해외 증례(China) Gastric neuroendocrine tumors in a BRCA2 germline mutation carrier: A case report

관리자
2023-09-12
조회수 47

World J Gastrointest Oncol 2023 August 15;15(8):1497-1504, DOI: 10.4251/wjgo.v15.i8.1497

* WHO에서는 gastric neuroendocrine tumors (NETs)를 4가지 형태로 나누고 있으며, 

: Histamine-producing enterochromaffin-like NETs (ECL-cell NETs)

: Somatostatin-producing D-cell NETs

: Gastrin-producing G-cell NETs

: Serotonin-producing enterochromaffin-cell NETs (EC-cell NETs) 

* ECL-cell NETs에서는 clinicopathological characteristics에 따라서

: Type 1, Type 2, Type 3로 나누며, Type 1 ECL-cell NETs가 거의 80~90%를 차지하며, autoimmune gastritis (AIG), anti-parietal cell antibodies (PCAb), and/or anti-intrinsic factor antibodies (IFAb)와 관련이 있습니다. 

* Gastric NETs에서 보이는 molecular changes에는

: Loss of heterozygosity or mutation of MEN1, CDKN1B gene mutation, P27 heterozygous mutation, ATP4A gene missense mutation이 있으며, 최근까지도 계속 연구 중에 있습니다.

* 이번 case는 BRCA2 gene germline mutation를 가진 type 1 ECL-cell NETs에 대한 첫 report 되는 case 입니다. 


CASE PRESENTATION 

Chief complaints 

A young woman was admitted to our hospital because of recurrent abdominal discomfort. 

History of present illness 

The patient's symptoms had lasted for 2 mo. 

History of past illness 

The patient had a history of iron-deficient anemia for 5 years, which was treated with oral iron. The patient had no history of prior surgeries. 

Personal and family history 

The patient did not disclose any family genetic or aggregation diseases. Other family members had no clear history of cancers. 

Physical examination 

The physical examination of the patient showed no abnormalities, and there were no obvious signs or symptoms of anemia, such as pale oral mucosa. 

Laboratory examinations 

Routine blood test results showed that the patient’s hemoglobin level was 106 g/L (normal range: 113-151 g/L). Biochemical indices were all normal. The levels of tumor markers, such as alpha-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 125, and carbohydrate antigen 19-9, were all normal. Serum ferritin was markedly lower than normal at 1.8 U/mL (normal range: 7.0-323.0 U/mL).

Imaging examinations 

The patient next underwent gastroscopy and abdominal ultrasound examination. Gastroscopy showed that there were multiple grain-like protrusions in the great curvature of the stomach, with a hyperemic erosive focus found in the middle of the great curvature of the stomach (Figure 1). Abdominal ultrasound examination showed no abnormalities.

Figure 1. Polyps and a ulcer of the gastric mucosa could be seen under an endoscope. A: Gastric mucosa atrophy and polyps were seen; B: A superficial ulcer with central scar-like changes was seen in the large curvature of the central part of the stomach.


FINAL DIAGNOSIS 

The patient underwent a biopsy after gastroscopy for pathological examination. Tumor cells could be seen in the lamina propria of the gastric mucosa in the pathological analysis of the biopsy sample. Immunohistochemically, the tumor cells diffusely expressed cytokeratin (CK), chromogranin A (CGA), synaptophysin (Syn), and CD56, indicating that the tumors were gastric NETs. 


TREATMENT 

Because gastroscopy revealed multiple lesions in the stomach, the patient underwent distal gastrectomy surgery, and the excised distal gastric tissue was sent for pathological examination.

Gross finding: several polyps, 4-5 mm in diameter, were found in the antrum 

Microscopic findings:

Multiple foci of tumor cells were found in the mucosa and submucosa, with tumor cells being organoid and arranged in nests and cords, with mild atypia; mitotic figures were not easily visible, and the stroma was rich in sinusoids (Figure 2).

Figure 2. Pathological morphology of gastric neuroendocrine tumors. A: Under low-power magnification, a neuroendocrine tumor was shown to infiltrate into the surrounding tissues; B: Under high-power magnification, tumor cells were rich in blood sinuses. 


The surrounding gastric mucosa showed atrophy with mild intestinal metaplasia or pseudopyloric gland metaplasia (Figure 3).

Neuroendocrine cells: diffuse linear, nodular, and adenomatous hyperplasia

Nests of neuroendocrine cells: observed at the upper resection margin but not at the lower margin

No tumor metastasis was observed in the surrounding lymph nodes  

Figure 3. Pathological changes of atrophic gastritis in the gastric corpus mucosa. A: Under low-power magnification, a reduction in the number of gastric fundus glands was seen; B: Under high-power magnification, gland intestinal metaplasia and lymphocyte infiltration were seen.


Immunohistochemical stain (Figure 4.)

: CK, CGA, Syn, and CD56. MLH1, PMS2, MSH2, and MSH6 were positive 

: CK20 and CDX2 were negative 

: Gastrin in the surrounding gastric mucosa was negative or focally positive

Figure 4. Immunohistochemical findings. A-C: The tumor cells were strongly positive for CgA (A), Syn (B), and CD56 (C); D: Immunohistochemical staining showed that gastrin was absent. An image showing positive immunohistochemical staining for gastrin is presented in the lower right corner as a positive control for comparison. 

* Tumor cells were positive for neuroendocrine markers, with 1 mitotic cell/2 mm2 at high magnification, and the Ki-67 index was 1%. The diagnosis was gastric NETs (G1)

* Anti-parietal cell antibodies were positive


Whole-genome high-throughput molecular sequencing 

: pathogenic germline mutation in the BRCA2 gene, a heterozygous germline frameshift mutation in exon 11, c.6443_6444del (p.S2148Yfs*2) (Figure 5).

Figure 5. Next-generation sequencing showed the presence of a heterozygous germline mutation in BRCA2 exon 11, c.6443_644del, (p_s2148Yfs*2). The upper and lower parts in the figure are tumor and control, respectively.

OUTCOME AND FOLLOW-UP 

The patient has been followed up to date, with regular routine blood examinations and semiannual gastroscopies performed. The patient still has anemia at present, and gastroscopies have shown no abnormalities. The latest routine blood test results showed a hemoglobin level of 72 g/L (normal range: 113-151 g/L). However, ultrasound examination revealed a cyst in the left ovary, with a diameter of < 2 cm, and the cyst was only regularly followed up without further treatment. 


DISCUSSION 

* BRCA2 gene

: long arm of chromosome 13 (normally expressed in breast cells)

: involved in DNA damage repair

* Germline mutation of the BRCA2 gene

: prostate neuroendocrine carcinoma, gallbladder neuroendocrine carcinoma, ovarian non-small cell neuroendocrine carcinoma

: hereditary diffuse gastric cancer syndrome

: 하지만, pathogenesis of gastric NETs에서 정확한 BRCA2 germline mutations 역할에 대해서는 추가 연구가 필요합니다. 

* Type 1 ECL-cell NETs 

: usually small (< 1 cm), median diameter of 5 mm, prone to recurrence, can be complicated by gastric adenocarcinoma 

: tumor diameter is greater than 1 cm 이면 metastasis 위험성도 있습니다. 

: Netazepide (YF476) (gastrin/CCK-2 receptor antagonist) 사용 시 치료 1년 뒤 eradication 되었다는 연구가 있습니다. 

: Somatostatin analogs (SSAs): gastrin 분비를 억제하고 ECL cells의 proliferation을 억제하여 종양의 크기를 줄이거나 recurrence를 억제할 수 있어서, multiple, unresectable, relapse-prone type I gastric NETs 에서 선택적으로 치료해 볼 수 있습니다. 

: Tmors with BRCA2 gene germline mutations에서 PARP inhibitors가 효과가 있으므로, 추후 patients with type 1 ECL-cell NETs with a BRCA2 gene germline mutation에서 사용이 도움이 되는지 추가 연구가 필요할 것으로 보입니다.


CONCLUSION

This is the first case report of gastric NETs (type 1 ECL-cell NETs) with a pathogenic germline mutation of the BRCA2 gene. The findings presented in this report will expand the germline mutation spectrum of gastric NETs and increase the understanding of the molecular changes present in gastric NETs for the improved diagnosis of gastric NETs in the future.


Abstract 

BACKGROUND The molecular changes present in gastric neuroendocrine tumors (NETs) include a loss of heterozygosity or mutation of MEN1, CDKN1B gene mutation, P27 heterozygous mutation, and ATP4A gene missense mutation. We identified and are the first to report a case of type 1 histamine-producing enterochromaffin-like cell NETs (ECL-cell NETs) with a BRCA2 gene germline mutation. 

CASE SUMMARY The patient had a history of iron-deficient anemia for 5 years, and gastroscopic examination indicated multiple gastric tumors. Then, the patient underwent distal gastrectomy. Microscopically, multifocal tumor cells were found in the mucosa and submucosa; tumor cells were organoid and arranged in nests and cords, and the stroma was rich in sinusoids. The surrounding gastric mucosa showed atrophy with mild intestinal metaplasia or pseudopyloric gland metaplasia. Neuroendocrine cells could be seen with diffuse linear, nodular, and adenomatous hyperplasia. Immunohistochemically, the tumor cells diffusely expressed cytokeratin, chromogranin, synaptophysin, and CD56. Whole-genome highthroughput molecular sequencing revealed a pathogenic germline mutation in the BRCA2 gene, a heterozygous germline frameshift mutation in exon 11, c.6443_6444del (p.S2148Yfs*2). The final diagnosis was gastric type 1 ECL-cell NETs with a BRCA2 gene germline mutation, accompanied by autoimmune gastritis. 

CONCLUSION This is the first report of a case of type 1 gastric ECL-cell NETs with a pathogenic germline mutation of the BRCA2 gene. The findings of this report will expand the germline mutation spectrum of gastric NETs and increase the understanding of the molecular changes present in these tumors for their improved diagnosis in the future.


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주소 : 경기도 용인시 기흥구 중부대로 579, 508-23호 (구갈동, 강남대프라자)

대표전화 : 070-8080-0453  이메일 : autogastritis@gmail.com 


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