Introduction

Mediastinal masses are frequently encountered in the pediatric population, and imaging evaluation is the cornerstone of accurate diagnosis and management of pediatric mediastinal masses [1,2,3]. Traditionally, mediastinal masses have been classified into lesions of the anterior, middle and posterior mediastinum, which are historical compartments defined by anatomical landmarks on the lateral chest radiograph. However, there is no clear consensus on the anatomical definition of the mediastinal compartments, and mediastinal compartmental division varies among radiologists, anatomists and clinicians [4]. This often results in different classification schemes and terminology, and confusion. With the advent of widely available cross-sectional imaging, which provides precise and defined imaging characterization, the diagnosis, staging and surgical planning for mediastinal masses has outgrown the original anatomical landmarks of the lateral chest radiograph.

The International Thymic Malignancy Interest Group (ITMIG) introduced a new classification system based on anatomical cross-sectional imaging in 2014. Since then, the new classification scheme had gained acceptance by multiple societies, including the International Association for the Study of Lung Cancer (IASLC), the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) [4, 5]. Consequently, there is a need for pediatric radiologists to clearly understand the ITMIG classification system and how it applies to the pediatric population, specifically in the imaging evaluation of mediastinal masses, which are common in children. The aim of this article is to provide an updated review of common pediatric mediastinal masses and mediastinal manifestations of systemic disease processes in the pediatric population based on the new ITMIG classification system.

The International Thymic Malignancy Interest Group classification system

Developed from a database of 10,000 patients, the ITMIG classification system divides the mediastinum into three compartments: pre-vascular, visceral and paravertebral [4]. These partitions are not dissimilar to the anterior, middle and posterior mediastinal compartments defined by lateral chest radiography. However, the ITMIG compartments have the added anatomical precision provided by cross-sectional imaging. In comparison to the four-compartment model proposed by the Japanese Association for Research of the Thymus (JART), which is more complex and includes non-anatomical partitioning of the mediastinum into superior and inferior components, the ITMIG system is purely anatomically based [6]. In addition, the ITMIG system provides a detailed division of lymph node stations for aggressive tumors, such as thymic carcinomas, which can assist in staging (although this might be more applicable to the adult population) [4, 5].

Practical approach to new classification system for children

Although pediatric mediastinal masses are likely to be first encountered on chest radiograph because of the greater use of radiography as a first imaging modality in the pediatric population, further characterization is nearly always performed with cross-sectional imaging, such as CT or MRI. Application of the new ITMIG model to pediatric mediastinal masses often shows similar classification of disease processes and entities in the pre-vascular (anterior) and paravertebral (posterior) compartments (Fig. 1). However, major advancements have been made in the understanding of disorders and manifestations of systemic disease in the visceral (middle) mediastinum in the pediatric population. These include underlying genetic mutations such as nuclear protein of the testis (NUT) cell carcinoma and dedicator of cytokinesis 8 (DOCK8) deficiency, as well as disorders related to adjacent mediastinal vascular structure such as pulmonary vein stenosis (Table 1).

Fig. 1
figure 1

Computed tomography (CT)-based mediastinal compartment scheme developed by the International Thymic Malignancy Interest Group (ITMIG). a Axial contrast-enhanced CT image just below the level of the main pulmonary artery shows the three mediastinal compartments including pre-vascular (blue), visceral (green) and paravertebral (orange). b Sagittal enhanced CT image obtained at midline demonstrates the three mediastinal compartments including pre-vascular (blue), visceral (green) and paravertebral (orange)

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Table 1 Disorders related to the pre-vascular (anterior), visceral (middle), and paravertebral (posterior) mediastinum according to the International Thymic Malignancy Interest Group model
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Spectrum of pediatric mediastinal masses

Pre-vascular (anterior) mediastinal compartment

Most anterior mediastinal masses in the pediatric population arise from the following origins: thymus (thymic hyperplasia, thymic cyst, thymoma and thymolipoma), germ cell (seminomas and non-seminomatous germ cell tumor, including teratoma), lymphocyte (Hodgkin and non-Hodgkin lymphomas), vessel (infantile hemangioma and venous malformation) and lymphatic (lymphatic malformation), which are discussed in the following sections.

Thymic hyperplasia

Thymic hyperplasia, or thymic rebound, is defined as an increase in thymic size in response to stress, medications (e.g., chemotherapy, immunotherapy and corticosteroids) or autoimmune conditions. True thymic hyperplasia demonstrates preserved histological architecture, whereas lymphoid thymic hyperplasia is characterized by increased lymphoid follicles and is more commonly associated with autoimmune conditions, such as myasthenia gravis and vasculitides [7]. Differentiation among thymic hyperplasia subtypes is not as clinically important as discerning thymic hyperplasia from thymic malignancies.

Because of its superior soft-tissue characterization capability, MRI is often used to evaluate thymic hyperplasia after CT, which often demonstrates nonspecific thymic enlargement (Fig. 2). On MRI, the normal pediatric thymus is well circumscribed and demonstrates homogeneous T2 hyperintensity and mild uniform enhancement [8]. Thymic hyperplasia might surround and encase adjacent structures, but demonstrates little mass effect [8]. Thymic enlargement regresses with alleviation of precipitating stress or immunomodulation.

Fig. 2
figure 2

Thymic hyperplasia in a 14-year-old boy with Hodgkin lymphoma. a Axial contrast-enhanced CT image obtained following initial chemotherapy shows an enlarged thymus (asterisk) with well-marginated borders, consistent with thymic hyperplasia. No associated calcification or mass is evident. b Axial contrast-enhanced CT image obtained following completion of chemotherapy demonstrates an interval decrease in size of thymus (arrow), consistent with interval involution

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Thymic cyst

Thymic cysts can be congenital, acquired following chemotherapy, or in parallel with other thymic tumors. Thymic cysts are typically found along the thymopharyngeal tract — a remnant formed after involution of the third pharyngobranchial duct located between the pharynx and thymus. Although often asymptomatic and incidentally discovered, affected children might present with dysphagia, respiratory distress or vocal cord paralysis if thymic cysts are sufficiently large.

Thymic cysts are usually unilocular with variable CT attenuation depending on the degree of proteinaceous or hemorrhagic contents. On MRI, thymic cysts are typically well-circumscribed and markedly T2-hyperintense, with variable T1 signal depending on cystic contents [9] (Fig. 3). MRI is valuable for detecting internal solid enhancing components that might point to an alternative diagnosis. However, complex thymic cysts might also demonstrate enhancing mural nodularity or thickened septa [9]. In such cases, MRI can be useful to guide recommendations and clinical decisions including serial imaging, evaluation with a different imaging modality, or even tissue sampling based on MR imaging appearance. Multiloculated thymic cysts are sometimes associated with autoimmune conditions and human immunodeficiency virus (HIV) [10].

Fig. 3
figure 3

Thymic cyst in a 16-year-old boy who underwent an MRI thoracic spine study for suspected spinal injury after trauma. a Axial T2-weighted fat-suppressed MR image shows an ovoid, well-circumscribed hyperintense lesion (arrow) in the pre-vascular space. Note that the lesion is anterior to trachea (T) and left common carotid artery (C). b Axial post-contrast T1-weighted fat-suppressed MR image demonstrates the lesion (arrow) with no contrast enhancement within the thymic cyst

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Thymoma

Thymomas are rare epithelial neoplasms in the pediatric population, only accounting for 1–2% of pediatric mediastinal tumors [3]. There are two types of thymomas: noninvasive and invasive. Invasive thymoma is typically larger, with irregular contours, necrosis and heterogeneous enhancement. Local invasiveness can extend into the adjacent pleural and chest wall. Most thymomas are asymptomatic; however, 40% have been associated with paraneoplastic syndromes, most frequently myasthenia gravis [3].

On CT, thymoma typically appears as a well-circumscribed, mildly enhancing pre-vascular (anterior) mediastinal mass, occasionally with a thin calcified capsule [3]. On MRI, thymoma is usually mildly T2-hyperintense and enhancing, without signal loss on out-of-phase MR imaging (Fig. 4). Treatment is typically surgical resection, with a higher risk of recurrence in the invasive subtype.

Fig. 4
figure 4

Thymoma in a 16-year-old boy who presented with cough. Axial T2-weighted fat-suppressed MR image shows a T2-hyperintense lesion (arrow) with internal cystic changes in the pre-vascular space

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Thymolipoma

Thymolipomas are rare, benign mediastinal masses composed of remnant thymic tissue interspersed within macroscopic fat. They demonstrate slow, progressive growth and greater pliability than other pre-vascular (anterior) mediastinal masses. As such, most thymolipomas are discovered incidentally with large size at diagnosis. On CT and MRI, thymolipoma typically appears as a well-defined mass with non-enhancing soft tissue and septa interspersed throughout fat, often in a whorled configuration [3] (Fig. 5). Treatment is often only considered when affected children are symptomatic from adjacent mass effect.

Fig. 5
figure 5

Thymolipoma in an 11-year-old girl who was incidentally found to have a mediastinal mass during evaluation for scoliosis. Axial unenhanced CT shows an ill-defined fat-attenuating lesion (asterisk) in the pre-vascular space

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Seminoma

Seminomas are a type of germ cell tumor that typically arises from the testis. The two most common extra-gonadal locations for seminomas include the mediastinum and retroperitoneum [11]. However, in the context of all pediatric mediastinal tumors, mediastinal seminomas are very rare. Unlike other germ cell tumors that produce both alpha-fetoprotein (AFP) and β-human chorionic gonadotropin (β-hcg), pure seminomas do not produce AFP.

On CT and MRI, seminoma, similar to most other germ cell tumors, appears as a poorly circumscribed and heterogeneous mass with solid and cystic components, often with local invasion [11] (Fig. 6). Unlike teratomas, which are discussed later, calcifications are rare, but when present they tend to be stippled or rim-like [12]. Pure mediastinal seminomas are usually curable with chemotherapy alone [13].

Fig. 6
figure 6

Seminoma in a 15-year-old boy who presented with shortness of breath. Axial T2-weighted fat-suppressed MR image shows a heterogeneous mass with cystic and solid (arrow) components in the pre-vascular space

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Teratoma (non-seminomatous germ cell tumors)

Non-seminomatous germ cell tumors include teratomas, yolk sac tumors, embryonal carcinomas, choriocarcinomas and mixed histological types. Among them, teratomas are the most common mediastinal non-seminomatous germ cell tumors, comprising approximately 60% of cases [3]. Children with Klinefelter syndrome (47, XXY genotype) are 19 times more likely to develop mediastinal non-seminomatous germ cell tumors [14].

On imaging, a teratoma typically appears as a well-circumscribed, often heterogeneous mass, with variable fat, cystic and calcified components, which can help differentiate teratoma from other mediastinal masses. The presence of a fat-fluid level or calcified components, such as teeth, on CT is pathognomonic [12] (Fig. 7). Hypointensity on T1-W imaging with fat suppression at MRI might help to support the presence of macroscopic fat when this is less clear on CT. It might not be possible to differentiate between immature and mature teratomas on the basis of imaging alone because of their shared imaging characteristics. However, the presence of irregular-shape and invasive solid tissue has been associated more with the immature subtype [1]. Immature teratomas, as opposed to mature types, demonstrate local recurrence after excision in up to a third of cases because of the presence of malignant germ cell components [1].

Fig. 7
figure 7

Teratoma in a 15-year-old boy who presented with respiratory symptoms. Coronal contrast-enhanced CT image shows a heterogeneous pre-vascular mass with calcification (arrow) and intralesional fat (arrowheads). Surgical pathology confirmed the diagnosis of mediastinal mature teratoma

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Lymphoma (Hodgkin and non-Hodgkin lymphomas)

Lymphomas are the third most common pediatric malignancy and the most common malignant mediastinal mass. Both Hodgkin lymphoma and non-Hodgkin lymphoma (NHL) occur in children, but they have different age and location predilections. For example, Hodgkin lymphoma, which is often associated with Epstein–Barr virus (EBV) infection, typically occurs in children older than 10 years and mainly in the chest [3]. Pediatric patients with Hodgkin lymphoma might present with B symptoms (fever, night sweats and weight loss), especially in the classic subtype, or compressive symptoms secondary to mass effect from extensive bulky adenopathy. In contrast, NHL more commonly affects children younger than 10 years and often affects both the chest and abdomen [3]. NHL can be further classified into four subtypes: diffuse large B cell lymphoma, Burkitt lymphoma, anaplastic lymphoma and lymphoblastic lymphoma [15, 16].

On imaging, both Hodgkin lymphoma and NHL typically appear as a bulky, heterogeneous, lobulated pre-vascular (anterior) mediastinal mass with a tendency to displace adjacent structures (Fig. 8). Hodgkin lymphoma has a greater incidence of intrathoracic involvement compared to NHL (85% vs. 50%) [3]. Prior to treatment, lymph node conglomerates in lymphoma rarely calcify. After treatment, calcification occurs in up to 5% of cases [3]. Hodgkin lymphoma can also present with pulmonary findings, including multiple pulmonary nodules, multifocal consolidations, and sometimes (15%) pleural effusions [3]. Currently, positron emission tomography (PET)/CT is the mainstay for evaluating treatment response.

Fig. 8
figure 8

Hodgkin lymphoma in an 18-year-old man who presented with a neck swelling that was biopsied and found to be a Hodgkin lymphoma. a Axial contrast-enhanced CT image shows a lobulated, minimally enhancing mass (arrow) in the pre-vascular mediastinum. Also note the enlarged lymph node (asterisk) in the subcarinal region. b Axial fused [F-18]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)/CT image demonstrates increased metabolic activity in both the pre-vascular mass (arrow) and subcarinal lymph node (asterisk). Increased FDG avidity is also noted in the left axillary lymph nodes (arrowheads)

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Treatment of mediastinal lymphoma in children typically includes chemotherapy, sometimes in combination with immunotherapy and radiotherapy for Hodgkin lymphoma and bone marrow transplantation for NHL. Prognosis is good, with 5-year survival rates of 90% for Hodgkin lymphoma and 70–85% for NHL [16].

Infantile hemangioma

Infantile hemangiomas are vascular neoplasms containing proliferative endothelium that affect 4–10% of children [17]. These benign vascular tumors typically arise and grow rapidly in the early proliferative phase within the first 3 months after birth [18]. More gradual growth occurs in months 5–8, leading into the plateau phase. Involution typically follows by the first year of age and can continue for several years [18]. Infantile hemangiomas occur in all tissues except bone and rarely occur as a pre-vascular (anterior) mediastinal mass.

On US, infantile hemangiomas appear as highly vascular, well-delineated masses with large feeding and draining vessels. At MRI, hemangiomas appear T1-isointense to muscle and markedly T2-hyperintense with marked uniform enhancement after contrast administration.

Venous malformation

Unlike infantile hemangiomas, venous malformations are present at birth, albeit sometimes undiscovered until later into adulthood. The incidence of venous malformations in the mediastinum is rare. Most venous malformations are found in the head and neck and 30% in the torso [19]. Similar to infantile hemangiomas, venous malformations are vascular lesions characterized by the presence of an endothelium. However, venous malformations demonstrate slow flow, sometimes contain phleboliths, and connect to the central venous system. Enhancement patterns vary widely in uniformity, intensity and timing, necessitating multiphasic imaging [19].

Lymphatic malformation

Lymphatic malformations arise from failure of lymphatic channels to connect to the central venous system. Lymphatic malformations can be classified as macrocystic (>1 cm), microcystic (<1 cm) or a combination. Similar to venous malformations, these lesions most commonly occur in the head, neck and axilla, with a minority (10%) arising in the mediastinum [20].

On MRI, macrocystic components appear as multiseptated proteinaceous cysts that exert mass effect on adjacent structures [20]. Conversely, microcystic components can appear solid. MRI evaluation of lymphatic malformations demonstrates T2 hyperintensity with variable T1 signal intensity based on intrinsic proteinaceous and hemorrhagic makeup (Fig. 9). Unlike infantile hemangiomas or venous malformations, macrocystic lymphatic malformations do not demonstrate internal enhancement, though septations typically demonstrate mild enhancement.

Fig. 9
figure 9

Lymphatic malformation in a 2-month-old boy. He was prenatally diagnosed with a mediastinal cystic mass, which was biopsy-proven to be a lymphatic malformation. a, b Axial (a) and sagittal (b) T2-weighted MR images show a cystic lesion (asterisk) in the pre-vascular mediastinal space with a thin septum (arrowhead), consistent with macrocystic lymphatic malformation

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Visceral (middle) mediastinal compartment

Foregut duplication cyst

Foregut duplication cysts comprise of bronchogenic, enteric and neurenteric cysts and collectively account for 10–11% of all mediastinal masses in the pediatric population [2, 21]. Most are found incidentally, but they can manifest with compressive symptoms such as dysphagia, dyspnea or chest pain. Bronchogenic cysts are most common, followed by enteric cysts. Bronchogenic cysts result from abnormal budding of the tracheobronchial tree and typically occur at the pre- or subcarinal stations [1]. Enteric cysts result from abnormal development of the posterior foregut and appear as a mass near the esophagus. Neurenteric cysts develop from a failure of foregut separation from the neural crest cells and can be differentiated from the other foregut duplication cysts based on their location in the paravertebral (posterior) compartment.

On CT, all three types of foregut duplication cyst typically appear as well-circumscribed round or oval cystic masses (Fig. 10). However, about half have proteinaceous or hemorrhagic internal components resulting in higher attenuation and might mimic a solid lesion [3]. In this situation, MRI evaluation can be helpful for characterization because marked T2 hyperintensity of foregut duplication cysts without contrast enhancement confirms the cystic nature of this lesion. Alternatively, dual-energy contrast-enhanced CT with virtual non-contrast reconstructions or single-energy CT with pre- and post-contrast imaging can be used to confirm lack of enhancement. Thickened walls with or without thick rim enhancement can suggest superinfection [22]. Treatment involves complete resection for symptomatic children.

Fig. 10
figure 10

Foregut duplication cyst in a 2-month-old girl who presented with respiratory distress. Axial contrast-enhanced CT image shows a cystic lesion (asterisk) in the visceral mediastinal compartment. Surgical pathology confirmed the diagnosis of bronchogenic cyst

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Infectious lymphadenopathy

Infectious mediastinal lymph node enlargement is seen in a wide variety of underlying etiologies including tuberculosis, fungal infections and bacterial pneumonias. Infectious lymphadenopathy is commonly found in conjunction with lung abnormalities (Fig. 11). For example, tuberculosis-related mediastinal lymphadenopathy is often associated with tree-in-bud-type pulmonary nodules and consolidation. Mediastinal lymphadenopathy related to fungal infection is often associated with pulmonary nodules that are often calcified. Antimicrobial therapy for the underlying infection is the mainstay of treatment.

Fig. 11
figure 11

Infectious mediastinal lymphadenopathy in a 16-year-old boy with cystic fibrosis and right lung pneumonia. a Axial contrast-enhanced CT image shows infectious lymphadenopathy (asterisk) in the visceral space caused by right lung pneumonia (arrowhead). Also note the right-side pneumothorax and subcutaneous emphysema. b Axial lung window CT image demonstrates right lung pneumonia (arrowhead) and bronchiectasis, an expected finding in a child with cystic fibrosis

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Primary neoplastic lymphadenopathy

Lymphoma is the most common cause of primary neoplastic lymphadenopathy in the visceral (middle) mediastinum in the pediatric population. Often lymphadenopathy arises from the pre-vascular (anterior) mediastinum. Imaging characteristics are nonspecific and can appear as homogeneously or heterogeneously enlarged lymph nodes or extensive nodal conglomerates. Calcifications might reflect treatment changes.

Metastatic lymphadenopathy

Metastatic mediastinal lymphadenopathy in the pediatric population most commonly occurs secondary to Wilms tumors, sarcomas or primary testicular neoplasms. Pediatric metastatic mediastinal lymphadenopathy typically presents as a heterogeneous soft-tissue mass with contrast enhancement (Fig. 12). Associated calcification is often seen in osteosarcoma metastases, although treatment-related calcification occurs in other malignancies.

Fig. 12
figure 12

Metastatic mediastinal lymphadenopathy in a 14-year-old boy with left thigh soft-tissue sarcoma. Axial contrast-enhanced CT image demonstrates extensive necrotic metastatic lymph nodes (asterisk) in the visceral compartment of the mediastinum in addition to a pulmonary nodule (arrow)

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Castleman disease

Castleman disease is a rare lymphoproliferative disorder with two subtypes that are broadly categorized by sites of involvement. Unicentric disease is more common (75%) than multicentric disease (25%) in children [23]. A form of multicentric disease is associated with human herpesvirus 8 (HHV-8), although this is very rare in the pediatric population [23, 24]. Contrary to adults, mediastinal involvement of Castleman disease is relatively less common, occurring in 11% of unicentric and 16% of multicentric disease [23]. On histology, two main subtypes predominate: the hyaline–vascular type (90%) and plasma cell type [24].

On CT, unicentric Castleman disease typically appears as a high-attenuating solitary oval or round mediastinal or hilar mass that demonstrates homogeneous hyperenhancement relative to muscle (Fig. 13). Associated calcifications are rare. MRI characteristics include T1 iso- to hyperintensity relative to muscle and T2 hyperintensity [23]. Diffuse contrast enhancement is particularly evident in the hyaline–vascular subtype. Lesions are typically 18FDG-PET-avid [23].

Fig. 13
figure 13

Castleman disease in a 16-year-old boy who presented with weight loss and elevated inflammatory markers. Axial contrast-enhanced CT image shows a lobulated mass (asterisk) with homogeneous contrast enhancement situated between the left atrium and the descending thoracic aorta (DA)

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Sarcoidosis

Pediatric sarcoidosis is a rare multisystemic granulomatous disease [25]. When manifesting in children, sarcoidosis most commonly affects the lungs and lymph nodes. Two distinct presentations exist in children. Older children (>5 years) typically present with nonspecific constitutional symptoms such as low-grade fever and malaise, whereas early onset childhood sarcoidosis (<5 years) is characterized by a triad of rash, uveitis and arthritis [26,27,28,29]. Compared to adults, pediatric mediastinal lymphadenopathy secondary to sarcoidosis is far rarer, with about one-tenth the incidence, or 0.22–1 in 100,000 [25, 30].

On imaging of pediatric sarcoidosis, pulmonary findings are scored based on chest radiography, with stage I disease (isolated bilateral hilar lymphadenopathy) the most common (71%). Pulmonary infiltrates with hilar adenopathy (stage II), without hilar adenopathy (stage III) and fibrosis (stage IV) are less common at radiography [26].

Computed tomography remains the gold standard for children requiring further evaluation. At CT, sarcoidosis can appear as lymphadenopathy accompanied by pulmonary nodules; pleural, fissure or interlobular thickening; ground-glass opacities; bronchiectasis; or pulmonary cysts. Some studies have shown promising use of fast-acquisition contrast-enhanced lung MRI for evaluating and surveilling children with sarcoidosis, with comparable detection of stages I, II and IV disease [31,32,33]. Lung MRI has been found to be similar to CT except for detection of subtle ground-glass opacities, mild bronchiectasis and nodules smaller than 3 mm [31]. Treatment typically involves corticosteroids with good outcomes.

NUT carcinoma

NUT carcinomas, formerly called NUT midline carcinomas, are a very rare distinct entity of poorly differentiated squamous cell carcinoma [34,35,36]. They are considered highly aggressive tumors in children and young adults, with an average survival from time of diagnosis of 6.7 months [37]. Development of NUT carcinoma is idiopathic, but genetically results from rearrangement of the nuclear protein in testis (NUT) gene on chromosome 15q14 [38]. In approximately 66% of cases, the NUT gene is fused to the BRD4 gene, resulting in a BRD4–NUT fusion oncogene [38]. NUT carcinomas arise 51% of the time in the thorax, 41% in the head and neck, 6% in bone or soft tissue and 1% elsewhere [37]. Affected children often present with symptoms related to regional mass effect from the tumor.

On CT, primary thoracic NUT carcinoma appears as a relatively low attenuating, heterogeneously enhancing infiltrative visceral (middle) mediastinal mass, which can exert mass effect on local structures (e.g., resulting in lobar collapse) or direct invasion [39,40,41] (Fig. 14). Mediastinal and hilar adenopathy and pleural involvement, in the form of effusions and nodular thickening, are frequently found [41]. Calcifications are sometimes seen [42]. The superior soft-tissue resolution of MRI can help to delineate neurovascular or chest wall invasion. FDG-avid lytic osseous lesions are the most common form of metastasis. PET/CT is central to monitoring treatment response.

Fig. 14
figure 14

Nuclear protein in testis (NUT) carcinoma in a 14-year-old girl who presented with progressive chest pain and weight loss. Axial contrast-enhanced CT image shows a heterogeneously enhancing mass (arrow) in the right hilar region of the visceral mediastinum

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Pulmonary vein stenosis

Primary pulmonary vein stenosis is a rare entity with an incidence of approximately 2 in 100,000 children [43,44,45,46]. Unlike secondary pulmonary vein stenosis, which is a well-described complication following surgical correction of anomalous pulmonary venous return and radiofrequency ablation in children and adults, primary pulmonary vein stenosis is idiopathic, less well understood, and difficult to diagnose [47].

In addition to characteristic angiographic findings, primary pulmonary vein stenosis can present with prominent extravascular thoracic findings, including a mediastinal mass along the course of the pulmonary veins (93%), ground-glass opacities (93%), interlobular septal thickening (33%) and pleural thickening (93%) [47]. Specifically, mediastinal masses associated with primary pulmonary vein stenosis have been described as well-defined, non-calcified, heterogeneously enhancing lesions following the contour of the atretic pulmonary veins (Fig. 15). The pathophysiology underlying the development of these mediastinal masses in the setting of primary pulmonary vein stenosis is not well understood; however, it is postulated to be the underlying fibrointimal myxoid proliferation seen on some histopathological samples [48]. Alone, a mediastinal mass has low specificity for primary pulmonary vein stenosis, but its presence in conjunction with characteristic pulmonary and angiographic findings can help to solidify the diagnosis of primary pulmonary vein stenosis.

Fig. 15
figure 15

Primary pulmonary vein stenosis in a 4-year-old girl with a mediastinal mass (most likely myofibroblast-like soft-tissue abnormality) presenting with hypoxia. Axial contrast-enhanced CT image shows non-enhancing mass (arrows) with irregular borders in the expected location of the left pulmonary vein, which is not visualized because of complete pulmonary vein stenosis. LA left atrium

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Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency and lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency and lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency are rare entities on the spectrum of immunodeficiency syndromes that were previously under the umbrella diagnosis of common variable immune deficiency [49, 50]. Clinical features include autoimmune cytopenias, enteropathy, lymphoproliferative infiltration and pulmonary manifestations including recurrent infection [51,52,53,54].

At CT, these immunodeficiency syndromes demonstrate a characteristic constellation of findings including bronchiectasis, ground-glass opacities, interstitial thickening, pulmonary nodules and visceral (middle) mediastinal lymphadenopathy [51, 54,55,56,57] (Fig. 16). While evaluation of these entities is limited to case series, trends demonstrate a greater extent of pulmonary disease and mediastinal lymphadenopathy in children with LRBA deficiency than in those with CTLA-4 haploinsufficiency [57].

Fig. 16
figure 16

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency in a 9-year-old girl who presented with respiratory distress. Axial contrast-enhanced CT image shows enlarged lymph nodes (asterisks) in the visceral mediastinal compartment. Note the multifocal airspace disease in both lungs

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Dedicator of cytokinesis 8 (DOCK8) gene mutation

Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare autosomal-recessive form of hyperimmunoglobinemia E syndrome [58,59,60,61]. The true prevalence is unknown, but as of 2021 approximately 230 cases had been reported, particularly in regions with high consanguinity [60, 62,63,64]. Given that DOCK8 is a regulator of T cells and B cells, DOCK8 deficiency presents in early childhood as immunological titer derangements, frequent infections (usually pulmonary) and increased susceptibility to atypical viral and fungal infections [58,59,60, 62, 64]. Consequently, children with DOCK8 deficiency demonstrate a progressive decline in overall survival, with 87% alive at age 10, but only 37% by age 30 [59]. Familiarity with the imaging characteristics of DOCK8 deficiency can facilitate prompt diagnosis.

On CT, a series of 17 children with DOCK8 deficiency demonstrated visceral (middle) mediastinal adenopathy in 64% and both mediastinal and hilar adenopathy in 18% of the children [65] (Fig. 17). Mediastinal adenopathy was frequently seen in conjunction with a constellation of pulmonary findings including bronchiectasis (65%), ground-glass opacities (53%) and pulmonary nodules (24%) [65]. Bronchiectasis typically has a middle lung zone predominance (73%), whereas ground-glass opacities and pulmonary nodules are uniformly distributed [65] (Fig. 17).

Fig. 17
figure 17

Dedicator of cytokinesis 8 (DOCK8) deficiency in a 5-year-old boy who presented with recurrent lung infections. a Axial contrast-enhanced CT image shows an enlarged mediastinal lymph node (asterisk) in the visceral mediastinal compartment. b Axial lung window CT image demonstrates extensive bronchiectasis in the right middle lobe and lingula

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Paravertebral (posterior) mediastinal compartment

Neuroblastoma, ganglioneuroblastoma and ganglioneuroma

Neuroblastomas, ganglioneuroblastomas and ganglioneuromas are all sympathetic ganglion tumors arising from primordial neural crest cells. Neuroblastomas account for 10% of all childhood cancers and commonly arise from the adrenal glands, but can be found anywhere along the sympathetic chain, including the paravertebral (posterior) mediastinum in 14–20% of cases [66]. Most affected children present by 4 years of age with nonspecific constitutional symptoms, such as anemia, and sometimes symptoms of spinal cord compression if there is aggressive local spinal canal invasion [66].

Ganglioneuroblastomas are considered a transitional tumor on the spectrum of sympathetic ganglion tumors, where ganglioneuromas are benign, neuroblastomas, are malignant and ganglioneuroblastomas have malignant transformation potential.

On MRI, differentiation among the three types of ganglion tumors is near impossible because of their similar imaging characteristics. These tumors typically appear as well-marginated, lobulated T1-hypointense and T2-hyperintense masses, sometimes with susceptibility artifact from calcifications [67] (Figs. 18, 19 and 20). Differences in cellularity and degrees of hemorrhage and necrosis contribute to variable diffusion restriction and enhancement patterns. Neuroblastomas are soft and amorphic tumors that tend to encase local structures and extend into the neuroforamina, whereas the other tumors are sometimes described as more discretely fusiform. Relatively older median age of presentation (10 years) might also help differentiate ganglioneuroblastomas and ganglioneuromas from neuroblastomas. Nuclear imaging might also be helpful because 90% of neuroblastomas, but only 57% of ganglioneuromas are avid on iodine-123 and 131-metaiodobenzylguanidine (MIBG) imaging [68, 69]. Histopathological diagnosis is, however, ultimately needed for confirmation.

Fig. 18
figure 18

Neuroblastoma in an 8-month-old girl who presented with lower-extremity weakness. a Axial post-contrast T1-weighted fat-suppressed MR image demonstrates a heterogeneously enhancing paravertebral mass lesion (arrow) with pleural involvement (asterisk) and intraspinal extension (arrowhead). b Sagittal post-contrast T1-weighted and fat-suppressed MR image shows the intraspinal extension (arrowheads) of the paravertebral mass

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Fig. 19
figure 19

Ganglioneuroblastoma in a 17-month-old girl who presented with fever and cough. Axial T2-weighted and fat-suppressed MR image demonstrates a left paravertebral mass (asterisk) with intraspinal extension (arrowhead). Surgical pathology confirmed the diagnosis of ganglioneuroblastoma

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Fig. 20
figure 20

Ganglioneuroma in a 6-year-old girl who presented with lethargy. Axial T2-weighted fat-suppressed MR chest image shows a hyperintense mass (asterisk) in the left paravertebral region. Surgical pathology confirmed the diagnosis of ganglioneuroma

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Schwannoma and neurofibroma

Schwannomas are the more common benign peripheral nerve sheath tumors (PNSTs) and are associated with neurofibromatosis type 2 [70, 71]. Conversely, neurofibromas have an association with neurofibromatosis type 1 [70]. Benign PNSTs are indistinguishable on imaging alone. They appear as smooth, lobulated, well-defined paraspinal masses, with adjacent osseous erosion or remodeling in 50% of cases at CT [70, 72]. Splaying of the ribs with a “split fat” sign might also be seen [73]. Calcifications are rare, but more common among neurofibromas. At MRI, neurofibromas have high signal intensity on T2-weighted imaging, low to intermediate T1 signal relative to muscle, and are avidly enhancing (Fig. 21). A “target” sign characterized by central hypointensity on T2-weighted sequences is more commonly associated with, but not exclusive to, neurofibromas [74]. Extension into the spinal canal can give a “dumbbell” configuration. Lack of MIBG avidity differentiates PNSTs from neuroblastomas, whereas high FDG PET metabolic activity distinguishes these tumors from malignant PNSTs with 95% sensitivity and 72% specificity [75].

Fig. 21
figure 21

Plexiform neurofibromatosis in a 7-year-old boy with known neurofibroma and scoliotic deformity of spine. Axial T2-weighted fat-suppressed MR image shows extensive plexiform neurofibromatosis (asterisks) involving bilateral paravertebral regions of thoracolumbar spine

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Extramedullary hematopoiesis

Extramedullary hematopoiesis most commonly presents as a thoracic paraspinal mass after hepatosplenomegaly and is associated with chronic hemolytic anemias, such as thalassemia and sickle cell disease [76]. Masses are typically well-marginated and are usually bilateral and heterogeneously attenuating with macroscopic fat at CT [76, 77]. Associated calcifications are rare. On MRI, there are variable T1, T2 and contrast-enhancement patterns because of the degree of fat (Fig. 22). While there might be a “split rib” sign, there is typically no osseous erosion.

Fig. 22
figure 22

Extramedullary hematopoiesis in a 17-year-old boy. Axial T2-weighted MRI of the thoracic spine shows a lobulated, well-circumscribed, heterogeneously enhancing paravertebral mass (arrow)

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Conclusion

Imaging evaluation is critical to the diagnosis and management of pediatric mediastinal masses. The ITMIG framework, compared to the traditional radiographic segmentation, allows for more specific and standardized diagnosis of mediastinal disease processes, including rare systemic pathologies with thoracic presentation. With greater utilization of cross-sectional imaging, the ITMIG paradigm also provides the opportunity for greater precision in treatment planning and evaluation of treatment response, which has potential to improve patient outcomes.