Esophageal cancer is relatively uncommon in the United States, with 16,910 new cases and 15,690 deaths anticipated in 2016 [1]. The major risk factors for esophageal adenocarcinoma include Barrett’s esophagus, gastroesophageal reflux, tobacco use and obesity [2]. The overall 5-year survival rate of patients diagnosed with esophageal cancer ranges from 15% to 25% [3]. Cases of cardiac metastasis from esophageal cancer are rare, but the incidence of cardiac metastases has risen over the last 30 years, perhaps attributable to increased life expectancy in oncologic patients benefitting from advances in cancer diagnosis and management. We herein report the diagnostic challenge and multidisciplinary management of a rare case of gastroesophageal junction (GEJ) adenocarcinoma, with diffused metastatic disease involving the brain, heart, lungs, liver and adrenal glands.

A 48-year-old gentleman with a history of Hepatitis C and cirrhosis was referred to oncology for a consultation. He underwent right liver lobe radiofrequency ablation for a liver mass, which was demonstrated by an abdominal CT scan two years ago (Figure 1). Initial differential diagnosis included hepatocellular carcinoma but AFP was within normal range and CA19-9 and CEA were elevated. An impression of metastasis from the gastrointestinal tract was investigated. A PET scan showed focal increased FDG avidity of the esophagus, the left ventricle/ pericardium, multiple bilateral pulmonary nodules, and bilateral adrenal gland (Figure 2). An Esophagogastroduodenoscopy was performed, which showed a GEJ mass; and biopsy showed esophageal adenocarcinoma. HER2/neu amplification was demonstrated by fluorescence in situ hybridization (FISH). Adrenal mass biopsy showed metastatic adenocarcinoma, immunohistochemically positive for CDX-2, CK 20, CK7 (focal) and negative for TTF-1.

Figure 1: (A) Abdominal CT showing ill-defined arterial enhancing lesion within the right lobe of the liver measuring approximately 3.2 × 2.6 × 2.4 cm. (B) No definitive residual tumor identified after right lobe liver ablation.

Figure 2: (A) Echocardiography showing a mass in the apical region of the left ventricle. The mass measures 2.14 cm × 1.32 cm in size. (B) Cardiac MRI scan demonstrating a focal mass in the apex of the lumen of the left ventricle measuring 2.3 × 2.3 × 2.1 cm.

An Electrocardiogram showed sinus tachycardia with frequent ventricular premature complexes, right bundle branch block with marked T-wave abnormality. A Transthoracic echocardiogram showed a mass in the apical region of the left ventricle measuring 2.46 cm × 1.32 cm (Figure 3A). The estimated ejection fraction was 60-65%. Cardiac MRI showed a 2.3 cm mass in the apex of the left ventricle (Figure 3B). A CT scan of the head revealed a mass in the third ventricle, a left frontal lobe mass and obstructive hydrocephalus (Figures 4A and 4B). A MRI of the brain showed a heterogeneously enhancing T1 hyperintense pineal region mass measuring 1.9 cm × 2.2 cm × 2.0 cm (Figure 4C). Peripheral blood ctDNA analysis showed mutations in TP53, AR, PIK3CA, and Erbb2 amplification. The patient was subsequently seen by a multidisciplinary team that included medical oncologists, radiation oncologists, interventional radiologists, cardiologists, thoracic surgeons and neurosurgeons. After a full recovery from left ventriculoperitoneal shunt for obstructive hydrocephalus, the patient was started on a combination regimen of trastuzumab, capecitabine and oxaliplatin. After the three cycles of chemotherapy, repeated PETCT scan demonstrated complete resolution of FDG avidity of left ventricle/pericardium, significant decreased avidity and size of adrenal gland masses, esophageal mass (Figures 2) and lung nodules. He also had a significant tumor marker reduction: CEA from 60.7 to 19.7 ng/mL (67.5%) and CA 19-9 from 2104 to 139 Units/mL (93.4%) (Figure 5). Currently, the patient remains active and his treatment is ongoing.

Figure 3: PET CT scan: (A) Mild focal increased FDG avidity of the left ventricle/pericardium, thick-walled esophagus with focal increased FDG avidity. (B) Bilateral FDG avid adrenal gland masses, right mass measuring 2.1 × 3.0 cm, left measuring 5.0 × 5.1 cm. (C) Resolution of FDG avidity of the left ventricle/pericardium and decrease avidity of primary esophageal mass after combination chemotherapy consisting of trastuzumab, capecitabine and oxaliplatin. (D) Decreased avidity and size of adrenal gland masses mass after combination chemotherapy consisting of trastuzumab, capecitabine and oxaliplatin.

Figure 4: (A) Head computed tomography scan demonstrating 2.2 × 1.7 cm dense mass in the posterior 3rd ventricle with internal calcifications. (B) Head computed tomography scan demonstrating mild to moderate hydrocephalus. 1.1 × 2.3 cm dense extra-axial mass in the left anterior parafalcine region. (C) Brain MRI: pineal region mass measuring 1.9 cm AP × 2.2 cm width × 2.0 cm length.

Figure 5: CA19-9 and CEA reduction after chemotherapy treatment with trastuzumab, capecitabine and oxaliplatin.

The two major subtypes of esophageal cancers are squamous cell carcinoma and adenocarcinoma. Barrett’s esophagus, tobacco use, obesity and gastroesophageal reflux disease (GERD) are associated with an increased risk of esophageal adenocarcinoma. Myocardial metastasis from esophageal cancer is rare [4]. Pericardium and epicardium (53%) are the most common sites of cardiac metastases, followed by myocardium (41%) and endocardium (6%). 33% of metastases invade the left ventricle & left atrium, 22% the right ventricle & right atrium and 7% invade the ventricular septum [5]. The routes of cardiac metastasis include the hematogenous route to the myocardium and endocardium, which is the most common route, the lymphatic route to the pericardium and direct invasion from adjacent tumors [6]. After an extensive literature search, we identified nine reported cases of cardiac metastasis from esophageal cancer (Table 1). All of these reported cases showed a poor prognosis. Surgical resection was performed in two patients (cases 5 and 8) to avoid sudden death due to complete obstruction of the right ventricular outflow tract by the tumor. All previously published cases involved squamous cell carcinoma, but our case involves adenocarcinoma. It seems that the clinical prognosis is usually disappointing regardless of whatever treatment is selected, and patients usually die within one year on an average from diagnosis with cardiac metastasis. Cardiac metastasis presentations include pericardial effusion, pericardial tamponade and arrhythmia. ECG may mimic acute myocardial infarction with ST elevation. Clinicians may raise concerns regarding cardiac metastasis in patients with a history of cancer who present with cardiac symptoms and ECG changes. CT chest, MRI, echocardiography and FDG/PET scans are efficient in diagnosing cardiac metastases.

Table 1: Cases of cardiac metastasis from esophageal cancer.

A multidisciplinary approach in a tertiary cancer center setting is essential for the optimal management of rare and aggressive cancers. Teams of specialists can balance the therapeutic efficacy, side effects and quality of life to develop the best individualized treatment plan. Davies et al. study also found that a multidisciplinary team approach significantly improves staging accuracy for gastro-esophageal cancers and leads to better management decisions for individual patients [7].

Circulating tumor DNA (ctDNA) is naked tumor DNA present in the plasma, which originates from tumor cells undergoing lysis, necrosis or apoptosis. ctDNA carries tumor-specific sequence alterations, and sequencing could be performed to detect somatic genomic alterations. It is an emerging noninvasive biomarker to monitor tumor dynamics, tumor genotyping and treatment response in metastatic breast and esophageal cancers [8,9]. Patients with advanced esophageal cancer are found to have significantly higher levels of ctDNA than healthy patients [10]. Mutations of TP53 and PIK3CA have been previously implicated in esophageal cancer. Lu et al. study revealed frequent mutations in TP53 (28.9%) and PIK3CA (4.4%) in esophageal cancer [11]. The use of ctDNA technology generated a novel therapeutic intervention in our patient. ctDNA provides molecular diagnostic information and a real-time, noninvasive approach for monitoring the therapeutic effects of chemotherapy. Representing as liquid biopsy, it could enable physicians to expand their knowledge of genetic mechanisms, provide personalized treatment and apply therapeutics more effectively.

The erbB-2 (HER2) is one of the members of the Epidermal Growth Factor Receptor (EGFR) family. This tyrosine kinase receptor has an intracellular tyrosine kinase activity and extracellular binding domains. The erbB-2 oncogene encodes a truncated form of EGFR that contains constitutive tyrosine kinase activity [12]. The overexpression and gene amplifications of erbB-2 have been demonstrated in 20% to 60% of patients with esophageal carcinoma [13]. Phase 3 clinical trials demonstrated clinical activity of trastuzumab in combination with chemotherapy in patients with HER2-positive advanced gastroesophageal junction cancer [14,15]. The concordance of erbB- 2 amplification in ctDNA and tumor tissue analysis is encouraging. Prospective trials will be needed to evaluate the clinical utility and cost effectiveness of ctDNA in the management of metastatic esophageal cancer.

In conclusion, this case presents a rare presentation of diffuse metastasis that includes cardiac metastasis from esophageal adenocarcinoma. A multidisciplinary approach is essential for optimal management of such aggressive cancers. The concordance of erbB-2 amplification in ctDNA and tumor tissue analysis is encouraging. The utility of ctDNA in patients with esophageal adenocarcinoma warrants further investigation in prospective clinical trials.