Not all that swells is angioedema: a hidden malignancy

Dear Editors, Angioedema is a well-known clinical condition characterized by acute, localized swelling of the skin or mucous membranes, triggered by various factors including allergic reactions, urticaria-associated angioedema, genetic variants such as hereditary angioedema and medications like angiotensin-converting enzyme (ACE) inhibitors. Most of the cases of angioedema that require treatment in emergency departments are urticaria-associated angioedema or idiopathic.1 While most cases respond promptly to medical therapy, rare mimickers such as superior vena cava (SVC) syndrome can lead to diagnostic delays. SVC syndrome results from obstruction or external compression of the superior vena cava, often due to malignancy, and presents with edema of the head, neck, and upper extremities, as well as respiratory symptoms.2 We report a rare case of small cell lung cancer (SCLC) presenting with angioedema-like symptoms, highlighting the diagnostic challenge and the importance of early recognition. A 67-year-old woman presented with progressive facial and lip swelling, shortness of breath, and wheezing for three weeks. Her medical history included hypertension and type 2 diabetes mellitus. She had been using perindopril (ACE inhibitors) for the past 3 months and had a 40-pack-year smoking history. On examination, she was tachycardic (102 bpm) but normotensive. The patient exhibited edema involving the lips, face, and neck, as shown in Figure 1a. Additionally, prominent superficial collateral veins were observed on the upper chest (Figure 1b). She was initially diagnosed with ACE inhibitor-induced angioedema and was started on oral methylprednisolone (16 mg/day) and bilastine (20 mg/day). Perindopril was discontinued. Despite treatment, her symptoms persisted at the 10-day follow-up. Laboratory tests were largely unremarkable, including normal C1 esterase inhibitor, C3, C4, total IgE, and tryptase levels. Lactate dehydrogenase was mildly elevated (280 U/l, reference range: 120–246 U/l). Given the lack of improvement, a contrast-enhanced thoracic CT scan was performed. This scan revealed a mediastinal mass causing significant compression of the superior vena cava (Figure 2a). Coronal views demonstrated marked narrowing of the mid-portion of the superior vena cava due to extrinsic tumor compression (Figure 2b). Differential diagnoses included hereditary or acquired angioedema, allergic reactions, pseudoangioedema syndromes (e.g., Cushing's syndrome, hypereosinophilic syndrome), and mechanical obstruction syndromes. The presence of venous engorgement and her smoking history increased suspicion for a malignant cause. A biopsy of the mediastinal tumor was obtained via endobronchial ultrasound-guided bronchoscopy. Immunohistochemical analysis of the mediastinal tumor biopsy showed tumor cells positive for synaptophysin (Figure 3a), neuron-specific enolase (NSE) (Figure 3b), and insulinoma-associated protein 1 (INSM-1) (Figure 3c), consistent with SCLC. Histopathological examination confirmed the diagnosis of SCLC. The patient underwent 15 cycles of radiotherapy followed by chemotherapy with cisplatin and etoposide. Post-treatment imaging showed a reduction in tumor size, regression of collateral veins, and significant improvement in symptoms of venous obstruction. The superior vena cava, formed by the convergence of the right and left brachiocephalic veins, is responsible for venous return from the head, neck, and upper extremities.3 SVC syndrome was initially described as a consequence of infections such as tuberculosis or syphilitic aortic aneurysm.4 Today, it most commonly arises from malignant causes, especially SCLC, which frequently originates in the central lung fields and causes mediastinal lymphadenopathy.2, 5 Clinical features include facial and neck swelling, respiratory distress, and visible collateral veins over the upper chest and arms.2 Angioedema, in contrast, is typically acute, localized, and most often related to allergic reactions or ACE inhibitor use. However, SVC syndrome may rarely mimic angioedema, leading to misdiagnosis and delayed treatment.1, 2 The principal distinguishing features between angioedema and SVC syndrome lie in the onset and distribution of edema. Angioedema typically presents with a sudden onset of localized, often asymmetric swelling involving the face, lips, or tongue, frequently accompanied by pruritus and urticaria. In most cases, the edema resolves within 24–72 hours with appropriate therapy.1, 6 Conversely, SVC syndrome exhibits a more insidious onset and is characterized by persistent, bilateral, and more diffuse swelling affecting the face, neck, and upper extremities. This condition is commonly associated with jugular venous distention, collateral venous circulation, and other signs of venous stasis, with edema often more pronounced in the morning.6, 7 In its early stages, the fluctuating clinical course of SVC syndrome may mimic angioedema, posing a diagnostic challenge that necessitates careful clinical assessment.6, 7 In patients with presumed angioedema who do not respond to standard treatment, SVC syndrome should be considered, particularly in the presence of risk factors such as a history of smoking or visible superficial veins. Contrast-enhanced thoracic CT is essential for identifying venous compression, assessing the extent of obstruction, and detecting underlying causes such as mediastinal tumors.2 Biopsy is often required to confirm malignancy. In the literature, only two prior cases have reported SVC syndrome due to SCLC presenting initially as angioedema. Both patients were on ACE inhibitors for hypertension.8 In our case, the initial presentation resembled ACE inhibitor-induced angioedema, but the lack of therapeutic response and presence of dilated chest wall veins prompted further evaluation. Imaging revealed SVC compression by a mediastinal mass, and histopathology confirmed SCLC. Following oncologic treatment, the patient showed marked clinical improvement, including resolution of venous congestion. This case underscores the importance of considering malignant causes of upper body edema in patients with poor response to angioedema treatment. Early identification of malignancy-induced SVC syndrome enables timely initiation of oncologic therapies, which can significantly alleviate symptoms and improve outcomes. None.