Brain Metastasis from Esophageal Cancer

Introduction

Esophageal cancer (EC) is one of the eight most common cancers throughout the world. The incidence of esophageal cancer varies worldwide with the highest rates in Eastern Asian and Southern African countries and the lowest rates in Western Africa, Central Africa, and Central America ( ). The worldwide incidence and the mortality rate of esophageal cancer are 3.2% and 4.9%, respectively ( ).

The most common forms of esophageal cancer are esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). Clinical outcome of patients with esophageal cancer is greatly affected by the extent of tumor dissemination and metastasis. Lymph nodes (including celiac lymph nodes and supraclavicular lymph nodes), liver, and peritoneum are the most common sites of metastasis from EC ( ). Other rare but important distant metastasis of esophageal cancer to lung, bone, or brain, as well as bone marrow involvement, has also been reported ( ).

Although brain metastasis is the most common neurological complication of systemic cancers with a poor prognosis, brain metastasis from esophageal cancer is a rare phenomenon with an incidence of approximately 1–3.6% ( ). On the other hand, the low incidence of brain metastasis from esophageal cancer can be due to underestimation, because brain imaging is not a routine diagnostic procedure in cancer patients without neurological symptoms ( ).

Over the recent decades, as a result of advances in diagnostic methods and therapeutic options, management of patients with brain metastasis from primary cancers has improved. However, for the brain metastases from esophageal cancer, basically due to the small number of reported cases, our knowledge is limited and their management is still controversial. In this chapter, we review the available literature on the brain metastasis of esophageal cancer.

Incidence

The real incidence of brain metastasis from esophageal cancer is unknown. To date, brain metastasis from esophageal cancer has remained a relatively rare phenomenon with a limited number of reported patients. Its incidence has been suggested to be approximately 0–2% in clinical studies and 0–5.1% in autopsies ( ). In a recently published series in 2014 on 1612 EC patients with primary esophageal cancer, 1.61% had brain metastasis ( ). In another large study published in 2002 by Ogawa et al., 1.4% of cases out of 2554 patients were identified to have brain metastases ( ). Moreover, in a case series on 1588 patients, the incidence of brain metastasis from esophageal cancer was found to be 1.7% ( ). A list of published studies on esophageal cancer patients with brain metastases has been summarized in Table 10.1 .

Clinical Presentations

Esophageal carcinoma is mostly asymptomatic at the beginning. When it becomes symptomatic, the symptoms are categorized into: (1) local tumor effects; (2) invasion to adjacent structures; and (3) distant disease. The most common complaint in patients with esophageal cancer is dysphagia which is due to the stricture of the lumen and is usually progressive. To overcome dysphagia, patients usually change their diet to small bites followed by soft or liquid food in the late stages. Therefore, they may not recognize the presence of any swallowing problem, due to the adaptive change of their diet; however, they may lose weight because of the diet changes and lack of energy intake. Chest pain and odynophagia along with cough, regurgitation and salivation, and gastrointestinal (GI) bleeding are other local symptoms. Invasion to adjacent structures may present with respiratory fistula, hoarseness due to recurrent laryngeal nerve invasion, and hiccups as the results of phrenic nerve invasion. Paraneoplastic symptoms (e.g., hypercalcemia majorly in ESCC), pneumonia, and symptoms of the metastasis (e.g., to lung, liver, bone, and brain) are other symptoms of the esophageal cancer. In physical examination, cachexia, supraclavicular lymphadenopathy, pleural effusion, and hepatosplenomegaly may be detected ( ).

The interval between the diagnosis of the primary tumor in the esophagus to the discovery of brain metastasis, or brain disease-free interval, ranges from 5.6 to 30 months in clinical studies with a median of 13 months ( ). A number of neurological symptoms might happen in patients with brain metastasis. Headache, motor deficit, gait disturbance, speech deficit, personality changes, nausea, visual defects, sensory deficit, cranial nerve deficit, and vomiting are the most common symptoms. Increased intracranial pressure as a result of the metastasis can lead to nausea and vomiting which might be mistakenly attributed to the primary tumor in esophagus ( ).

Risk Factors

A large number of risk factors have been identified for esophageal cancer. These vary dramatically between EAC and ESCC. Major risk factors for the EAC are Barrett’s esophagus, gastroesophageal reflux, and obesity; while tobacco use, alcohol consumption, and nutritional imbalance have been identified as the risk factors of ESCC ( ). Gastroesophageal reflux alone increases the risk of EAC by three fold, whereas Barrett’s esophagus, a metaplastic transformation of the normal stratified squamous esophageal epithelium, increases the risk of EAC by 30-folds ( ). Obesity, as a consequence of overnutrition, is a risk factor that may lead to gastroesophageal reflux and subsequent EAC ( ). Nitrosamines, found in salted vegetables and preserved foods, have also been confirmed as powerful carcinogens in esophageal cancer ( ). Human papillomavirus (HPV) is another important risk factor for ESCC ( ). Moreover, genetic alteration and abnormalities may lead to esophageal cancer ( ).

Studies have shown that large primary esophageal tumor and advanced stages are two major risk factors in the development of brain metastasis. noted that more than 80% of brain metastasis from esophageal cancer are found in stages III or higher. Moreover, reported that 70% of their metastatic patients were in stage IV of esophageal cancer. Similar findings have been reported by indicating more than 70% of esophageal cancer patients with brain metastasis were in stages III or higher.

reported a significant difference between the size of tumor in patients with and without brain metastasis. They showed a mean tumor size of greater than 8.63 cm in patients with brain metastasis compared to a size less than 5.12 cm in patients diagnosed with no metastases. have also found a mean tumor size of 6.0 cm in patients with brain metastasis. They concluded that proper management of the primary esophageal tumor can decrease the rate of brain metastasis and may influence the time to brain metastasis. Despite these reports, our knowledge of the risk factors of brain metastasis from esophageal cancer is restricted. Therefore, more studies on larger databases are necessary.

Histology

Contradictory results have been published on the histology of esophageal carcinoma and its relation to brain metastasis. In Western countries, EAC has been the most prevalent histology in brain metastases from esophageal carcinoma ( ); while in Asian countries such as Japan and China, ESCC is the most common histological type ( ). These results may be due to the current higher prevalence of EAC in Western countries and ESCC in Asia. It has also been suggested that tumor histology is not an independent risk factor for esophageal brain metastasis ( ). Another reported subtype is basaloid squamous cell carcinoma which has a poor prognosis ( ).