Primary mediastinal tumors in children and adults: a clinicopathological spectrum

Introduction

Mediastinal tumors are a heterogenous group of unrelated neoplasms that share the mediastinal anatomical location. Mediastinal masses are rare neoplasms which usually affect adults, with an estimated incidence in the adult general population of 0.01% (1). The mediastinum is the central portion of the thoracic cavity in which many vital organs reside such as the heart and large vessels. Traditionally, the mediastinum has been divided into three compartments, anterior, middle and posterior (2), with preferences of some histological tumor types for each compartment. Therefore, thymomas and lymphomas predominate in the anterior compartment, germ cell tumors (GCTs) are more frequent in the middle compartment, while neurogenic tumors are more frequent in the posterior compartment (3).

The incidence of benign and malignant tumors in children and adults has contradictory results depending on the case series and predominance of tumor location (4-6). Multicenter studies in different continents have shown different distribution patterns, mainly in terms of tumor types (7). There are no local publications regarding mediastinal masses, as such the clinical and pathological characteristics of this group of tumors in our population has been overlooked. With the aim of describing the clinicopathological characteristics of mediastinal masses in children and adults, a 13-year period [2010–2022], including only primary mediastinal tumors, was retrospectively reviewed. Upon comparison, some statistically significant results regarding tumor location, tumor type, histological type and presenting complaint were found, which run contrary to the results of surveys with similar objectives. We present this article in accordance with the STROBE reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-24-25/rc).

Methods

Ethics and cases acquisition

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This retrospective study was approved by the Institutional Review Board of Hospital San Vicente Fundación (No. 082021). Individual consent for this retrospective analysis was waived. University of Antioquia is informed and agreed the study. All patients were Colombian, and residents of Antioquia (Colombia). After searching the Hospital San Vicente Fundación and University of Antioquia Pathology Department’s database from 2010 to 2022 for mediastinal masses, 589 reports were retrieved. Then, reports with diagnoses of infections, metastatic disease, thyroid and pulmonary tumors were excluded, leaving 110 patients with primary mediastinal tumors. The anatomical location was extracted from radiology imaging reports such as computed tomography (CT), positron emission tomography-CT (PET-CT) and magnetic resonance imaging (MRI). Four anatomical locations of the neoplasms were differentiated, anterior mediastinum (prevascular), middle mediastinum (visceral), posterior mediastinum (paravertebral) and a “whole” category when the neoplasm occupied all the previously mentioned locations. The slides from the 110 primary mediastinal tumors were reviewed for diagnostic confirmation, and the medical charts were also reviewed for confirmation of demographic variables and identification of presenting complaint.

The 5^th edition of the World Health Organization (WHO) Thoracic Tumours was use to establish a single coherent neoplasms classification (8). The 110 cases were divided based on age into two groups, children and adults. According to Colombian regulation a child is a right-holding subject from birth to 12 years old, and an adolescent is a right-holding subject from 12 to less than 18 years old. Therefore, both children and adolescents were included in the child group, while the adult group included patients of more than 18 years of age.

Statistical analysis

The two groups were compared, looking for statistically significant differences (P<0.05), by age, sex, tumor type, location, histological type, sex and presenting complaint. The two-proportions z-test (X-squared, two-sided, 95 percent confidence) in R software version 4.0.3 (2020-10-10) was used for statistical analysis.

Results

A total of 110 patients with primary mediastinal tumors were identified, 47 children and 63 adults. The mean age in the child group was 8 years and in the adult group 41.7 years (Table 1). In the child group, there were 30% (14/47) females and 70% (33/47) males, while in the adult group there were 46% (29/63) females and 54% (34/63) males. In both groups, most of the tumors were malignant, 81% (38/47) in the child group and 90% (57/63) in the adult group. There were non-significant statistical P values upon comparison of sex and tumor type between the groups.

There were 19 different presenting complaints in patients with primary mediastinal masses. The most frequent presenting complaint was dyspnea, chest pain, fever, cough and superior vena cava (SVC) syndrome. Mediastinal mass as an incidental finding was present in three patients, and 11 patients have unique presenting complaints in the study group (Table 1). Fever was the only presenting complaint with a significant statistical difference among children and adults (P=0.02), due to its high incidence in the child group.

Tumor type and location of mediastinal tumors

The most common location of mediastinal tumors in children and adults was the anterior mediastinum with an overall incidence of 61%, and a distribution of 49% (23/47) and 70% (44/63) respectively (Table 2). Upon comparison for all tumors, the anterior mediastinal location had a statistically significant difference in favor of the adult group (P=0.042).

The second most frequent location was the posterior compartment with an overall incidence of 25%, present in 40% (19/47) in the child group and 13% (8/63) in the adult group. Posterior location of tumors had significant differences in all tumors in favor of the child group (P=0.001), explained by the high incidence of tumors in this location in the child group, 19/47 cases, compared to just 8/63 cases in the adult group. Tumor incidence of 12% in the middle compartment and 2% in the whole mediastinal location represented a low proportion of cases. There were three tumors in which the anatomical location cannot be specified due to their large size and were thus interpreted as occupying the whole mediastinal compartment.

Most of the benign tumors in children were located in the mediastinal posterior compartment 56% (5/9), whereas adult benign tumors were mostly located in the posterior mediastinum 83% (5/6). Comparing malignant tumors between groups, malignant tumors were more frequent in the anterior mediastinum in both groups, 58% (22/38) in children and 79% (45/57) in adults. Statistically significant results regarding malignant tumors were related to posterior mediastinal location (P=0.001) in the child group, and the anterior location (P=0.02) in the adult group.

Profile of mediastinal tumors

The mediastinal compartment can harbor benign and malignant tumors like any other anatomical location. As previously stated, most of the pediatric mediastinal masses were malignant, and 66% were lymphoid tumors (25/38) (Table 3). Among lymphomas, T-cell lymphoblastic lymphoma was the most frequent hematolymphoid neoplasm present in 39% of the cases (15/38), a mean patient age of ten years, followed by B-cell lymphomas with 16% of the cases (6/38), and a mean patient age of 12 years. Hodgkin lymphoma corresponded to 11% of cases (4/38), with a mean patient age of eleven years. The second most frequent histological type of malignant neoplasm were neurally derived (29%), comprised of 21% (8/38) neuroblastomas with a mean patient age of 3 years, and 8% (3/38) ganglioneuroblastoma cases. Benign tumors were from several origins such as germ cells (3 benign cystic teratomas), neurally derived (one neurofibroma and one ganglioneuroma), and three benign cystic lesions of different epithelial linings.

Regarding adults, lymphoid neoplasms were also the most frequent malignant tumors, being present in 56% (32/57) of cases. Most of the mediastinal lymphomas were B-cell lymphomas 63% (20/32), with a mean patient age of 37.7 years, while Hodgkin lymphomas with 25% (8/32), a mean patient age of 27 years, and T-cell lymphomas with 13% (4/32) and a mean patient age of 35 years were the second and third in frequency respectively. The second most frequent malignant tumors in adults were thymic epithelial tumors representing 25% (14/57). Malignant GCTs represented 13% of cases (7/53), with a mean patient age of 26 years, with cases in the histological spectrum for this kind of neoplasm. There were two malignant, soft tissue tumors, one high grade fibrosarcoma and an undifferentiated pleomorphic sarcoma. followed by three neurally-derived tumors, two Schwannomas and one neurofibroma, and three benign cystic lesions. One patient with B-cell lymphoma was human immunodeficiency virus (HIV) positive.

For all tumors, most of the anteriorly located neoplasms in both groups were represented by lymphoid type tumors (45/110), and the significant difference in the anterior compartment (P=0.042) in favor of the adult group can be explained due to the exclusive location of thymic tumors in this anatomical site (Table 4). The same reason for anterior-exclusive thymic epithelial tumor location explained the significant difference (P=0.02) in malignant tumors in the anterior compartment of adults, because thymic tumors were only present in patients from this group (P=0.004).

Regarding posterior location, the significant differences in the child group (P=0.001), are due to the important presence of neurally-derived tumors in this compartment, specifically neuroblastomas (P=0.002) (Table 4) and ganglioneuroblastomas, considering there were no malignant, neurally-derived tumors in the adult group. Thymic tumors were exclusive to the adult group, as were poorly differentiated endocrine tumors and malignant soft tissue tumors. There were no malignant GCTs in the child group, and the predominant lymphoid tumors varied with significant statistically differences according to the group. T-cell lymphoblastic lymphomas had a higher incidence in the child group (P=0.001), and B-cell lymphomas in the adult group (P=0.04) and there was no statistically significant difference regarding Hodgkin lymphoma. The only statistically significant result when comparing the sexes was for male children with T-cell lymphoblastic lymphomas (P=0.01).

Presenting complaints

Despite their common location, the clinical symptoms of mediastinal tumors vary. We cannot find any concordance related to symptoms and anatomical locations (Table 5). Fever (P=0.02) and chest pain (P=0.02) were the symptoms presenting a statistically significant difference between children and adults. All the patients with fever as the presenting complaint had malignant tumors, specifically lymphoid tumors, located in the anterior (seven cases) and posterior compartment (one case). Chest pain was associated with adult tumors without any statistically significant differences in tumor type or anatomical location. Fever and cough were two ominous symptoms related to malignant type tumors in the clinical context of an anterior mediastinal mass in adults.

Discussion

In the analyzed mediastinal mass groups, we found some statistically significant differences, regarding tumor location, tumor type, histological type, sex and presenting complaint. Regarding location, the anterior mediastinal compartment was the most frequent location considering all tumors, with a significant difference (P=0.042) favoring the adult group. This difference was also present in malignant tumors (P=0.02), which can be explained in both situations by the exclusive incidence of thymic tumors in the adults’ anterior compartment. In contrast, malignant tumors show a statistically significant difference (P=0.001) in the posterior compartment of the child group, associated with the high incidence of neurogenic tumors in this group (P=0.001), specifically neuroblastoma (P=0.002). Additionally, T-cell lymphoblastic lymphomas had a higher incidence in the child group (P=0.001), especially in males (P=0.01), and B-cell lymphomas in the adult group (P=0.04). Fever in the child group (P=0.02) was the most statistically significant presenting complaint related exclusively with lymphoid tumors. Symptomatology is related to size and/or compression or direct invasion of adjacent structures, that is why there is a wide spectrum of symptomatology associated with mediastinal masses (9,10). In the background review, we cannot find a specific symptomatology consistently associated with a histological type or mediastinal compartment location.

Azarow and colleagues analyzed almost 40 years of mediastinal masses in a pediatric population (62 patients) and adults (195 patients) at a single center in the United States, finding a significantly increased incidence of lymphomas in adults (P<0.05) and neurogenic tumors in child (P<0.05), while there were no differences in thymic tumors (11). In our results, there were no differences in lymphoma incidence among the groups, thymic tumors were exclusively present in the adult population, whereas neurogenic tumors were also higher in the child group.

From Osaka (Japan), a 43-year mediastinal tumor review, found 106 children (with a cut off age of 15 years), and 522 adult patients. In this review, benign tumors were most frequent in both groups (66.9% in children and 53.1% in adults). The most frequent tumors in children and adults were neurogenic tumors (44.3%) and thymomas (36.2%) respectively, and regarding neurogenic tumors in children ganglioneuromas represented most of the tumors at 30% (12). Most of the tumors in the child and adult groups in our study were malignant, and most of them in both groups were lymphomas. Concerning neurogenic tumors in children, neuroblastoma had a statistically significant difference (P=0.002) among children and adults.

In another Japanese institution, Takeda and colleagues made a 49-year review of mediastinal tumors in 130 child and 676 adult patients (3). Takeda found in order of frequency in the adult group, 244 thymomas (36%), 106 GCTs (19%), 95 cysts (14%), and 82 lymphomas (12%). While in the child group, 60 neurogenic tumors (46%), 24 GCTs (19%), 17 lymphomas (13%), 10 congenital cysts (8%), and 5 thymomas (4%) were found. The most common location was the anterior compartment (68%) in adults and the posterior compartment (52%) in children. Contrary to these results, lymphoid tumors were the most frequent tumors in both groups of our study, we did not observe thymoma cases in the child group, and the anterior compartment was by far the most frequent location of tumors in both groups.

Regarding neurogenic tumors, age seems to be an important parameter increasing the odds of malignant behavior. In adults, neurogenic tumors are usually benign and represented by schwannomas and neurofibromas, with slight symptoms at presentation or discovered as an incidental finding (13). But in the case of children, neurogenic tumors are symptomatic (14), most of them are malignant and mostly neuroblastomas (15). In concordance with our results, neurogenic tumors were more frequent in the child group, most of them were malignant (P=0.001), and mostly neuroblastomas (P=0.002). Little is known about risk factors for developing neuroblastoma, and a huge variety of modifiable and non-modifiable conditions have been related, to date without clinical impact (16).

In our series, the most frequent malignant neoplasm in children and adults lacks clear risk factors. As expected, T-cell lymphoblastic lymphomas were most frequent in the child group and especially in males (17), and B-cell lymphomas were most frequent in adults (18). Risk factors for T-cell lymphoblastic lymphomas and mediastinal, diffuse B-cell lymphomas are mostly unknown, and so far, not related to virus (19,20). HIV positive patients have an increased risk for developing neoplasms, aggravating the natural history of the disease, especially those associated with Epstein-Barr chronic infection (21). However, most primary mediastinal lymphoid tumors are neither associated with any infectious agents nor Epstein-Barr virus, so there is no higher incidence of mediastinal masses in HIV patients. The latter, is a clear example of how a strong risk factor elsewhere, cannot influence an anatomical location like the mediastinum, if the most frequent tumors in this location have no association with that risk factor. There were not nuclear protein in testis (NUT) mutation associated midline carcinoma diagnosis.

Conclusions

In conclusion, mediastinal mass epidemiological data vary according to populations, thus it is of utmost importance to acknowledge local patients’ characteristics in order to narrow the clinical and pathological differential diagnosis. Differences regarding histological type of tumors could be associated with population risk factor exposure in each geographical locale. Unfortunately, risk factors for most of the different types of mediastinal tumors are still unknown, therefore the unraveling of those possible risk factors could be an important field for further investigation.

Acknowledgments

We would like to thank the recently deceased professor of pathology and mentor of many pathologists in Colombia, Professor Luis Fernando Arias Restrepo, for sharing all his knowledge and experience with the authors of this article.

No artificial intelligence was used in the writing of the article or in the generation of the tables.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-24-25/rc

Data Sharing Statement: Available at https://med.amegroups.com/article/view/10.21037/med-24-25/dss

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-24-25/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-24-25/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Institutional Human Ethics Committee of Hospital San Vicente Fundación approved this study (No. 082021). Individual consent for this retrospective analysis was waived. University of Antioquia is informed and agreed the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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