genes have an autosomal dominant inheritance [1, 5, 6].

BRCA mutations in women confer a high risk for breast and ovarian cancer [1]. On the other hand, the male BRCA mutation carriers are also susceptible to breast cancer (cumulative age-adjusted risk 5.8%) [1] and have higher risk for prostate, pancreatic, gastric, melanoma, and hematologic cancers [1, 2, 7].

In contrast to women, who have a greater lifetime risk of cancer with mutations of the BRCA1 gene, BRCA2 gene is more concern for men [1] (for cancers of all sites combined, the estimated penetrance of BRCA2 mutations was greater for males than for females, 35% vs. 38%) [8].

Male carriers of BRCA1 mutation have an increased risk of prostate and breast cancer, while those with BRCA2 mutation carriers have an increased risk of breast, prostate, and pancreatic cancers, but also at risk of stomach, esophagus cancers and melanoma (of the skin and eye), and the relative risk is higher before the age of 65 years [2, 7].

In some studies, the relative risks in stomach and esophagus cancers and uveal melanoma are 2.7, 4.1, and 99.4, respectively. The risk for prostate and pancreatic cancers in BRCA2 carriers is equivalent to a four-fold risk [2].

Other studies provide strong confirmation of an increased risk of pancreatic and prostate cancer, in BRCA2 mutation carriers, as well as in stomach (sex related, as it occurs primarily in males), gallbladder and bile ducts,

Figure 1: Family tree. The arrow identifies our patient. The individuals fill the black indicate achievement by oncologic disease.

Figure 2: Images of CT with no gastric lesion clearly identifiable. There is no densification of perigastric fat, abnormal lymphnodes, or liver metastases.



Devezas et al. 3

melanoma of the skin, buccal cavity, and pharynx [3, 9]. Stomach cancer, before the age of 70 years, was twice as frequent in families, with breast and ovarian cancers same as in the general population, and is more frequent in males [10].

Male stomach cancer is part of the spectrum of the disease in BRCA2 families and is not a casual association. The association with other cancers provides evidence that BRCA2 mutations result in a less restricted disease phenotype than BRCA1 mutations [9].

Men with BRCA mutations should be considered at high risk for breast, prostate, stomach, pancreatic, and colorectal cancers. For some authors [1], appropriate surveillance should begin at 40 years of age. Part of this surveillance should include UGE especially in BRCA2 mutation carriers. Even young patients with no alarm symptoms should undergo UGE for earlier diagnosis of gastric cancer [11, 12]. Currently UGE substantially increases the sensitivity and specificity for the diagnosis of cancers becoming one of the best investigation to diagnose early-stage gastric cancer [4, 13, 14].

Even though our patient presented with nonspecific symptoms of epigastric malaise, we decided to submit him to UGE, due to the risk of cancer arising from germline mutation BRCA2. We should remember that symptoms suggesting gastric cancer are often nonspecific: gastrointestinal bleeding, weight loss, and to a lesser degree, anorexia and fatigue [11]. Some patients also complain of early satiety, epigastric pain, or dysphagia [12].

The T1 stage gastric cancer has an excellent prognosis, most of the patients are asymptomatic or complain of long-standing nonspecific dyspepsia [15, 16], therefore the diagnosis is challenging and mostly incidental. Moreover, in these cases no endoscopic screening protocols are established.

The BRCA mutation carriers, especially male BRCA2, are of great risk to develop other cancers than breast, prostate, and pancreas, such as gastric and esophageal cancers. So that, they should be planned for surveillance of gastric cancer (in addition to other surveillance) at the age of 40 years through UGE, or early if they have symptoms, even nonspecific. Given the low five-year survival rate in gastric cancer patients, preventive measures should be emphasized including avoidance of tobacco, to eat a well-balanced diet, and to be treated for ‘‘premalignant’’ conditions such as Barrett’s esophagus, atrophic gastritis, or Helicobacter pylori colonization [1].

CONCLUSION

The BRCA2 mutations increase the risk of gastric cancer, especially in men. This family documents the oncological aggressiveness of these mutations. It is important to perform an UGE, even with nonspecific symptoms, for the success of early diagnosis of gastric cancer, preferably inserted in surveillance programs,

beginning at 40 years of age or earliest, if they have symptoms.

REFERENCES

1. Mohamad HB, Apffelstaedt JP. Counseling for male BRCA mutation carriers: A review. Breast 2008;17(5):441–50.

2. Moran A, O’Hara C, Khan S, et al. Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Fam Cancer 2012;11(2):235–42.

3. Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 1999;91(15):1310–6.

4. Mayer RJ. Gastrointestinal tract cancer. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine. 18ed. New York: The McGraw-Hill Companies, Inc; 2012. p. 765–8.

5. Meric-Bernstam F, Pollock RE. Oncology. In: Brunicardi FC, Andersen DK, Billiar TR, Dunn DL, Hunter JG, Pollock RE, editors. Schwartz’s Manual of Surgery. 8ed. New York: The McGraw-Hill Companies, Inc; 2006. p. 193–6.

6. Friedenson B. BRCA1 and BRCA2 pathways and the risk of cancers other than breast or ovarian. MedGenMed 2005;7(2):60.

7. Lorenzo Bermejo J, Hemminki K. Risk of cancer at sites other than the breast in Swedish families eligible for BRCA1 or BRCA2 mutation testing. Ann Oncol 2004;15(12):1834–41.

8. Risch HA, McLaughlin JR, Cole DE, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 2001;68(3):700–10.

9. Jakubowska A, Nej K, Huzarski T, Scott RJ, Lubiński J. BRCA2 gene mutations in families with aggregations of breast and stomach cancers. Br J Cancer 2002;87(8):888–91.

10. Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: A review of the literature. J Clin Oncol 2004;22(4):735–42.

11. Bołdys H, Marek TA, Wanczura P, Matusik P, Nowak A. Even young patients with no alarm symptoms should undergo endoscopy for earlier diagnosis of gastric cancer. Endoscopy 2003;35(1):61–7.

12. Ryan J, Murkies A. Diagnosis of upper gastrointestinal malignancy. Aust Fam Physician 2006;35(4):200–1.

13. Ono H. Early gastric cancer: Diagnosis, pathology, treatment techniques and treatment outcomes. Eur J Gastroenterol Hepatol 2006;18(8):863–6.

14. Tajiri H, Doi T, Endo H, et al. Routine endoscopy using a magnifying endoscope for gastric cancer diagnosis. Endoscopy 2002;34(10):772–7.

15. Axon A. Symptoms and diagnosis of gastric cancer at early curable stage. Best Pract Res Clin Gastroenterol 2006;20(4):697–708.

16. Hallissey MT, Allum WH, Jewkes AJ, Ellis DJ, Fielding JW. Early detection of gastric cancer. BMJ 1990;301(6751):513–5.



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Author ContributionsVítor Devezas – Conception of the work, Design of the work, Acquisition of data, Analysis of data, Interpretation of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Silvestre Carneiro – Conception of the work, Design of the work, Acquisition of data, Analysis of data, Interpretation of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Laura Elisabete Barbosa – Conception of the work, Design of the work, Acquisition of data, Analysis of data, Interpretation of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

José A. Barbosa – Conception of the work, Design of the work, Acquisition of data, Analysis of data, Interpretation of data, Drafting the work, Revising the work critically

for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Guarantor of SubmissionThe corresponding author is the guarantor of submission.

Source of SupportNone.

Consent StatementWritten informed consent was obtained from the patient for publication of this article.

Conflict of InterestAuthors declare no conflict of interest.

Data AvailabilityAll relevant data are within the paper and its Supporting Information files.

Copyright© 2019 Vítor Devezas et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.

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