Recurrent unilateral pleural effusion in a 63-year-old man: the answer lies in the mediastinum

Extract

A 63-year-old male non-smoker was referred to our pleural disease unit from a peripheral hospital due to a persistent unilateral pleural effusion. Despite being followed for 1 year, no definitive diagnosis had been reached. The patient had no comorbidities and was not on any chronic medication. Prior to the patient's transfer to our facility, a chest computed tomography (CT) scan had been performed. This revealed no significant findings, aside from a small mediastinal lesion, which the radiologist described as compatible with an angioma, initially believed to be an incidental finding (figure 1).

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Benign vascular masses in the mediastinum, such as haemangiomas, should be considered in the differential diagnosis of unexplained pleural effusions https://bit.ly/4fOjtO1

A 63-year-old male non-smoker was referred to our pleural disease unit from a peripheral hospital due to a persistent unilateral pleural effusion. Despite being followed for 1 year, no definitive diagnosis had been reached. The patient had no comorbidities and was not on any chronic medication. Prior to the patient's transfer to our facility, a chest computed tomography (CT) scan had been performed. This revealed no significant findings, aside from a small mediastinal lesion, which the radiologist described as compatible with an angioma, initially believed to be an incidental finding (figure 1).

FIGURE 1.

Previous chest computed tomography scan, carried out at the referring hospital.

Left-sided diagnostic thoracentesis had then been performed at the referring hospital. The aspirated pleural fluid was described as light-yellow in colour and the pH was 7.4. The laboratory analysis of the fluid showed a protein level of 4.5 g·dL⁻¹ (corresponding serum proteins were 7.5 g·dL⁻¹), lactate dehydrogenase (LDH) of 75 U·L⁻¹ (corresponding serum LDH was 148 U·L⁻¹), therefore, the fluid was slightly exudative. Glucose was 101 mg·dL⁻¹, triglycerides were 40 mg·dL⁻¹. No bacteria, including acid-fast bacilli, were identified. No malignant cells were detected on cytological examination. Given the results of these examinations, colleagues at the referring hospital ordered a positron emission tomography-computed tomography scan, that showed no pathological fluorodeoxyglucose uptake (figure 2).

FIGURE 2.

Positron emission tomography-computed tomography scan findings.

At that point, due to the ongoing pleural effusion, our colleagues at the referring hospital decided to perform a medical thoracoscopy. The biopsy results revealed nonspecific inflammation of the pleura. As a result, a course of oral corticosteroids was administered in an attempt to halt the effusion, but it persisted. The patient was therefore referred to our unit. At our clinic, the patient appeared in good general condition, with a body temperature of 37°C, blood pressure of 120/70 mmHg and heart rate of 75 beats per min. His respiratory rate was 16 breaths per min and oxygen saturation was 93% on room air. Clinically, the patient reported worsening dyspnoea. Pulmonary examination revealed diminished breath sounds over the left hemithorax. There were no other relevant findings on physical examination. Complete blood count and blood chemistry were within normal limits. A chest ultrasound at our examination confirmed a massive, free-flowing, non-septated, anechoic pleural effusion. A new contrast-enhanced computed tomography (CECT) scan of the thorax was then performed.

Task 1

What does the CECT scan of the thorax (figure 3) reveal? Describe the CT findings.

FIGURE 3.

Baseline chest computed tomography scan.

FIGURE 3.

Baseline chest computed tomography scan.

Answer 1

The scan reveals a 35×30 mm expansive, inhomogeneous, highly vascular lesion in the mediastinum. It features hypodense areas within and is located at the level of the aorto-pulmonary window, in contact with the mediastinal pleura. This is accompanied by a massive left-sided pleural effusion.

The previously identified mediastinal lesion had enlarged compared with the prior chest CT scan.

Task 2

Which of the following is not a possible differential diagnosis for hypervascular mediastinal masses?

1. Castleman disease

2. Vascular tumours

3. Paraganglioma

4. Metastatic disease

5. Bronchogenic cyst

Answer 2

Correct answer: e. Bronchogenic cyst. A bronchogenic cyst is typically not hypervascular, as it is a benign congenital anomaly arising from abnormal development of the bronchial tree and is usually filled with fluid or mucus rather than vascular tissue. Castleman disease (a), vascular tumours (b), paragangliomas (c) and metastatic disease (d) are all possible differential diagnoses. Castleman disease, a lymphoproliferative disorder, can present as a vascular mass. Vascular tumours, such as haemangiomas, are highly vascularised and may appear as masses with intense blood flow. Paragangliomas (neuroendocrine tumours) are also known for their rich vascularity. Finally, metastatic diseases, particularly from cancers like renal cell carcinoma, may have a hypervascular aspect due to neovascularisation.

Differential diagnosis of hypervascular mediastinal masses by compartment are as follows.

Anterior mediastinum:

• Castleman disease

• Ectopic parathyroid adenoma

• Vascular lesions

• Metastatic disease

• Thymic carcinoid

Middle mediastinum:

• Castleman disease

• Paraganglioma

• Vascular lesions

• Metastatic disease

Posterior mediastinum:

• Castleman disease

• Paraganglioma

• Vascular lesions

• Metastatic disease

• Neurogenic tumour

Despite a negative result from the initial medical thoracoscopy, the context of massive pleural effusion warranted a reassessment of possible pleural involvement due to malignancy. Consequently, a second medical thoracoscopy was performed with the goal of obtaining biopsies. If the endoscopic appearance strongly suggested neoplastic disease, talc poudrage would be administered to prevent re-accumulation of pleural fluid.

Task 3

Which of the following thoracoscopic findings are highly suggestive of malignancy?

1. Nodules with “Grape-like” distribution

2. Masses

3. Cauliflower-like formations on the parietal pleura

4. Plaques

5. “Sago-like” nodules

Answer 3

Correct answers: a, b, c and d. Findings such as nodules with “grape-like” distribution, masses, cauliflower-like formations on the parietal pleura and plaques are highly suggestive of malignancy in thoracoscopic evaluations. Nodules are small formations ranging in size from 1 to 10 mm. They are typically round, with a consistency that varies from hard to friable. They are often sessile, reddish and vascularised, appearing either isolated or more frequently disseminated in clusters. Masses and vegetations are larger pathological formations exceeding 10 mm in size. They tend to be irregular, lobulated, reddish and friable. Neoplastic thickening, appearing as plaques, are whitish, poorly vascularised and star-shaped, with variable thickness and size. They arise on a surrounding hyperaemic, irregular serosa with the intercostal pattern often obliterated. In contrast, the presence of “Sago-like” nodules on gross visual appearance under medical thoracoscopy is significantly associated with pleural tuberculosis. Answer e is incorrect.

Task 4

What is the endoscopic appearance of the parietal pleura during medical thoracoscopy (figure 4)?

FIGURE 4.

Endoscopic appearance of parietal pleura during medical thoracoscopy.

FIGURE 4.

Endoscopic appearance of parietal pleura during medical thoracoscopy.

Answer 4

The parietal pleura appears hyperaemic, with areas of irregular whitish patches, consistent with chronic exudation. No lesions were identified despite a thorough inspection of the pleural cavity.

Multiple samples of parietal pleura were taken, and a fresh sample of yellow-citrine pleural fluid was collected for cytological analysis. Histological examination revealed nonspecific pleuritis, and the cytology was negative for neoplastic cells. These findings made pleural malignancy unlikely, suggesting that the enlarged mediastinal lesion was the probable cause of the recurrent left-sided pleural effusion. 4 days after medical thoracoscopy, the chest tube was removed, and the patient was discharged. He was referred to the thoracic surgery unit, where, a few days later, he underwent robotic-assisted thoracoscopic surgery for complete excision of the mediastinal lesion (figure 5).

FIGURE 5.

Excision of the mediastinal lesion in robotic-assisted thoracoscopic surgery.

Pathological findings revealed irregular vascular proliferation. The vascular channels were lined with endothelial cells, which showed no atypia. These cells were positive for the endothelial markers CD31 and CD34 on immunohistochemistry and contained occasional erythrocytes. Immunohistochemistry for podoplanin was negative (figure 6).

FIGURE 6.

a) At histology, the lesion displayed heterogeneous morphology (haematoxylin and eosin (HE), 10×). b) Next to edematous and hypocellulated areas, there was a highly cellular tissue, with numerous vessels of capillary type, with sparse haemorrhagic foci (HE, 100×). c, d) At higher power, capillary spaces were lined by endothelium with occasional hobnail features and showed positivity for CD34 immunostain (HE, 200×).

Task 5

What is the most likely diagnosis based on the pathological findings?

1. Kaposi sarcoma

2. Mediastinal capillary haemangioma

3. Lymphangioma

4. Angiosarcoma

Answer 5

Correct answer: b. Mediastinal capillary haemangioma. Characteristic features of Kaposi sarcoma include spindle-shaped cells, slit-like vascular spaces channels, haemorrhage, haemosiderin deposition and hyaline globules. The so-called “promontory sign” consisting of small vessels protruding into the lumen of a larger vessel is a characteristic sign. It is associated with HHV-8 (human herpesvirus 8) infection, and HHV8 immunohistochemistry serves as the diagnostic key. Answer a is incorrect. Lymphangiomas are benign tumours of lymphatic origin. They are characterised by irregular, dilated lymphatic channels lined by endothelial cells. Immunohistochemistry often shows positivity for podoplanin (D2-40), which is absent in this case, ruling out this diagnosis. Answer c is incorrect. Angiosarcoma is a malignant vascular tumour. Tumour morphology varies widely, from low-grade appearances resembling haemangiomas to high-grade undifferentiated sarcomas. Vasoformation includes cavernous spaces, irregular channels or solid patterns with spindled or epithelioid cells. Common features are haemorrhage, haemosiderin deposition and endothelial multilayering, with necrosis and mitotic activity correlating to grade. The absence of endothelial atypia and other malignant features excludes angiosarcoma as a diagnosis. Answer d is incorrect. Capillary haemangiomas are benign vascular tumours characterised by small, well-formed capillary-like vascular channels lined with endothelial cells without atypia. The positive staining for CD31 and CD34 confirms the endothelial nature of the cells, and the absence of podoplanin indicates the absence of lymphatic differentiation, consistent with a diagnosis of capillary haemangioma. Answer b is correct.

Post-operative recovery was uneventful, and the patient reported feeling better after surgery. 1 month later, a chest radiograph (figure 7) showed complete resolution of the pleural effusion. In subsequent months, we followed the patient in our pleural disease unit with chest ultrasounds, and no recurrence of pleural effusion was noted.

FIGURE 7.

Chest radiography 1 month after surgery.

Task 6

Which of the following mechanisms are less likely to have contributed to the formation of pleural fluid in this case?

1. Endothelial cell injury leading to increased vascular permeability

2. Increased intrapleural negative pressure

3. Obstruction of lymphatic drainage

4. Reduction of plasma colloid osmotic pressure

Answer 6

Correct answers: b and d. The pathophysiology of pleural fluid formation is not certain. In the cases of vascular benign tumours determining pleural effusions described in the literature, abnormalities or vulnerability of the vessel walls are commonly thought to contribute to the development of pleural fluid. Therefore, answer a is incorrect. Another cause could be impaired lymphatic drainage, mainly due to a mass effect exerted by the haemangioma compressing adjacent structures such as lymphatic vessels, leading to fluid accumulation in the pleural cavity. Therefore, answer c is also incorrect. Increased intrapleural negative pressure due to obstructed airways is the likely explanation for the formation of pleural effusion in the setting of atelectasis, altering the balance of the forces described in the Starling equation, which is not the case described. Answer b is correct. A decrease in plasma colloid osmotic pressure, mainly due to low plasma albumin levels, causes fluid to move from the vascular space into the pleura. Again, this is not the case, since the blood tests were normal. Answer d is correct.

Discussion

Haemangiomas are classified as benign vascular tumours according to the International Society for the Study of Vascular Anomalies (ISSVA) [1]. Mediastinal haemangiomas are rare, accounting for <0.5% of all mediastinal masses [2]. These lesions are typically seen in young adults, with no significant difference between the sexes [3]. More than half of these lesions are located in the anterior mediastinum, followed by the posterior mediastinum, while the middle mediastinum, as in this case, is the least common site [4]. Histologically, haemangiomas are categorised into cavernous, capillary and venous types based on the size of the vascular spaces. Over 90% of cases are either cavernous or capillary haemangiomas, with cavernous haemangiomas being the most common, while venous haemangiomas are exceedingly rare [4]. Mediastinal haemangiomas are typically well-circumscribed, unencapsulated and can range from 2 to 20 cm in size. Histological examination reveals large, dilated, interconnecting vessels lined with vascular endothelium, interspersed with stromal elements such as fat, myxoid or fibrous tissue, particularly in cavernous haemangiomas [3].

The clinical presentation of mediastinal haemangiomas varies depending on tumour size and its relationship with adjacent structures. While most patients are asymptomatic, some may experience nonspecific symptoms such as cough, chest pain or dyspnoea, often due to compression of adjacent organs [2]. Invasive growth into mediastinal structures is rare. The association between pleural effusion and mediastinal haemangiomas is uncommon, with only a few cases described in the literature [5–7]. The exact pathophysiology remains poorly understood, but abnormalities or vulnerability in the vessel walls are thought to contribute to the development of pleural effusion. Haemangiomas in other thoracic locations, such as the pleural cavity [8–14] and ribs [15], have also been linked to pleural effusion. Interestingly, pleural effusions can be either non-haemorrhagic, as in our case, or haemorrhagic [12]. Bilateral bloody pleural effusion has also been reported [16, 17], as seen in other rare malignancies [18].

The development of worsening dyspnoea due to the formation of a massive pleural effusion may prompt earlier medical consultation. However, in most cases of mediastinal haemangiomas without fluid accumulation, diagnoses are typically incidental and made through imaging studies. CT and magnetic resonance imaging are the most commonly used imaging tools for characterising these lesions [19]. On noncontrast-enhanced CT scans, haemangiomas typically appear as heterogeneous, well-circumscribed soft-tissue masses. On CECT scans, the enhancement pattern varies, with peripheral, central, mixed or homogeneous patterns described [20]. Approximately 10% of cases show calcified phleboliths from organised thrombi within vascular channels. Li et al. [21] highlighted the diagnostic value of multiphase CECT, reporting a characteristic peripheral nodular enhancement in early phase images and progressive centripetal fill-in on delayed phase images.

Despite imaging findings, it remains challenging to differentiate mediastinal haemangiomas from other lesions of the mediastinum, especially when rare presentations, such as massive pleural effusion, are involved. The differential diagnosis for hypervascular mediastinal masses includes both benign and malignant entities, such as congenital or acquired vascular abnormalities, benign vascular neoplasms (e.g. haemangiomas, lymphangiomas), malignant vascular neoplasms (e.g. epithelioid haemangioendothelioma, angiosarcoma), ectopic parathyroid adenoma, Castleman disease, paraganglioma, carcinoid tumours, and hypervascular nodal metastases, commonly originating from renal cell carcinoma, melanoma, neuroendocrine tumours, or thyroid carcinoma [22].

The definitive diagnosis of haemangioma relies on pathological examination, with surgical tissue sampling often preferred due to the risk of uncontrolled haemorrhage associated with biopsies of hypervascular lesions. Therapeutic options for haemangiomas include surgical resection (as in this case), cryotherapy, embolisation or vascular ligation. The choice of treatment depends on the lesion's location, size and depth of infiltration [13]. However, surgical excision remains the most common approach, given the difficulty of obtaining a diagnosis without histopathological confirmation and the risks associated with biopsy.

In this case, medical thoracoscopy was performed to investigate the recurrent pleural effusion, which initially raised concerns about a possible malignancy. Medical thoracoscopy, a minimally invasive procedure increasingly performed by pulmonologists, is a safe and effective diagnostic tool for investigating suspected pleural malignancies. The growing importance of histopathological and genetic analysis, particularly as more targeted therapies become available for advanced malignancies, has further popularised this technique [23]. The pleural biopsies in this patient revealed nonspecific inflammation, supporting the hypothesis that the mediastinal lesion was responsible for the pleural effusion. After the surgical excision of the lesion, the pleural effusion resolved, confirming that the tumour had caused the fluid accumulation. The patient remains asymptomatic with no recurrence of the pleural effusion.

In cases of pleural effusions of unknown origin, when a suspected malignant cause is ruled out, other possible causes, including rare ones, should be considered. A thorough evaluation of the mediastinum is crucial. Although rare, benign vascular mediastinal masses like haemangiomas, particularly when associated with pleural fluid, should be included in the differential diagnosis during the workup.