Multilocular thymic cysts- a diagnostic challenge on computed tomography

Abstract

A recent case report provided a patient scenario, wherein, a 39-year-old male patient presented with occasional palpitations, headache, and fever. Evaluation of tumor markers did not show any abnormal results. Subsequently, a computed tomography (CT) scan was undertaken, and its findings were affirmative of thymic cancer. Finally, the postoperative histopathological assessment of the mass, after its resection, confirmed it as an anterior mediastinal multilocular thymic cyst (MTC), with concurrent acute upper respiratory tract infection and acute myocarditis. Accordingly, this case report advocates the need for a preoperative histopathological examination with CT imaging to minimize the risk of confusing an MTC with a malignant thymic tumor.

Key Words: Imaging findings; Multilocular thymic cyst; Histopathology; Thymic cancer; Mediastinal mass

Core Tip: The simultaneous use of histopathology and imaging modalities is the best approach to distinguish a rare mediastinal lesion, such as multilocular thymic cyst, from thymic cancer. Surgeons must not solely rely on computed tomography findings and correlate them with preoperative pathological investigation of the mediastinal mass to avoid the risk of incorrect diagnosis.

TO THE EDITOR

We had the opportunity to read the case report by Sun et al[1] that described the misdiagnosis of a multilocular thymic cyst (MTC) as thymic cancer. A fluid-filled MTC develops in the anterior superior mediastinum, presents with a distinct cystic density, and is associated with inflammation. It could also be associated with infection and bleeding in rare scenarios. An earlier study by Suster and Rosai[2] described dyspnea, chest discomfort/chest pain as the prominent acute symptoms of thymic cyst. However, its histological characteristics include cuboidal/columnar/squamous epithelium, cystic cavities, non-neoplastic thymic tissue, and scattered nests[2]. The MTC could also be accompanied by reactive lymphoid hyperplasia, hemorrhage, necrosis, and fibrovascular proliferation. The inflammatory processes associated with MTC and thymoma may trigger the development of Hassall corpuscles from the abnormally differentiating epithelial cells[3].

Not more than 5% of mediastinal masses include irregularly shaped elliptical/circular MTCs; however, their clinical manifestations and symptomatology vary by their anatomic location. Patients with MTCs may also develop Horner’s syndrome. Medical imaging procedures detect MTCs by depicting their boundaries and cystic densities. However, contemporary literature reveals the misdiagnosis of MTCs by the computed tomography (CT) scan procedure. The incorrect assessment of MTCs as thymomas/thymic carcinomas through the CT approach is evidenced by several clinical studies[4].

Other approaches used for MTC diagnosis include routine chest radiograph as it is the most performed imaging approach that is suggested for thymic lesions[5]. CT with contrast is another imaging modality for assessing thymic tumours as it has high spatial and temporal resolution, convenience and easy access. CT can help identify location, size, shape, margin, and changes in adjacent structures of invasion[6]. CT can be equal or superior to magnetic resonance imaging (MRI) in the mediastinal masses evaluation[7]. Other advancing imaging modalities, such as functional CT imaging that has CT perfusions, provide details for the evaluation of tumour angiogenesis, infiltration, and therapy response[8]. Dual-energy CT can be used to evaluate the differentiation of prevascular masses. High concentrations of iodine will be observed in malignant tumours compared to benign tumours[9].

MRI is not used as a routine in evaluation of thymic tumour evaluation. They are used in special cases like solid and cystic lesion differentiation, evaluation of cystic or necrotic mass and assessing the extent of invasion. Chemical shifting imaging can be used for the detection of microscopic or intravoxel fat, which helps in differentiating thymic neoplasia and hyperplasia[10]. Non-invasive functional MRIs like apparent diffusion coefficient values and diffusion-weighted imaging can help in the evaluation of thymic epithelial tumours. Functional MRI imaging technique with dynamic contrast-enhanced MRI can be used for prevascular mediastinal tumour evaluation. Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT is another method that can be used for thymic mass evaluation[5]. Other methods like biopsy, detection of serum markers such as platelet/albumin ratio, CysC, and Cyfra 21-1, multislice CT and radiomics can also be used for identification and differentiation of MTCs[11].

Advanced imaging modalities like multislice CT and MRI play an important role in differentiating between benign and malignant thymic lesions, yet each technique has its own challenges. While CT is the standard for mediastinal imaging, it also faces some challenges in accurately characterizing thymic cysts and distinguishing thymic hyperplasia from thymic tumours. MRI can address some of these limitations but it also has some limitations such as reductions in signal intensity on chemical shift imaging, size-related constraints, unusual signal intensity for cysts, pseudonodularity on T2-weighted images, misinterpretation of early imaging, overlap of diffusion coefficients between malignant and benign lesions also hinders the diagnosis. FDG PET/CT is not routinely indicated due to overlapping uptake between benign and malignant processes. This is significant in staging and detecting occult metastasis, especially in aggressive thymic carcinomas[12]. These challenges must be considered carefully while integrating image modalities into clinical practice. So, additional histopathological assessments can help in reducing the risk of misdiagnosis and help in distinguishing mediastinal lesions like MTC, from thymic cancer.

The current case report elaborates on a similar scenario concerning the misdiagnosis of MTC in a patient aged 39 years, who presented to the hospital with occasional palpitations, headache, and fever. It is important to note that despite the negative tumor marker results, the incorrect diagnosis of thymic carcinoma was confirmed by the CT approach. The diagnostic process for myocarditis was initiated as the patient had presented fever, palpitations, and abnormal electrocardiogram (ECG) findings. The ECG revealed atrial fibrillation, ventricular tachycardia, and elevated T-waves, which are common in myocarditis cases due to inflammation of the heart muscle. The elevated levels of lactate dehydrogenase (572 U/L) and α-hydroxybutyrate dehydrogenase (441 U/L) further suggested myocardial damage because these enzymes are released when cardiac cells are injured.

In this case, myocarditis was considered after ruling out other potential causes due to the normal tumour markers and the absence of typical ischemic changes on imaging. The presence of acute upper respiratory tract infection, alongside these cardiac findings, has supported the diagnosis of viral myocarditis. Additionally, the patient had occasional palpitations, headaches, and fever which can be considered as systemic manifestations of this condition. While CT imaging was primarily focused on assessing the mediastinal mass, the combination of clinical symptoms, abnormal cardiac enzymes, and ECG findings led to the final diagnosis of myocarditis.

The x-ray and CT findings revealed an irregularly shaped solid-cystic mediastinal mass of uneven density. Additionally, the contrast-enhanced CT provided the exact anatomic location of the nodule, in the proximity of the left brachial vein, superior vena cava, and ascending aorta. The CT results further indicated an unclear boundary of the mediastinal mass and ruled out any possible vascular invasion. Notably, the CT approach could not appropriately delineate the MTC morphology, thereby leading to the misdiagnosis of thymic cancer.

The MTC is a rare type of thymic cyst, probably triggered by inflammatory processes in patients with a known history of thymic trauma, Sjögren syndrome, arthritis, autoimmune diseases, or immune deficiency syndrome. Bleeding is the possible cause of the infiltration of gelatinous substances or cloudy/transparent liquids in the MTC. It is important to evaluate the histopathological characteristics of the MTC to differentiate it from thymic carcinoma. Some of these characteristics include reactive lymphoproliferative processes, cholesterol granuloma, hemorrhage, necrosis, fibrovascular proliferation, and chronic inflammation.

When comparing the CT characteristics of thymic tumours and mediastinal thymic cysts, thymic tumours in the anterior mediastinum appear as round or ovoid masses located in the retrosternal prevascular area. These masses have well-defined borders, uniform density, and slight improvement with contrast. The absence of the surrounding fat layer may suggest invasive thymoma, which is marked by non-uniform density, signs of cystic degeneration or necrosis, and strong enhancement of the solid portions on contrast-enhanced CT[11]. On the other hand, thymic cysts are observed in oval-shaped structures with smooth edges, centrally located in the midline, and without any visible surrounding thymic tissue in CT[13].

MTCs mostly display variations in protein content, with increased protein levels, haemorrhage, and inflammation leading to higher CT values within cystic areas. When these values are increased over 20 Hounsfield units (Hu) it shows a solid density. That can result in an increased risk of misidentification of MTCs as thymic tumour[14]. Additionally, the morphological similarity between MTCs and low-risk thymomas, which are commonly presented as round or oval masses, makes it difficult to accurately differentiate them[15]. Therefore, relying only on CT imaging to distinguish MTCs from thymic tumours is challenging. This states the need for improved preoperative diagnostic techniques as well as histopathological examination to avoid unnecessary treatments.

While we agree with the authors’ claim of using appropriate imaging modalities to improve the diagnostic and treatment algorithms concerning MTC management[1]; however, correlation of thymic mass characteristics based on the CT (Hu) value is necessary to avoid the risk of a misdiagnosis[16]. Furthermore, the tumor marker findings must be taken into consideration while interpreting the CT outcomes for the mediastinal masses. The authors of this case report could have utilized these aspects in the diagnostic workup to improve the CT-based diagnosis. Nevertheless, the case report did not provide details of the diagnostic algorithm guiding the assessment of acute myocarditis and its associated causes. Importantly, they did not mention the transudative/exudative pleural effusion type and excluded a cytology examination of the pleural fluid for differential diagnoses.

The incidental findings from the CT procedure usually qualify for the thymic lesions, including thymic cysts. The World Health Organization (WHO) classifies thymic tumors in terms of type A, atypical type A variant, type AB, type B1, type B, type B3, micronodular thymoma, metastatic thymoma, and other rare types[17]. This characterization is based on the patterns of CD20+ epithelial/polygonal epithelial cells, perivascular spaces, Hassall’s corpuscles, medullary islands, plasma cells, monoclonal B cells, lymphoid follicles, EMA-positive spindle cells, keratin/actin, and epithelial cell pleiomorphism. However, the authors of the current did not discuss the WHO characterization of thymic cysts. They also did not delineate the patterns of other potential markers while immunohistochemically characterizing thymic carcinoma vs MTC. These significant markers could include cytokeratin19, cytokeratin 20, P63, P40, TdT, CD5, CD20, and CD117[17].

Differentiating MTCs from thymomas involves understanding the unique histopathological characteristics and immunohistochemical profiles. The exact cause of MTC development is not fully understood. However, Suster and Rosai[2] suggested that MTCs may have originated from the medullary duct epithelium of the cyst, which becomes dilated due to acquired inflammatory processes. Similarly, the study by Shen et al[18] has also associated MTC with chronic inflammation, fibrotic changes, haemorrhage, and necrosis. This indicates that their formation may be related to inflammatory conditions rather than the mass effects of the tumour.

In the study by Nakamura et al[3] the immunohistochemical profiles of the epithelial lining of Hassall corpuscles and MTCs showed similar staining patterns for markers like AE1/AE3, CK13, p63, CK5/6, and D2-40. Sometimes, metastatic tumours can also be associated with MTC. Identifying atypical type A from B3 thymomas is a challenging process. Atypical type A thymomas lack CD20 expression but show prominent perivascular spaces, while type A thymomas display CD20 positivity and characteristic histological features. So immunohistochemical staining for CD20 and recognizing characteristic histological patterns are needed to accurately differentiate atypical type A and B3 thymomas that are related to MTCs[18].

Importantly, the authors of this case report ignored the current consensus regarding the use of tissue pathology investigation, in addition to CT scan, for the diagnostic assessment of mediastinal masses[1]. Of note, this case report presented a unique case of MTC evaluation, compared to the conventional assessment of the unilocular thymic cyst. While several contemporary studies defy the reliability of the CT scan in the preoperative assessment of thymic cysts, the pathological assessment is a standard approach to further investigate their density/components, such as colloidal material, turbid liquid, and bleeding. This case report provides further evidence to evaluate mediastinal nodules/cyst for reactive lymphoid hyperplasia, septum, and the cyst wall. The authors also discussed a few clinical studies, wherein, the CT-guided evaluation of the mediastinal/thymic cyst's solid density resulted in a misdiagnosis[14,19].

Notably, a comprehensive assessment of the different stages of the solid density of the mediastinal mass, including its hyperplastic thymic tissue, protein-based viscous liquid, reactive lymphoproliferation, bleeding, calcification, or cholesterol granuloma is paramount to avoiding the risk of misdiagnosing an MTC[1,20]. This case report further emphasizes the need to investigate the etiology of the associated pleural effusion via pleural fluid cytology. Since the authors of this case report failed to investigate the cardiac causes of pleural effusion, they could not track this significant clue to assist them in avoiding the possibility of misdiagnosing MTC as thymic cancer. The authors also missed stating the validity of the Stanford diagnostic parameter in tracking the suspected MTC’s inflammatory elements, cholesterol granulomata, and hyperplasia (focal regions)[21]. Furthermore, the histopathological assessment of lymph nodes could have helped the authors to identify the occurrence of reactive changes.

The authors of this case report could confirm the correct MTC diagnosis, and associated infection and bleeding, following the postoperative pathological evaluation of the mediastinal mass[1]. The outcomes of this report underscore the need for the appropriate preoperative assessment of MTCs, to inform their treatment strategies. Future studies should investigate and define risk stratification procedures to improve the current diagnostic approaches for evaluating the mediastinal masses, including MTCs. Nevertheless, the determination of confounding factors, such as unenhanced CT (> 20 Hu) and cyst diameter (≤ 3 cm) could substantially reduce the occurrences of misdiagnosing MTCs as malignancies[22].