|Year : 2014 | Volume
| Issue : 8 | Page : 296-303
Neuroimaging and clinical characteristics of brain metastases from esophageal carcinoma in Chinese patients
Wei Feng, Peng Zhang, Xiao Zheng, Guoping Shan, Ming Chen, Weimin Mao
Department of Radiation Oncology, Zhejiang Key laboratory of Radiation Oncology, Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
|Date of Web Publication||17-Feb-2015|
Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022
Source of Support: This work was supported by grants from the Zhejiang Province Science and Technology Project of Traditional Chinese Medicine (2011ZB017) and the Talent Project of Medical and Health Sciences Fund of Zhejiang Province (2012RCB005), Conflict of Interest: None
Objective: The objective was to describe the magnetic resonance imaging (MRI) and clinical characteristics of brain metastases from esophageal carcinoma diagnosed in patients from the Zhejiang Province of China, in order to provide a useful reference for the future diagnosis and treatment of similar patients.
Materials and Methods: Medical data were obtained for 31 patients who received treatment for brain metastases from esophageal carcinoma at the Zhejiang Provincial Cancer Hospital between January 1998 and July 2013. For this retrospective analysis, the primary tumors were pathologically confirmed. In addition, 6 cases had both pathologic records of brain metastasis events and complete MRI records available. Survival follow-up data were also obtained.
Results: Thirty-one patients (30 males, 1 female) with a total of 62 tumors were diagnosed with squamous cell carcinoma (n = 26), adenocarcinoma (n = 3), and small cell carcinoma (n = 2). While most patients complained of movement disturbance (51.6%) and headaches (32.3%), MRI characterized tumors with cystic elements (80.6%), tumors with thin cyst walls and enhancement (59.7%), and tumors with a peripheral edema zone <2 cm in diameter (59.7%). Moreover, a major radiological indicator for prognosis was a shift of midline.
Conclusion: Most of the patients with brain metastases from esophageal carcinoma were male. Furthermore, many of the T1-weighted MRI images detected thin wall, enhanced single or multiple cystic lesions with an edema zone <2 cm in diameter. These imaging characteristics may represent this type of brain metastasis.
Keywords: Brain metastasis, esophageal carcinoma, magnetic resonance imaging
|How to cite this article:|
Feng W, Zhang P, Zheng X, Shan G, Chen M, Mao W. Neuroimaging and clinical characteristics of brain metastases from esophageal carcinoma in Chinese patients. J Can Res Ther 2014;10, Suppl S4:296-303
|How to cite this URL:|
Feng W, Zhang P, Zheng X, Shan G, Chen M, Mao W. Neuroimaging and clinical characteristics of brain metastases from esophageal carcinoma in Chinese patients. J Can Res Ther [serial online] 2014 [cited 2020 Jun 4];10:296-303. Available from: http://www.cancerjournal.net/text.asp?2014/10/8/296/151536
| > Introduction|| |
Brain metastasis from esophageal carcinoma is very rare. Correspondingly, there are only 200 cases published in English that were reported in the Medline database between January 1977 and July 2013. Moreover, 97% of these patients were from the United States, Japan, and China. When a literature search was performed of Chinese and Japanese medical journal databases, an additional 50 cases were identified. However, most of these cases were reported at conferences in Japanese, and some data were reported more than once. In 2001, Takeshima et al.  reported radiological features of eight esophageal carcinoma patients in Japan, and no additional relevant literature has been published since. In addition, it remains unclear whether the features reported for these cases are similar to those of affected Chinese patients.
As magnetic resonance imaging (MRI) has been more widely applied, both clinical and radiological physicians have been able to better understand the neuroimaging and clinical features of brain metastases from esophageal carcinoma.  Moreover, MRI has enabled the early detection of this condition. However, metastasis of esophageal carcinoma can occur without neurological symptoms, and brain metastasis can occur before an esophageal carcinoma is detected. Thus, detection of esophageal carcinoma is particularly critical in countries where the incidence of this disease is high.
The onset of esophageal carcinoma is characterized by local infiltrative growth and lymph node invasion. Furthermore, as the tumor progresses, metastases can develop in lung, liver, pleura, stomach, peritoneum, kidney, renal capsule, bone, and brain tissues via the bloodstream , . After computed tomography (CT) had been introduced for clinical use in the 1970s, brain metastasis from esophageal carcinoma began to be reported clinically. ,,,,, However, the majority of esophageal carcinoma reports were still based on autopsies. , With the clinical application of MRI, a larger number of reports of esophageal carcinoma have been published, ,,,,,,,,, although, few reports have described both MRI findings and clinical features. Worldwide, the incidence of brain metastases from esophageal carcinoma ranges from 0.3% to 13%. ,,, In the present study, 31 cases involving brain metastases from esophageal carcinoma were identified in the Zhejiang Province of China between 1998 and 2013. The radiological and clinical features of these patients were retrospectively reviewed in order to potentially identify useful references for this type of metastasis.
| > Materials and methods|| |
Patients who received treatment for brain metastases from esophageal carcinoma at the Zhejiang Provincial Cancer Hospital between January 1998 and July 2013 were included in this retrospective study. All of these patients had pathologically confirmed esophageal carcinoma and following treatment were readmitted due to metastasis of esophageal carcinoma to the brain.
All patients underwent a cranial MRI scan and a contrast-enhanced scan. For 3 cases of the present cohort, the scans were performed using a 3.0-T unit. Spin-echo (SE) T1-weighted images (TR 1500, TE 9.0), T2-weighted images (TR 5500, TE 95), and contrast medium (gadolinium-diethylenetriaminepentaacetic acid [Gd-DTPA]) enhanced T1-weighted images (TR 1500, TE 9.0) were collected. The other 28 cases had scans performed using a 1.5-T unit. SE T1-weighted images (TR 380, TE 7.7), T2-weighted images (TR 3000, TE 111), and Gd-DTPA enhanced T1-weighted images (RE 380, TE 7.7) were collected.
The Statistical Package for Social Sciences version 18 (SPSS Inc., Chicago, IL, USA) was used to perform statistical analyses. Survival analysis was performed using the Kaplan-Meier method. A P < 0.05 was considered statistically significant.
| > Results|| |
For the present cohort, 29/31 patients were from China, 30/31 patients were male, and the median age at diagnosis was 60 years (range: 42-74 year). The duration of follow-up ranged from 2 to 146 months, and 26/31 patients did not survive. [Table 1] lists the general characteristics of the present cohort, including the time between diagnosis of the primary esophageal carcinoma and the discovery of brain metastases. Details of the treatment regimens that were applied are also provided.
|Table 1: Summary of 31 patients with brain metastases from esophageal carcinoma|
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The mean interval between the diagnosis of primary esophageal carcinoma and radiological confirmation of a brain metastasis was 13.36 months (range: 0.43-55.20 months). While 4 patients developed a brain metastasis one month after their diagnosis of esophageal carcinoma, 11 patients did not present with neurological symptoms. In addition, the majority of the patients were diagnosed with stage III or stage IV esophageal carcinoma before their brain metastases were detected. In contrast, brain metastases did not develop for more than 3 years following the diagnosis of patients with stage I or stage II esophageal carcinoma.
Brain metastases were confirmed in 6 patients by craniotomy and by MRI for the remaining 25 patients. There were 26 (83.87%) cases of squamous cell carcinoma (SCC) and 2 cases of basal cell carcinoma (6.5%). Of the former, 2 cases were well-differentiated (6.5%), 15 cases were moderately differentiated (48.4%), and 7 cases were poorly differentiated (22.6%). There were also 3 patients with well-, moderately-, and poorly differentiated adenocarcinomas (ACs) (each accounting for 3.2%); and 2 cases of small cell carcinoma (6.5%). Lesions were found in various regions of the esophagus, with 10 (32.3%) cases proximal to the locus medialis, 9 (29.0%) in the locus inferior, 1 (3.2%) in the locus superior and locus medialis, 9 (29.0%) in the locus medialis and locus inferior, and 3 in multiple regions (6.5%). Lesion length ranged from 1 to 9 cm (mean, 4.94 cm). Dual lesions were found in 5 patients. Patient #24 [Table 1] also had a history of lung cancer, while patient #27 had the liposarcoma. A total of 17 patients had metastases in other organs (liver [n = 3], lung [n = 8], and bone [n = 6]).
The main clinical symptoms of brain metastasis were varying degrees of headache (n = 16) and movement disturbance (n = 10). [Table 2] lists additional signs and symptoms that were reported by the present cohort.
Distribution and number of lesions
In 18/31 (58.1%) patients, a single brain metastasis was detected, while 13/31 (41.9%) had multiple brain metastases (including 4 cases of anatomy position). Overall, there were 62 lesions identified in MRI scans by senior physicians. Most of the 62 lesions localized to the cerebrum, with 12 being in the frontal lobe, 24 in the parietal lobe, 6 in the temporal lobe, and 5 in the occipital lobe. The other 15 lesions localized to the cerebellum. Pathologically, 49 lesions were identified as SCC, of which 40/49 (81.6%) were located in the cerebrum and 9/49 (18.4%) were located in the cerebellum. In addition, 8 AC lesions were identified, with 7 (87.5%) in the cerebrum and 1 in the cerebellum. All five lesions of small cell carcinoma were located in the cerebellum [Figure 1]. There were no cases involving leptomeningeal or dural metastases, although 2 cases of skull metastases were identified.
T1-weighted images of 85.5% of the tumor rims detected exhibited either hypo-intensity (n = 26) or slight hypo-intensity (n = 27). Other lesions exhibited iso-intensity and slight hyperintensity on the same images. Similarly, 85.5% of the lesions detected in T2-weighted images also exhibited hyper-intensity (n = 35) and slight hyper-intensity (n = 18). Other iso-intense and hypo-intense lesions were also observed. It is possible that some of the tumors imaged may have contained fat or were hemorrhaged. In Gd-DTPA enhanced, T1-weighted images, homogeneous enhancement in single nodes was observed (14.5%), heterogeneous enhancement (21%) was observed, annular enhancement of lesions (59.7%) was observed, as well as nonenhancement (4.8%). In addition, the thickness of each lesion wall was not homogeneous. The mean thickness was 3.39 mm and ranged from 0 to 16.93 mm.
Lesion rims and sizes
It was difficult to define and measure the rim of most of the lesions detected in MRI images due to adjacent edema. However, using Gd-DTPA enhanced T1-weighted imaging, 74.2% of the lesions analyzed exhibited a well-defined rim. The minimum lesion size was
4.02 mm 3 × 4.02 mm 3 × 4.02 mm 3 , and the maximum lesion size was 53.46 mm 3 × 61.57 mm 3 × 59.89 mm 3 . Furthermore, 32/62 (51.6%) lesions had a diameter <20 mm.
Association between magnetic resonance imaging and pathologic types
To compare the radiological presentation of pathologically different carcinomas, the lesions of the present cohort were categorized as cystic, solid, or cystic + solid. These types were distinguished using enhanced MRI T1-weighted images [Figure 2] and the following criteria: (1) Cystic - A wall thickness <3 mm, having long signals on both T1- and T2-weighted images inside the cyst, and the presence of homogeneous enhancement [Figure 3]; (2) Solid - The absence of a wall, a long signal on T1-weighted images and a short signal on T2-weighted images inside the lesion, and either homogeneous or absent enhancement [Figure 4]; (3) Cystic + solid - A wall thickness ≥3 mm, a lobular sign, or the presence of a nodule in the cyst [Figure 5].
|Figure 3: A typical cystic lesion with homogeneous enhancement of its thin cyst wall. No nodule was observed, and the edema present was classified as level 2|
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|Figure 4: Following enhancement, a solid nodular lesion presented as a homogeneous nodule. A wide peripheral edema zone was also observed|
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|Figure 5: A heterogeneous signal was observed on a magnetic resonance imaging scan of a cystic + solid lesion following enhancement. Hemorrhage and necrosis signals and an obvious shift of midline were also detected|
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Tumors of various sizes at different locations may exhibit differing degrees of adjacent edema in the same patient. In the present study, five categories were used to describe the adjacent edema observed:  "0" - No edema [Figure 6]; "1" - An edema zone ≤2 cm [Figure 7]; "2" - An edema zone between 2 cm and half the cerebellar hemisphere [Figure 3] and [Figure 5]; "3" - An edema zone between half a cerebellar hemisphere and an entire cerebellar hemisphere; and "4" - More than two brain tissues exhibited an edema zone and at least one zone was equal to or greater than half a cerebellar hemisphere, or equal to or greater than an entire cerebellar hemisphere [Figure 8]. Lesions that were detected in the deep brain, cerebral cortex, and brainstem exhibited only slight edema or an absence of obvious edema in the present cohort.
|Figure 7: Cystic + solid lesion in the vermis of the cerebellum. A nodular lesion present in the cyst was observed following enhancement, accompanied by level 1 edema|
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Treatment and prognosis
Treatment was provided to all of the patients of this cohort following confirmation of their diagnosis. Four patients underwent surgical resection, radiation, and chemotherapy, 9 patients received radiation therapy applied to the brain, and 3 patients only received chemotherapy. In addition, 11 patients underwent both radiation and chemotherapy, while only 2 patients underwent surgical resection and received radiation therapy. There were 6 patients who received targeted drug treatment, including recombinant human endostatin injections, thalidomide, erlotinib hydrochloride tablets, and/or gefitinib tablets. Moreover, there were 2 patients who opted to receive traditional Chinese medical treatment instead of further radiation or chemotherapy due to progression of the primary tumor and the presence of other systemic metastases.
Survival following treatment ranged from 0.43 to 148.13 months. For 1 patient with SCC, he survived 12 years posttreatment. This patient underwent surgical resection, radiation, and chemotherapy for the treatment of the primary tumor, and then underwent surgical resection and radiation therapy 1 year later when a brain metastasis was detected. Based on this case, postsurgery adjuvant treatment for a single brain lesion may prolong a patient's survival [Table 3].
An indicator for prognosis was found to be a shift of brain midline by a lesion (P < 0.05), with the shift associated with a poor prognosis.
| > Discussion|| |
Based on the reported incidence of esophageal carcinoma in China (19.3/100,000), , the number of patients who have visited our hospital for the treatment of esophageal carcinoma in the past few years is relatively small. There are several possible reasons for this. First, patients with esophageal carcinoma are generally poor and do not visit a doctor until their condition becomes serious. Furthermore, some patients will decline treatment if diagnosed with late-stage esophageal carcinoma and metastases. Second, CT and MRI scans only became widely available in China after 1990. Prior to this, the cystic characteristics and insignificant edema zone of brain metastases often led to the misdiagnosis of esophageal carcinoma brain metastases. Thus, the actual incidence rate of brain metastases due to esophageal carcinoma is not able to be determined. For Western countries, the incidence of brain metastasis from esophageal AC has been reported to be as high as 13%,  while the incidence rate for brain metastasis from esophageal SCC has been reported to range from 0.3% to 5%. ,,, In a study conducted by Kanemoto et al. in 2011,  7/12 patients received a stage III recursive partitioning analysis evaluation, and 66% of them had multiple lesions. Moreover, the median survival period for these patients was 3.6 months. The poor prognosis of these patients may have been due to their median age (>65 year) when their esophageal carcinoma was diagnosed. In the present study, although the clinical and demographic features of the patients differed, the MRI scans showed similar features. Radiological evidence from more than 8 patients with esophageal carcinoma and brain metastases from Japan  may also verify the present results.
The most frequently reported clinical signs and complaints from patients with brain metastasis from esophageal carcinoma have previously been reported to include: Fatigue (58%), headaches (28%), seizures (22%), and cerebellar dysfunction (14%).  In the present study, the most common complaints were movement disturbance (16/31, 51.6%) and headaches (10/31, 32.3%). Due to differences in the evaluation systems applied, "fatigue" was not considered to be a clinical symptom of immediate concern.
In the present study, lesions were classified as cystic, solid, and cystic + solid. For these categories, if cyst wall thickness and the presence of a nodule in a cyst had not been considered as criteria, lesions with cystic elements would have accounted for 80.6% of the lesions analyzed. However, cystic and solid lesions could both be present in the same patient. In our experience, solid lesions are usually small. Thus, it should be further investigated whether brain metastases are anemic, and whether this leads to increased intratumoral necrosis and cyst degeneration that is accompanied by rapid growth. Advances in radiological techniques have also improved the identification of solid lesions in their early stages. In cases where solid lesions were misdiagnosed as cerebral abscesses, encephalopuncture later confirmed the presence of malignant squamous cells. 
According to Weisberg,  13% of metastatic tumors have an annular enhanced cyst wall. In the present study, peripherally enhanced thin cyst walls (37/62, 59.7%) were more frequently observed compared to other common metastatic brain tumors. In [Table 4], imaging features of brain metastases associated with esophageal carcinomas that have been published since 2004 ,,,,,,,,, are presented. In particular, cystic, enhanced tumors with minimal edema were notable. Furthermore, six of the latter were ACs. Thus, typical MRI features of metastatic brain ACs derived from esophageal carcinoma may include cystic, enhanced tumors with mild edema.
|Table 4: MRI imaging of patients with brain metastasis from esophageal carcinoma reported in the literature between 2004 and 2013 (including ACs and SCCs)|
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In the present study, the average width of the edema zone for the lesions analyzed was 17.33 mm (maximum, 66.03 mm). Furthermore, level I edema was identified for 59.7% of the lesions analyzed. In a study by Kobayashi et al.,  metastatic lung SCC was found to have a higher probability of exhibiting severe edema than other types of lung tumors. However, other reports have indicated that level of edema is not significantly related to tumor type, and may instead be related to tumor location. , For example, white matter edema observed in the cortex, basal ganglia, and thalamus can be obvious, while edema in the brainstem is more difficult to detect. The development of tumor angiogenesis has also been associated with increased enhancement, which is consistent with the increased vascular permeability that characterizes this process. 
Expression of epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER-2) has been detected in brain metastases from esophageal carcinoma. ,,, Correspondingly, Geldart and Astras  have reported that trastuzumab, a monoclonal antibody that targets HER-2, is effective for a subset of patients who have failed treatment for brain metastases. These results also demonstrate the feasibility of applying targeted treatment to esophageal carcinoma patients. In the present study, a radiological indicator for prognosis was the shift of lesions across the brain midline. A shift of midline, which can be caused by cerebral edema, not only results in local pressure, but can also lead to mental dysfunction and the spread of tumor cells.
In China, patients with esophageal carcinoma are increasingly expressing a greater expectation for quality-of-life. Moreover, with the more widespread use of MRI scans for patients that present with neurological symptoms, detection of brain metastasis from esophageal carcinoma has been improving in recent years. Therefore, upon identification of a thin cyst wall, annular enhancement, and mild edema in an MRI scan of a patient with a history of esophageal carcinoma, brain metastasis should be considered.
| > Acknowledgments|| |
This work was supported by grants from the Zhejiang Province Science and Technology Project of Traditional Chinese Medicine (2011ZB017) and the Talent Project of Medical and Health Sciences Fund of Zhejiang Province (2012RCB005).
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3], [Table 4]