Anterior mediastinal masses and thymic cysts

Abstract

Cystic lesions of the anterior mediastinum in children suggest a well-known group of benign lesions that are comparatively frequent. Thymic cysts (TCs) are mostly positioned in the anterior mediastinum and some patients in the neck. Benign TCs classified as congenital intra-thoracic mesothelial cysts are commonly asymptomatic and have slight clinical significance. Multilocular TC, which can mimic another anterior mediastinal cystic tumor and is seen in adults, is more clinically important. It is a sporadic mediastinal lesion thought to arise in the course of acquired inflammation. Congenital mediastinal cysts represent 3%-6% of all mediastinal tumors and 10%-18% of radiologically reported mediastinal masses. Mediastinal TCs are uncommon and it is hard to know their true incidence. About 60% of cases with mediastinal TCs are asymptomatic, and the remainder of patients complains of nonspecific symptoms (e.g., chest pain, dyspnea, or cough). The literature suggests that most cysts are benign, but an indefinite percentage may have a neoplastic process and result in significant compressive symptoms over time. Clinical symptoms of TCs vary depending on the location. In addition, frequent symptoms at the appearance of enlarged benign thymic and mediastinal cysts generally contain compressive symptoms (e.g., respiratory distress, thymic pain, and symptoms related to Horner syndrome, hoarseness, dysphonia, dyspnea, orthopnea, wheezing, and fever). Many TCs have cystic density and a neat border and are simple to diagnose with radiological imaging. However, some TCs are hard to identify before surgery and may be misidentified as thymomas depending on their site and computed tomography results. Excision by thoracotomy, median sternotomy, or video-assisted techniques is essential for conclusive diagnosis, management, and abolition of relapse of anterior mediastinal masses and TCs. Histopathologic examination may be required after surgery. Considering the extent of the mass and the preliminary inability to make a definitive diagnosis, en bloc excision of the cyst was thought to be preferred to circumvent likely complications (e.g., perforation, spillage of the contents, or incomplete excision).

Key Words: Mediastinal mass; Thymic cyst; Malignant tumor; Cysts; Thymoma; Computer tomography

Core Tip: Since thymic cysts may show malignant transformation, they pose a diagnostic challenge requiring only surgical excision and histologic examination. Because of cystic changes that mask tumoral features, extensive sampling is necessary to avoid missing a malignancy.

INTRODUCTION

In this editorial article, we comment on the article published in the recent issue of the World Journal of Clinical Cases[1]. In this editorial, with particular reference to the article, the correct diagnosis of such multilocular thymic cysts (MTCs) and the importance of different laboratory and radiologic methods will be mentioned after general information. In this regard, diagnostic developments in particular will be discussed in light of recent literature.

Cystic lesions of the anterior mediastinum in children suggest a recognized set of benign lesions that are comparatively frequent. TCs are mostly positioned in the anterior mediastinum although some are located in the neck. Many are circular, elliptical, and uneven in form, with discrete or nondiscrete structures[2,3].

Benign TCs are frequently unilocular, comprise clear fluid, and have thin walls. Benign TCs classified as congenital intra-thoracic mesothelial cysts are commonly asymptomatic and have slight clinical significance[4]. MTC, which can mimic another anterior mediastinal cystic tumor and is seen in adults, is more clinically important[5]. MTC is a sporadic mediastinal lesion thought to arise in the course of acquired inflammation. It is generally described by distinct cystic density and filled with clear fluid[6].

Mediastinal tumors are rare and are mostly thymic epithelial neoplasms such as thymoma or thymic carcinoma. Although cystic changes can occur in any tumor in the mediastinum, the occurrence of cystic alterations as in MTC is rare. It is of great importance to have a high index of suspicion, keeping in mind that a morphologic abnormality such as MTC may conceal another neoplasm or that sampling may not be sufficient to accurately detect an extra tumoral condition related to MTC[5].

EPIDEMIOLOGY AND PREVALENCE

Congenital mediastinal cysts represent 3%-6% of all mediastinal tumors and 10%-18% of radiologically reported mediastinal masses. Mediastinal TCs are uncommon and it is hard to know their true incidence. People of any age from 1 month to 79 years can be affected by this rare disease without any sex preference[2]. Cystic changes of the thymus are rare lesions as well as occurring in nonneoplastic congenital and acquired conditions. In radiologic imaging for lung cancer scanning, any mediastinal mass was found in 0.77% and mediastinal TCs in 0.01%. Another study demonstrated that TCs accounted for only 1% to 4% of mediastinal masses[2].

Benign TCs are less common and account for roughly 3% of all mediastinal masses[2]. The true frequency of MTC is hard to assess as it is underreported due to its benign clinical prognosis. It has been reported that MTC recurred in cases where complete surgical resection could not be achieved and additional chemotherapy and radiation therapy were given in some cases[5].

PATHOPHYSIOLOGY OF TCs

Mediastinal TCs were extensively defined by radiologist Ronald Seltzer in 1968[2]. The thymus embryologically forms from the third pharyngeal pouch in the 6th week of pregnancy and goes down to its location in the anterior part of the chest along the midline 2 weeks later, where it fuses with other tissues. Due to problems during this descent, ectopic thymic tissue can form anywhere from the hyoid to the diaphragm. According to the most extensive studies, TCs are most commonly detected in the anterior and less frequently in the middle and posterior mediastinum[2].

Immunologic causes such as Lupus, Sjögren's disease, and immunoglobulin G4 disease, among others (e.g. human immunodeficiency virus [HIV], bacterial infection), as well as various inflammatory processes such as surgical procedures have been associated with the development of MTC. Furthermore, neoplastic processes related to the development of MTC are very diverse and include the following examples: (1) Langerhans histiocytosis; (2) Hodgkin lymphoma; (3) Non-Hodgkin lymphoma; (4) Thymoma; (5) Thymic carcinoma; (6) Papillary adenocarcinoma; (7) Seminoma; and (8) Mature teratomas[2].

HISTOLOGY

The thymus develops from the third pharyngeal pouch and descends from the neck into the anterior-superior mediastinum. The leading theory hypothesizes the formation of these cysts from the remnants of the thymopharyngeal ducts. This duct is a remnant of one of the paired tracts of embryological thymic descent. Congenital benign thymic cysts (unilocular type) occur after cystic disintegration of ductal Hassall corpuscles in the thymopharyngeal ducts[4]. Histologically, TCs are most easily defined by the annexation of Hassall corpuscles in the cyst wall. These vortex-shaped keratinized structures contained by epithelial cells, Hassall corpuscles, are distinctive to the thymus. Fibrous stratified squamous epithelium is prominent in the cyst walls. Aspiration of the cyst substances is typically not diagnostic and only lymphocytes are observed[2].

MTC consists of multiple cystic areas coated with squamous epithelium. These cystic areas are characterized by inflammatory modifications that may consist of necrosis, cholesterol granulomas, fibrosis, germinal centers, calcifications, and hemorrhage[2]. Depending on the inflammatory process on which the cyst formation is based, additional histologic findings (e.g., myofibroblasts in teratoma, dense oval cells with central nuclei in thymoma, cuboidal or columnar cells in papillary adenocarcinoma, follicular hyperplasia in HIV, and layers of spindle, basaloid, papillary and squamous cells in thymic carcinoma) may be observed[2].

TCs can range in dimension from 1 cm to 18 cm in maximum measurement. The outer surface is usually smooth and the cyst wall might be thin and fibrous or thicker and compact. The interior of the cyst might be unilocular or multilocular with a smooth inner surface and frequently serous fillings. The contents of the MTC may range from clear and watery to turbid or hemorrhagic, and the inner surface might be smooth or uneven. Microscopic investigation shows changing quantities of thymic tissue in the cyst wall. In unilocular TC (UTC), the cyst wall is thin and the coating is composed of flattened, columnar, or cuboidal cells or stratified squamous epithelium. The MTC structure is more complex and often shows fibrosis, reactive lymphoid follicle formation, and elaborate inflammatory or degenerative variations (e.g., chronic inflammatory cell infiltrates, cholesterol cleft granulomas, and granulation tissue). MTC frequently occurs in conjunction with thymic neoplasms (e.g., thymic epithelial neoplasms, germ cell tumors, lymphomas), and cautious assessment of the cyst with suitable tissue specimen is recommended to eliminate this risk[6].

CLASSIFICATION OF TCs

TCs are grouped as unilocular, multilocular, congenital, and acquired (Table 1). They are mostly congenital and represent embryologic remnants. Inflammatory MTC formation due to enlargement of Hassall bodies in response to antigens supports this classification[2]. Acquired cysts are usually multilocular and may follow after thoracotomy, chemotherapy/radiotherapy, or various inflammatory processes[3]. In addition to post-inflammation, they are also thought to occur in association with immunodeficiency diseases (e.g., HIV), autoimmune diseases (arthritis or Sjögren's syndrome), or thymic trauma. Thus, MTC is also referred to as an acquired and multilocular cyst[7-9].

Table 1 Mediastinal pathologies mimic thymic cysts.

Thymic pathology/mimics	Nature	Localization
Thymic hyperplasia	Benign	Anterior mediastinum
Thymoma (noninvasive)	Benign	Anterior mediastinum
Thymoma (invasive)	Malignant	Anterior mediastinum
Thymic cyst	Benign	Anterior mediastinum
Unilocular	Benign	Anterior mediastinum
Multilocular	Benign	Anterior mediastinum
Thymolipoma	Benign	Anterior mediastinum
Thymic carcinoma	Malignant	Anterior mediastinum
Thymic carcinoid	Malignant	Anterior mediastinum
Thymic sarcoma	Malignant	Anterior mediastinum
Thymic germ cell tumor	Malignant	Anterior mediastinum
Thymic lymphoma	Malignant	Anterior mediastinum
Lymph node	Benign	Anterior mediastinum
Mediastinitis	Benign	Anterior mediastinum
Morgagni hernia	Benign	Anterior mediastinum
Pleuro/pericardial recess/cyst	Benign	Anterior/middle mediastinum
Parathyroid cyst	Benign	Anterior mediastinum
Bronchogenic cyst	Benign	Middle/posterior mediastinum
Enteric cysts	Benign	Middle mediastinum
Thoracic duct cyst	Benign	Middle/posterior mediastinum
Mediastinal cyst with mullerian differentiation	Benign	Posterior mediastinum
Esophageal duplication cyst	Benign	Anterior mediastinum
Gastric cyst	Benign	Anterior mediastinum

CLINICAL SYMPTOMS AND FINDINGS

About 60% of cases with mediastinal TCs are asymptomatic and the remainder of patients complain of nonspecific symptoms (e.g., chest pain, dyspnea, or cough)[3]. The literature suggests that most cysts are benign, but an indefinite percentage may have a neoplastic process and result in significant compressive symptoms over time[2]. Clinical symptoms of TCs vary depending on the location. In addition, frequent symptoms at the appearance of enlarged benign thymic and mediastinal cysts generally contain compressive symptoms (e.g., respiratory distress, thymic pain, and symptoms related to Horner syndrome, hoarseness, dysphonia, dyspnea, orthopnea, wheezing, and fever)[2,4]. Congenital posterior mediastinal cysts may exist throughout the thorax and are particularly associated with vertebral dislocation and neurologic symptoms. When these cysts enlarge, symptoms and compressive effects must occur in patients[4].

Compression symptoms due to cysts also may be variable and unique depending on the location of the cyst. Right atrial compression may mimic symptoms of right heart failure. Compression of the superior vena cava (SVC) leads to facial congestion. The formation of cysts near the SVC and right atrium can lead to atrial fibrillation and rescindable heart failure. Syncope may occur in the case of left atrial compression. Mass effect on pulmonary structures and atelectasis due to cysts explain the dyspnea that normally occurs in healthy subjects. Spontaneous cyst ruptures representing pleural effusions and related to pleuritic chest pain have been reported in the literature. Neurologic symptoms such as anhidrosis, miosis, and ptosis occur in Horner’s syndrome due to exterior compression of sympathetic structures. Transient unilateral vocal cord paralysis due to possible recurrent laryngeal nerve compression has also been described. If spontaneous anemia, rapid cyst growth, pleural effusions, and mediastinal enlargement occur without an identifiable cause, emergency surgical intervention may be required[2].

DIAGNOSIS

Many TCs have cystic density and a neat border and are simple to diagnose with radiological imaging[2]. However, some TCs are hard to identify before surgery and may be misidentified as thymomas depending on their site and computed tomography (CT) results. Histopathologic examination may be required after surgery. MTC can also easily be mistaken for a malignant tumor, especially on CT, as in this case report by Sun et al[1]. This editorial article provides updated data in the light of the literature to make this distinction easier.

Chest radiographs were the chief diagnostic method used to evaluate mediastinal masses before the development of cross-sectional CT imaging. Since early times, lateral chest radiographs have been recommended for routine daily examinations because the anterior location of thymic cysts is a common feature[2].

CT imaging, rather with contrast, is often ordered in the assessment of mediastinal masses. Depending on the largest series examining the CT features of TCs, these masses are usually sharply circumscribed, round/oval and located laterally in the anterior mediastinum[2].

On CT, the normal thymus can be recognized by its smooth-edged and bilobed triangular structure situated in the anterior mediastinum[3]. In children, CT shows homogeneous soft tissue attenuation. Before puberty, the thymus looks like a quadrilateral or triangular shape with convex lateral borders. After puberty, as fat involution occurs, the density declines and a more heterogeneous form occurs. In adults, the silhouette is triangular and the edges develop linear or concave. After 40 years of age, a generalized low density seen on CT should be due to almost widespread fatty involution of the thymus. The remaining thymic tissue might be observed as a linear or oval soft tissue density in the anterior mediastinum. In general, significant imitators of the normal thymus on CT may be the lymph nodes and the superior sinus of the pericardium.

Magnetic resonance imaging (MRI) is regularly used as an added imaging modality to aid in the diagnosis of such cysts. T2 sequences, which appear very bright, have an explicit but nonsensitive quality that may aid in differentiating thymic cysts from other pathologic conditions. The most common MRI sequences are T1- and T2-weighted scans. The sequence weighting highlights differences on the T2 (transverse/spin-spin) relaxation time of tissues. T2 transverse relaxation time is the time constant which determines the rate at which excited protons reach equilibrium or go out of phase with each other. Signal intensity on T2-weighted images (T2 sequences) is near to that of fat[3]. T1 sequences are also useful and signal intensity ratios of 1 to 1.5 can be used to differentiate thymic cysts[2]. On MRI, the thymus shows homogeneous signal intensity, which is higher than that of muscle on T1-weighted imaging[3]. T1 (longitudinal relaxation time) is the time constant which determines the rate at which excited protons return to equilibrium. Chemical shift MRI is especially helpful in distinguishing thymic hyperplasia from tumors. Again, cystic thymomas may mimic cysts and MRI is useful to differentiate them.

Positron emission tomography (PET) is another additional imaging technique that can be used to differentiate cysts from other pathologies with a low maximum regular uptake value suggestive of benign characteristics[2].

Endoscopic ultrasound, a newer technology, is another hypothetically helpful method in the identification of thymic cysts. When a thymic or mediastinal cyst is doubted, endoscopic aspiration of the cyst contents should be performed with extreme caution because fine needle aspiration analysis is usually, 73% of the time, nondiagnostic and carries the risk of infection, sepsis, and death[10].

Decisive diagnosis dependent on imaging alone is difficult and eventually, the conclusive diagnosis is based on histologic assessment of surgical samples. Since biopsy evaluation of cysts is usually not conclusive, tissue sampling by biopsy should not be performed before surgical excision[2].

DIFFERENTIAL DIAGNOSIS

CT can differentiate between congenital simple and complicated thymic cysts; the prior shows homogeneous fluid density and smooth, indiscernible edges[3]. Since cystic thymomas, which are solid masses, can mimic complicated thymic cysts that appear hyperdense on CT, identification and differentiation of solid constituents in the cystic mass is very important. Multidetector CT of high-density thymus gland nodules (maximum span ≤ 3 cm) may disclose explicit characteristics that may help in the differential diagnosis of thymic cyst from thymoma[11]. Enhanced CT associated with MRI is higher than enhanced CT or MRI alone for the preoperative differential diagnosis of thymomas, < 5 cm and < 3 cm in diameter, from thymic cysts[12].

MRI is useful in the diagnosis of complicated cysts showing high T2-weighted signal intensity with stratification due to low signal. Smooth edge enhancement and absence of solid enhancing components on images after contrast administration is affirmative of a complicated thymic cyst. Low intensity on T1-weighted images, high intensity on T2-weighted images, and absence of contrast enhancement would mean that the MRI features of these uncomplicated cysts have signal intensity reminiscent of any simple cyst[3].

The following benign diseases are included in the differential diagnosis on imaging of diseases confused with MTC: (1) Lymphangioma; (2) Hemangioma; (3) Seminoma; (4) Hodgkin's disease; (5) Pericardiac cysts; (6) Cystic teratoma; and (7) Cystic degeneration of malignant tumor (Table 1). A septum within the cyst is an exclusive evidence to distinguish MTC among these disorders. However, it is difficult to assertively distinguish MTC from these other likely diagnoses by imaging alone[13-15].

Teratomas usually display characteristics (e.g., fat, cartilaginous tissue or calcification, and a thick wall). Lymphangiomas characteristically comprise cervical or axillary constituents. Hemangiomas show contrast augmentation. Cystic disintegration of malignancies usually manifests as cysts with a solid component. These diseases included in the differential diagnosis do not typically show natural contraction excluding unilocular cysts[14].

Regardless of the known limits of imaging, new developments in technology e.g. "radiomix", which uses computer analysis of the acquired images, have been recognized to be helpful in the precise diagnosis of cysts[2,16].

True hyperplasia and lymphoid (follicular) hyperplasia symbolize two different histologic subtypes of thymic hyperplasia. Both seem symmetric, with diffuse enlargement of the gland, and cannot be notable by radiologic imaging alone. Diffuse symmetric enlargement of the gland is the main characteristic in defining thymic hyperplasia. Other features that help distinguish thymic hyperplasia from normal thymus contain the existence of round soft tissue masses larger than 7 mm, convex contour of the thymus after the age of 19 years, soft tissue lobulation and augmented thymic width (normal, ≤ 1.3 cm after the age of 20 years)[3,17,18].

Thymomas stem from the thymic epithelium and signify the most common crucial neoplasm of the anterior mediastinum in adults. Most thymomas (70%) occur in the 5^th and 6^th decades of life without any sex preference. CT is the present imaging option of choice for classification as invasive or noninvasive. Lobulated or irregular contours, cystic or necrotic modifications, and multifocal calcification findings are more indicative of invasive thymoma. Larger thymomas are more liable to experience hemorrhage and necrosis and will usually have a heterogeneous or cystic form. MRI of thymomas is inexplicit and has a restricted role in demonstrating invasiveness. Thymomas show muscle-like T1 signal intensity and T2 signal intensity close to that of fat[3,17,18].

PET imaging may pose a difficulty in discriminating thymic tumors from hyperplasia because both may show amplified fluorine-18 fluorodeoxyglucose uptake. Adjunctive imaging with CT and MRI may help differentiate physiologic thymic involvement from malignancy[3].

In patients older than 16 years, chemical shift MRI can help differentiate hyperplasia from a thymic tumor. Thymic hyperplasia, unlike tumors, is anticipated to have fat infiltrating normal tissue. Consequently, thymic hyperplasia will display a homogeneous decline in signal intensity in contrast phase sequences compared to in-phase. The lack of a reduction in signal intensity on the contrast phase sequence images indicates a thymic mass rather than hyperplasia[19].

TREATMENT

After clinical judgment, the surgical pathway is followed in the therapy of mediastinal thymic cysts. In symptomatic cysts, resection should be recommended cases considering the excellent surgical results and complications seen only in 1.1%-6.5% of cases[2].

Management of asymptomatic cysts is less direct. Most accessible literature indicates that most thymic cysts are benign, although this is contradicted by abundant case reports telling the development of concealed neoplastic processes, spontaneous hemorrhages, and significant deceptive subclinical compressive symptoms in these patients[2]. Almost all neoplastic cysts are multilocular and composed of solid components that appear to be common characteristics of neoplasia. Previous studies have shown that the solid components in MTC may include a variety of nonneoplastic tissues (e.g., thymic hyperplasia, thymic remnants, hemorrhagic cysts, or multiple small cysts septated by thick inflammatory thymic tissue). In these, the risk of malignancy is probably < 1% and the rate of surgical complications is between 1% and 5%[2].

There is currently no agreed-upon treatment for patients with benign thymic cysts, both asymptomatic and symptomatic. Anticipatory administration with surveillance imaging (watch and wait) is the most common method. Both fine needle and mediastinoscopic aspiration and biopsy strategies for diagnostic and therapeutic purposes have also been described with variable outcomes[4].

Excision by thoracotomy, median sternotomy, or video-assisted techniques is essential for conclusive diagnosis, management, and abolition of relapse. Considering the extent of the mass and the preliminary inability to make a definitive diagnosis, en bloc excision of the cyst was thought to be preferred to circumvent likely complications (e.g., perforation, spillage of the contents, or incomplete excision)[4].

PROGNOSIS

Although recent large original studies indicate that mediastinal thymic cysts are benign, numerous case series indicate otherwise, establishing a neat relationship between neoplastic processes and inflammatory cysts[2].

Local relapse of an excised thymic cyst has not been demonstrated to date. A wait-and-see attitude can be applied, but the definitive diagnosis can only be made by excision. A conclusive diagnosis is significant because bronchogenic and acquired MTC caused by inflammation and neoplasm must be excluded. It should also be kept in mind that thymic cysts may concur with various malignancies e.g. teratoma, Hodgkin's disease[20], neurofibromatosis, thymoma, thymic carcinoma, etc. Cystic variant of thymoma might also be existent[4].

Extremely rare, cases of thymoma with intracystic spreading stem from a UTC have been reported[21,22]. About 40% of thymomas may experience cystic transformation. Hemorrhage into large cysts is also an important worry. Although it has been demonstrated in young subjects, thymic cysts large enough to result in compression symptoms are observed in individuals aged 40-60 years[4].

CONCLUSION

Cystic lesions of the anterior mediastinum in children suggest a well-known group of benign lesions that are comparatively frequent. Thymic cysts are mostly positioned in the anterior mediastinum and some patients in the neck. Benign thymic cysts classified as congenital intra-thoracic mesothelial cysts are commonly asymptomatic and have slight clinical significance. MTC, which can mimic anterior mediastinal cystic tumor and is seen in adults, is more clinically important. About 60% of cases with mediastinal thymic cysts are asymptomatic and the remainder complain of nonspecific symptoms e.g. chest pain, dyspnea, or cough. Many thymic cysts have cystic density and a neat border and are simple to diagnose with radiological imaging. However, some thymic cysts are hard to identify before surgery and may be misidentified as thymomas depending on their site and CT results. Excision by thoracotomy, median sternotomy, or video-assisted techniques is essential for conclusive diagnosis, management, and abolition of relapse of anterior mediastinal masses and thymic cysts. Considering the extent of the mass and the preliminary inability to make a definitive diagnosis, en bloc excision of the cyst was thought to be preferred to circumvent likely complications (e.g., perforation, spillage of the contents, or incomplete excision). Histopathologic examination may be required after surgery. The spectrum of tumoral entities related to MTC demonstrates the significance of not only taking a detailed clinical/radiological history but also the significance of sampling any mediastinal cystic tumor to accurately reach a diagnosis[5].