Retrospective Analysis of the Clinical and Image Presentation of Eight Primary Benign Mediastinal Schwannomas

Objective: Mediastinal schwannomas sometimes can be confused with other neoplasms in the initial radiological studies, especially when there is a history of cancer in another site and that require a more accurate analysis by computed tomography (CT) or even magnetic resonance (MRI). Our study was aimed to perform a retrospective analysis of the clinical and imaging features in a series of patients with mediastinal schwannomas that were conrmed by histology and immunohistochemistry. Results: We found eight patients, ve man and three women with an average age of 51 years. The main signs and symptoms at time of diagnosis were chest pain, dyspnea, cough and dysphagia. CT showed that the tumor was located in the posterior compartment of the chest in 7/8 cases. Tumors >10 cm were more heterogeneous and showed cystic changes. All cases underwent posterolateral thoracotomy and radiological follow-up showed no evidence of recurrence. Histological analysis was the gold standard to conrm diagnosis in addition to at least one neurogenic IHC marker. In conclusion, mediastinal schwannomas are benign encapsulated tumors. By CT, schwannomas >10 cm showed cystic degeneration more frequently. Posterolateral thoracotomy allows complete resection and is considered the surgical approach of choice. AFINES: Program to support and promote student research; CT: Computed tomography; 18 F-FDG PET/CT: 18 F-uorodeoxyglucose positron emission tomography and computed tomography; GFAP: Glial brillary acid protein; IHC: Immunohistochemistry; MRI: Magnetic resonance imaging; de Alta radiograph.


Introduction
Schwannomas are benign neoplasms that arise from Schwann cells that surround peripheral nerve bers. [1,2] Less than 9% of schwannomas occur in the mediastinum. [3] They often originate at the root of a spinal nerve and may involve the thoracic nerve. More than 90% of these lesions are unique and sporadic. [3] They have a peak incidence between fourth to sixth decades of life. [3] Even though there are case reports of giant mediastinal schwannomas, [4][5][6] they generally measure less than 5 cm at the time of diagnosis, they are characterized by its slow growing, and lack of speci c symptoms; therefore, a common presentation occurs as a well-de ned lesion without a mass effect while performing a radiographic study aimed to various other complaints. However, when schwannomas are large, it is possible for them to present by localized pain; histologically, common features are cystic degeneration, low cellularity, hemorrhage and small calci cations. [3] There are few studies in the Mexican population that analyze the characteristics of mediastinal schwannomas. [7,8] Our objective was to perform a retrospective analysis of the clinical and tomographic features of patients with primary benign mediastinal schwannoma.

Main Text
Material and methods Study design and population characteristics A retrospective study was performed that included patients with a diagnosis of mediastinal schwannoma. All cases were obtained from the surgical pathology archives of UMAE Hospital de Oncologia Centro Medico Nacional Siglo XXI. IMSS, from January 2011 to January 2018. Permission was requested in the clinical le to review patient records. Clinical features such as age, gender, time of evolution, type of treatment and follow-up data obtained from medical records. Its association with neuro bromatosis type 2, schwanomatosis and Gorlin-Koutlas syndrome was also investigated. From the radiology le, chest CT scans from each patient was obtained and submitted for re-assessment by two experienced radiologists who investigated the location, shape, size and features of each lesion (ALRC and LMH). All cases were reevaluated by three experienced pathologists (CCU, AMM and FCG) using the WHO criteria. [9] Immunohistochemistry All tissues were xed in formaldehyde buffered at 10% and para n embedded. Histological sections were stained with hematoxylin and eosin. For immunohistochemistry (IHC) analysis, 5-μm sections of a representative block in each case were obtained. The following antibodies were used: S100 protein (Biosb), glial brillar acid protein (GFAP; Invitrogen), CD34 (Biocare), and Ki-67 (Biosb), which were performed on an automated immunostainer (Ventana, Biotek System Tucson, Ariz) with an appropriate positive and negative control run simultaneously. Brie y, para n sections mounted on charged glass slides, air -dried over-night, and then de-para nized. To enhance immunostaining, a heat-induced epitope-retrieval procedure was performed. After incubation with blocking serum, sections were incubated with primary antibodies, followed by a biotinylated polyvalent secondary antibody solution. All sections were then incubated with horseradish peroxidase-conjugated avidin-biotin complex, followed by 3,3diaminobenzidine and hydrogen peroxidase.

Clinical features
During the period analyzed, 163 primary soft tissue tumors of the mediastinum were resected, of which only eight patients corresponded to mediastinal schwannomas (5%). Five men (63%) and three women (37%). The average age was 51 years (range, 32-78 years). The average age of the women was 43 years versus 56 years for men. Seventy-ve percent of the patients had symptoms. The main clinical manifestations were chest pain in four patients (64%), dyspnea in one patient (17%), cough in one patient (17%), dysphagia in one patient (17%) and two patients were asymptomatic (25%). No weight loss found in any patient. The average time of clinical evolution was 4 months (range, 1 to 6 months). In none of our cases was found an association with neuro bromatosis type 2, schwannomatosis or Gorlin-Koutlas syndrome.

Tomographic features
All patients had a chest X-ray and a chest CT, which allowed identifying the lesion. Chest X-ray lms showed a well-de ned round radiopaque mass in all cases. Only in three cases, a diagnosis of schwannoma was suspected at the time of CT. In one patient, the mediastinal tumor was identi ed as an asymptomatic nding secondary to a kidney transplant check-up. Other of our patients had a history of clinical stage IIB breast cancer, which in follow-up with chest X-ray revealed a mediastinal mass in the left hemithorax. Initially it was thought that it could correspond to recurrence of the disease. This was ruled out by performing a CT scan in which the diagnosis of schwannoma was proposed, leading the patient to a surgical approach.
In seven patients, the tumor was located in the posterior mediastinum (88%) by CT; in one of them, the mass was located in the posterior upper para-esophageal compartment. No patient had evidence of tumoral activity was observed elsewhere. In all cases, the mass was ovoid and well de ned. In four cases, the lesion was homogeneous and in four cases it showed heterogeneous reinforcement with hypo and hyperintense areas after the application of contrast material ( Fig. 1a and b).  . 1c and d). All cases were completely resected and in none was necrosis.

Immunohistochemistry ndings
By IHC, all cases were intensely positive for S100 protein in nucleus and cytoplasm, and showed focal expression of GFAP, mainly in Antonia A areas. Neither case showed expression for CD34. The proliferation index with Ki-67 was less than 1% in all cases. One cases (case # ve) showed hypercellularity with a storiform pattern in approximately 50% of the tumor mimicking solitary brous tumor. However, the neoplastic cells were positive for two neurogenic markers (S100 protein and GFAP) and negative for CD34 (Fig. 3).
Treatment and follow-up of patients All the patients underwent surgery through posterolateral thoracotomy and radiological follow-up. In four cases, the thoracotomy was on the left-sided versus three right-sided cases. In all patients the tumor resected completely. The mean follow-up of the patients was 27 months (range 0-48 months). All patients were found alive without clinical or radiological recurrence of the disease at their last visit. In none of the patients a malignant transformation of the disease was diagnosed.

Discussion
It is estimated that 9% of all schwannomas occur in the mediastinum. [10] Fifty percent of neurogenic tumors of the mediastinum are schwannomas. [3] In our series, schwannomas represented 5% of all soft tissue tumors of the mediastinum. More than 90% of schwannomas are solitary, sporadic, and slowgrowing neoplasms. These lesions affect both genders equally, all age groups reached a higher incidence between the fourth and sixth decades of life. [1][2][3] In our series, the average age was 51 years while women were found to be a decade younger than men.
The clinical history, physical examination and image evaluation must be considered. Mediastinal schwannomas can originate from spinal, paravertebral sympathetic branches, vagus, phrenic and intercostal nerves, respectively. [1][2][3]11] In our study, about half of cases originated in the paravertebral region. The classic presentation is an incidental asymptomatic mass found on routine investigations as simple as a chest X-ray. [12] Interestingly, some patients experience paresthesia or chest pain from compression of adjacent structures or extensions of the tumor in the thoracic spine. Other clinical manifestations are dry cough, dyspnea, and dysphagia. In our study and in contrast to other international publications, 57% of the patients had symptoms attributable to a mediastinal schwannoma. The ideal treatment consists of video-assisted thoracic surgery with complete resection of the mass because of its subsequent growth and mass-effect. [1][2][3] In our study, all patients underwent open posterolateral thoracotomy as standard.
CT and MRI can help accurately to determine the exact location of the mediastinal tumor and also de nes its relationship to adjacent structures. On CT scanning, schwannomas appears as well-de ned rounded mass with smooth margins, they are isodense or hypodense in the paravertebral region or long the courses of intercostal nerves. [13] They have a variable enhancement pattern after administration of the intravenous contrast material including multiple hypodense or cystic areas with central hypodensity and central enhancement, as well as peripheral hypodensity. [13,14] Calci cations are occasionally detected, and low attenuation correlates with areas of hypocellularity, cystic change, hemorrhage, and lipidisation. [3,15] While there are few cases reports of giant mediastinal schwannomas, these are often identi ed incidentally by chest X-ray, followed by CT scans that show a clearly de ned mass with low densities and mild enhancement. [4][5][6] Giant schwannomas are more heterogeneous with cystic degeneration. [3] In our series, cystic degeneration was observed more frequently in tumors larger than 10 cm. Tumors smaller than 10 cm were more frequently homogeneous with solid areas in the absence of cystic degeneration.
This supports the idea that degenerate changes directly related to the size of the tumor. Heterogeneous changes observed by CT have a histological translation. In our study, the schwannomas that were homogenous by CT more frequently identi ed in the histological analysis of classical areas Antoni A and Antoni B. While in tumors that were heterogeneous by CT scan, they presented microscopically extensive hypocellular areas with marked cystic degeneration, reticular pattern, edema, hemorrhage and sometimes calci cations. However, by IHC positivity for S100 protein con rms the diagnosis in all cases.
Mediastinal schwannomas can be misdiagnosed as lymph node metastasis from locally advanced breast cancer. [16] The clinical distinction between mediastinal schwannoma and metastasis in cases that have a history of cancer, can be di cult and requires its surgical removal and histopathological analysis. The location and composition through imaging studies are critical to make a differential diagnosis. Even through sophisticated studies such a 18 F-uorodeoxyglucose positron emission tomography and computed tomography ( 18 F-FDG PET/CT), mediastinal schwannoma can simulate metastases to breast cancer lymph nodes, as shown by Martinez-Esteve et al. [16] Similarly, we found a patient with a clinical history of stage IIB breast cancer during follow-up showed a mediastinal mass on a chest X-ray that was initially thought to be a recurrence of the disease. However, when a CT scan was performed, the site of origin of the tumor was de ned precisely and it proposed that it could correspond to schwannoma. Finally, it was resected and the histopathological analysis showed a schwannoma with diffuse expression of S100 protein and GFAP.
Cellular schwannoma are an infrequent variant with a predominantly cellular growth pattern, in the absence of Verocay bodies. Usually seen at paravertebral, pelvic, retroperitoneal, or mediastinal location. [17] This variant can be confused with a malignant peripheral nerve sheath tumor or with a solitary brous tumor. [18,19] In our study, we found only one case of a cellular schwannoma (13%) with storiform pattern mimicking a solitary brous tumor. The diagnosis of schwannoma was supported by light microscopy and corroborated by S100 protein and GFAP expression and negative for CD34.

Conclusion
Mediastinal schwannomas are benign encapsulated tumors, which on CT are more frequently located in the posterior compartment. Tumors >10 cm are usually heterogeneous with cystic degeneration. Posterolateral thoracotomy allows complete resection and is the surgical approach of choice. Histological analysis remains the gold standard to con rm the diagnosis along with IHC markers that include at least one neurogenic marker.

Limitations
It is a retrospective study with a small sample. Therefore, a large-scale study that includes a larger number of patients is necessary. Figure 1 Benign mediastinal schwannoma. a-b) CT imagen the tumor was located in the posterior mediastinum.
Tumor showed heterogeneous reinforcement with hypo and hyperintense areas after the application of contrast material; c) Macroscopic images of the well-encapsulated ovoid tumor with smooth surface, gray-yellow color; d) Cross section of the tumor shows solid areas with cystic degeneration.

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