Aspects of thymic pathologies in paediatric patients. Case study of true thymic hyperplasia and the diagnostic approach

INTRODUCTION

The thymus, which is located within the anterior mediastinum, plays the role of the primary (central) lymphoid organ of the immune system, responsible for the controlled maturation of T-cells. During one’s lifetime the thymus undergoes substantial morphological changes reaching its largest size during puberty (Figure 1), then involution of the gland begins and continues with advancing age, being gradually replaced by adipose tissue [2].
Proliferative lesions of the thymus are very rare in children and represent only 2% of all mediastinal tumours in paediatric patients. An enlarged thymus may occur due to thymic hyperplasia, congenital or acquired cysts, epithelial neoplasms – thymolipoma, thymoma, carcinoma, or thymic neuroendocrine tumour (carcinoid) [3]. Among all anterior mediastinum tumours in neonates and infants, germ cell tumours (especially teratomas), congenital cysts, and thymic hyperplasia are most common. Teratomas, yolk sac tumours, and cysts are predominant in pre-schoolers. In children over 5 years of age, the most common type of anterior mediastinum tumours are lymphomas, while thymomas and thymic carcinomas are rarely observed. Sarcomas, although very rare, must be included in differential diagnosis in all paediatric patients [4].

CASE REPORT

A 2.5-year-old girl was admitted to hospital due to pneumonia treatment failure in an outpatient setting. Her history included productive cough for 2 weeks, without fever; and persistent asymmetry in lung auscultation with the negation of foreign body aspiration.
On admission, she presented with symptoms of nasopharyngitis, dullness over the whole right lung in percussion, and bronchial sound over the right upper lobe in auscultation. Blood tests revealed leucocytosis, lymphocytosis (Table 1), and low levels of C-reactive protein. In a chest X-ray massive inflammatory and atelectasis lesions were described within the mid and inferior right lobes without mediastinal shift and pleural effusion (Figure 2A). Antibiotic treatment (ceftriaxone, clarithromycin) was introduced, without lung improvement; hence, further diagnostic steps were performed. In flexible bronchoscopy there was evidence of purulent bronchitis and bronchomalacia within the middle lobe, with negative results of microbial culture tests of bronchoalveolar lavage fluid. Humoral, and in further follow-up also cellular, immune deficiencies were ruled out (Table 1). A follow-up chest X-ray was performed (Figure 2B) together with chest computed tomography (CT), which showed a massive, heterogeneous in composition, tumour lesion localised within the right anterosuperior mediastinum, reaching the right supradiaphragmatic area with consolidation/atelectasis of the right lung and some pleural effusion at this side, without enlargement of the chest lymph nodes (Figure 2C, D, E, F). Because CT scan morphology raised suspicions of an immature teratoma, blood tests for tumour/carcinoma markers were done, with negative results (Table 2). Computed tomography scans of the head, abdomen, and pelvis showed no pathologies.
On the 21^st day of hospitalisation the patient was qualified for an ultrasound-guided core biopsy of the tumour, performed through the intercostal space. The intraoperative histopathological examination of the frozen biopsy specimen revealed a benign lesion originating from the thymus. In the next step during the same procedure, right-sided thoracotomy was performed, and 2 lesions (first 15.5 × 9 × 5 cm mass of 315 g, and second 3.5 × 1.5 × 0.8 cm mass of 3.2 g) were totally resected. The tumour was located in the anterior mediastinum, adjacent to lung parenchyma, pericardium, and right dome of the diaphragm with its top reaching the superior vena cava. The right phrenic nerve adjacent to the tumour was preserved without damage. After removal of the tumour, the right lung expanded properly. The tumour mass equalled 2.58% of the girl’s body weight. Histopathological examination (Figure 2I, J) confirmed morphology consistent with a hyperplastic thymus. The patient was discharged home on the seventh day after the surgery. In further follow-up the clinical course was uneventful without tumour recurrence in chest control evaluation (Figure 2G, H) and in the blood testing after one and 6 months since the intervention (Table 1). One year after this operation she presents with no medical problems, subjective complaints, no infections, and good tolerance of physical activities.

DISCUSSION

True thymic hyperplasia (TTH) is a diffuse organ over-enlargement in relation to the age-specific size and mass with normal thymic microscopic architecture. True thymic hyperplasia is typically observed in 3 clinical conditions:

• without any associated disorders,
• enlargement caused by a rebound effect in regeneration process after steroid therapy, cancer treatment, thermal burns, or tuberculosis,
• association with endocrine disorders (thyrotoxicosis, Addison’s disease, acromegaly, aplasia of the pituitary gland), sarcoidosis, or Beckwith-Wiedemann syndrome [5].

The clinical case presented above involved a very rare example of the first clinical condition.

EPIDEMIOLOGY AND AETIOLOGY

Incidence and prevalence rates of TTH are not known, but most often it occurs in neonates and in young children, unlike thymomas, thymic carcinomas, and lymphoid follicular hyperplasia, being mostly identified in adolescents and adults. The aetiology and pathogenesis of TTH are still not clear [4].

SYMPTOMS AND DIAGNOSTIC

True thymic hyperplasia very rarely causes clinical symptoms. Most often, disease is identified incidentally in follow-up medical imaging. However, massive TTH may cause compression of surrounding structures (mass effect – with atelectasis, acute or recurrent respiratory tract infections, cough, dysphagia and aspiration, discomfort in the chest) and even life-threatening conditions (respiratory and/or circulatory failure, haemorrhagic shock as the result of haemorrhage from the thymus) [4, 6, 7]. In symptomatic children cough, respiratory tract infection, or respiratory insufficiency are the leading clinical presentations (Table 3).
Blood tests in some cases show lymphocytosis – normalised in the postoperative period, while humoral and cell-mediated immunity markers remain within normal range [8].
There are no pathognomonic features specific to TTH. A chest X-ray shows the widening of the anterior mediastinal shadow, absence of calcifications, in some cases the thymic sail sign or wave sign, and – depending on the extent of organ enlargement – features consistent with lung parenchyma and great vessel compression, mediastinal shift, or pleural effusion. In chest CT, TTH presents with a homogeneous and diffuse appearance with symmetrical enlargement in most cases with adipose tissue in their composition [9]. Histopathology reveals normal thymic structure with normal lobular architecture. Immunohistochemical tests show no deviations from a normal thymus and present normal cellular response to growth stimulation with interleukins [8]. However, some authors described a quantitative decrease of m
ature T-cells in the cortical and medullary components of the thymus with accumulation of immature forms of T-cells [10].

DIAGNOSTIC CRITERIA

True thymic hyperplasia is defined as organ enlargement in relation to the age-specific size and mass of the thymus with normal microscopic architecture. Figure 1 and Table 4 show the relationship between mass of the thymus and the patient’s age. True thymic hyperplasia can be classified as massive when the following criteria are met: the thymic shadow is larger than the heart shape in chest posterior-anterior X-ray, and the mass of the thymus is several times greater than the normal mass specific to the patient’s age and exceeds more than 2% of the patient’s body weight [6, 7]. The presented case fulfilled these additional diagnostic criteria.

DIFFERENTIAL DIAGNOSTICS

True thymic hyperplasia should be differentiated from other chest tumours within the anterior mediastinum (thymoma, carcinoid tumour, thymolipoma, Hodgkin’s or non-Hodgkin’s lymphomas, germ cell tumours) and non-neoplastic diseases (cysts of various aetiologies or diseases accompanied by benign enlargement of the mediastinal lymph nodes, e.g. angiofollicular ganglionic hyperplasia (Castleman’s disease]) [2, 3]. The most frequently occurring types of mediastinal lesions grouped by age in the context of a diagnostic approach are presented in the form of an algorithm (Figure 3) [11, 12].
Important factors in differential diagnostics are age, clinical manifestation, as well as the patient’s history.
Anterior mediastinum tumours might present with similar clinical symptoms, regardless of pathology. Cases of very rapid expansion of TTH mass require urgent diagnostics for neoplastic pathology. In children with a history of severe stress (thermal burn, surgery, cancer therapies), subsequent “rebound” hyperplasia might be considered in differential diagnosis of enlarged thymus [5].
Recommended laboratory tests include a complete blood count, α-fetoprotein, β-hCG, chromogranin, neuron-specific enolase, lactate dehydrogenase, and uric acid levels. Computed tomography of the chest, and when indicated, also of the abdomen and head, are usually performed, but there are no pathognomonic features differentiating between various thymic pathologies. The decisive tool for definitive diagnosis is histopathological examination in combination with immunohistochemical tests.

TREATMENT

True thymic hyperplasia treatment is controversial (low effectiveness) and depends on the patient’s age and clinical symptoms. The conservative approach is based on systemic glucocorticosteroid therapy (prednisone 2 mg/kg) [13]. However, surgical intervention (thymectomy) in children up to one year of age is associated with decreasing circulating T-cells. Therefore, in patients younger than 18 months presenting with confirmed diagnosis, watchful observation is suggested with the introduction of glucocorticosteroid therapy in the course of symptom propagation. In the case of further thymus enlargement or life-treating condition, thymectomy becomes a necessity [6]. However, considering the very few symptoms that accompany TTH, the lack of pathognomonic features in additional examinations, and the much more common occurrence of non-benign anterior mediastinal tumours, the first line of treatment in suspicion of TTH seems to be a complete resection of the thymus and histopathological examination to unequivocally confirm the diagnosis.

CONCLUSIONS

From the presented case, it can be concluded that thymic pathologies have non-specific manifestations; therefore, oncological vigilance should be maintained in the case of chronic and untypical symptoms, especially no response to conventional treatment. We believe that the presented algorithm (Figure 3) could be suitable in the diagnostic approach of middle mediastinal tumours, keeping in mind that history taking is of high importance in suspected cases.

DISCLOSURES

1. Jagiellonian University Medical College Research Ethics Committee agreement was obtained (KEBN UJ CM 118.6120.56.2023).
2. Assistance with the article: None.
3. Financial support and sponsorship: None.
4. Conflicts of interest: None.

REFERENCES