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Gastric metastasis from ovarian adenocarcinoma presenting as a subepithelial tumor and diagnosed by endoscopic ultrasound-guided tissue acquisition

We describe an uncommon case of a patient with a metastatic adenocarcinoma of ovarian origin presented as a gastric subepithelial tumor (SET) and that was diagnosed by endoscopic ultrasound fine-needle biopsy (EUS-FNB). Malignant gastric lesions are rarely metastatic and the primary tumor is mainly breast, lung, esophageal cancer or cutaneous melanoma. Gastric metastasis from ovarian cancer is unusual, presenting synchronously with the primary tumor but also several years later than the initial diagnosis. From an endoscopic point of view, gastric metastasis does not present specific features. They may mimic both a primary gastric tumor or, less frequently, an SET. This case demonstrates the importance of EUS-FNB in distinguishing SETs and how this may alter treatment and prognosis.

Institutional review board statement: Since this is not a clinical study, this case report was not reviewed by the institutional review board.
Informed consent statement: Written informed consent for endoscopic examinations was obtained from the patient.
Conflict-of-interest statement: The authors state that they have no conflicts of interest regarding this case report.
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Abstract
We describe an uncommon case of a patient with a metastatic adenocarcinoma of ovarian origin presented as a gastric subepithelial tumor (SET) and that was diagnosed by endoscopic ultrasound fine-needle biopsy (EUS-FNB). Malignant gastric lesions are rarely metastatic and the primary tumor is mainly breast, lung, esophageal cancer or cutaneous melanoma. Gastric metastasis from ovarian cancer is unusual, presenting synchronously with the primary tumor but also several years later than the initial diagnosis. From an endoscopic point of view, gastric metastasis does not present specific features. They may mimic both a primary gastric tumor or, less frequently, an SET.

INTRODUCTION
Gastrointestinal (GI) subepithelial tumors (SETs) are lesions located under a normal-appearing mucosa that include several neoplastic and non-neoplastic conditions. Most of the GI-SETs are asymptomatic, therefore their real incidence is unknown. Stomach is the GI tract where the highest incidence is documented [1] . The diagnosis of SETs can be challenging because conventional endoscopic biopsies are frequently inconclusive. Endoscopic ultrasound (EUS) is currently recommended as the preferred investigation modality to establish the exact nature of SETs because of its accuracy in differentiating them from extrinsic compression and providing information about morphology and layer of origin [2] . Lesions arising from the muscularis propria usually represent mesenchymal tumors, such as gastrointestinal stromal tumors (GIST), leiomyomas and schwannomas [1,2] . Metastasis to the GI tract generally involves the fourth and fifth layers and can be misleading as a GIST [1,2] . Herein, we describe an uncommon case of a patient with a metastatic adenocarcinoma of ovarian origin presented as a gastric SET mimicking a GIST and diagnosed by EUS-guided tissue acquisition.

CASE REPORT
The patient was a 61-year-old woman diagnosed in November 2013 with stage Ⅳ high-grade serous carcinoma of the ovary treated with cycles of carboplatin and taxol chemotherapy with partial clinical response. After 1-year of therapy, due to the persistence of abdominal and pelvic disease, cytoreductive surgery had been performed. In June 2015, her CA125 levels had increased to 138 U/mL (normal value < 35 U/mL) and a computed tomography (CT) of the abdomen showed progression of the disease.
She was referred at that time to our endoscopic center for evaluation of dyspepsia. Upper GI endoscopy revealed an SET covered by normal mucosa on the posterior wall of the gastric antrum ( Figure 1). Biopsies of the overlying mucosa proved inconclusive. EUS showed a 23-mm mass within the muscularis propria, hypoechoic but more hyperechoic than the muscular tissue (Figure 2). EUS-guided fine needle biopsy (FNB)

Figure 2 Endoscopic ultrasonography showing a homogenous, hypoechoic mass within the muscularis propria (white arrows)
. Its echogenicity appears to be more hyperechoic than that of the muscle layer.
was performed for tissue diagnosis. Histology showed adenocarcinoma with immunohistochemistry positive for WT1 and CK7, and negative for CK20 and CDX2 (Figure 3). These findings supported the final diagnosis of a metastatic adenocarcinoma of ovarian origin. The patient started paclitaxel chemotherapy and was alive at the 18-mo follow-up visit.

DISCUSSION
Gastric metastasis is rare and has been reported mainly from breast, lung, esophageal cancer or cutaneous melanoma [3] . Ovarian carcinoma regularly metastasizes to the peritoneal surface [4] . The acquisition of invasiveness in ovarian carcinoma is accompanied by the process of epithelial to mesenchymal transition. Cancer-associated fibroblasts originating from stromal fibroblastic cells are a component of the tumor microenvironment and promote tumor angiogenesis and lymphangiogenesis [5] . Also, the MUC4 mucin has a role in the invasiveness of ovarian cancer cells because it is overexpressed in ovarian tumors. The overexpression of MUC4 in ovarian cancer is a morphological alteration, along with a decreased expression of epithelial markers (E-cadherin and cytokeratin-18) and an increased expression of mesenchymal markers (N-cadherin and vimentin) [6] . GI involvement from ovarian cancer is limited to the seromuscular layer of the small and large bowels but it also metastasizes through the lymphatic and hematogenous route, with a frequency ranging from 0.7% to 1.8% [7] . The stomach is highly vascularized, therefore the dissemination of ovarian carcinoma is possible but rare. Gastric metastasis from ovarian cancer is unusual, either as synchronous with the primary tumor or appearing several years after its initial diagnosis [8] . The diagnosis is challenging because of its low incidence. Clinical manifestations include epigastric pain, nausea, vomiting, anemia, melena or occult GI blood loss. Obstructive symptoms may WT1 CK7 CK20 CDX2 be present in case of involvement of the cardia or pylorus [9] . In asymptomatic patients, CA-125 levels beyond normal range may be the only warning sign [7,9] . The prognosis of gastric metastases of ovarian carcinoma is still unknown, a 1-year survival rate can be optimistically expected [10,11] . From an endoscopic point of view, gastric metastases do not present specific features. They may mimic both a primary gastric tumor or, less frequently, an SET [8,12] and can be solitary or more rarely multiple [13] . Several cases of metastatic ovarian cancer presenting as gastric SET have been reported in the literature [10,[13][14][15][16][17] but only few have been diagnosed by EUS-guided tissue acquisition, as in our case (Table  1). In other cases, surgical excision or endoscopic submucosal dissection with enucleation has been performed [8,11] . In the present case, the lesion was mimicking a GIST, even if a metastasis from ovarian cancer had been considered. For these reasons, a tissue diagnosis was considered necessary. After a diagnosis of metastatic ovarian cancer to the stomach had been achieved, surgical intervention or more aggressive options would become unnecessary considering the progression of the disease.
In conclusion, although rare, gastric metastasis from primary ovarian cancer should be considered in any patient with a history of ovarian adenocarcinoma who presents with gastric tumor. This case emphasizes the crucial role of EUS-FNB in the differential diagnosis.

Case characteristics
A 61-year-old woman diagnosed 3 years previously with stage Ⅳ highgrade serous carcinoma of the ovary and treated with debulking surgery and chemotherapy presented for evaluation of dyspepsia.

Clinical diagnosis
General physical examination was unremarkable.

Laboratory diagnosis
CA125 levels had increased to 138 U/mL (normal value < 35 U/mL).

Imaging diagnosis
Endoscopic ultrasonography (EU) showed a 23-mm mass within the muscularis propria, hypoechoic but more hyperechoic than the muscular tissue.

Pathological diagnosis
Histology obtained via EUS-guided fine needle biopsy showed adenocarcinoma with immunohistochemistry positive for WT1 and CK7, and negative for CK20 and CDX2, supporting the final diagnosis of a metastatic adenocarcinoma of ovarian origin.

Treatment
Palliative chemotherapy.

Related reports
Several cases of metastatic ovarian cancer presenting as gastric subepithelial tumor have been reported in the literature, but only few of them have been diagnosed by EUS-guided tissue acquisition, as in our case. In other cases, surgical excision or endoscopic submucosal dissection with enucleation has been performed.

Experiences and lessons
Although rare, metastatic ovarian cancer to the stomach should be considered in any patient with a history of ovarian adenocarcinoma who presents with gastric tumor.

Peer-review
This is an interesting case report.