Radiation-Associated Mesothelioma With Mixed Constrictive-Restrictive Physiology After Mantle-Field Radiotherapy

Abstract

Background

Malignant mesothelioma is a rare late complication of thoracic radiotherapy and may contribute to complex cardiothoracic manifestations decades after treatment.

Case Summary

A 60-year-old woman treated for Hodgkin lymphoma with mantle radiotherapy and chemotherapy more than 40 years earlier presented with recurrent pleuropericarditis, heart failure symptoms, and recurrent pleural and pericardial effusions. Echocardiography and cardiac catheterization suggested constrictive physiology, whereas cardiac magnetic resonance was nondiagnostic. Positron emission tomography–computed tomography showed hypermetabolic pleural, mediastinal, and pericardial lesions. Despite anti-inflammatory therapy and corticosteroids, progressive congestion required near-total pericardiectomy. Histopathology revealed high-grade mesothelioma involving the mediastinum, pericardium, pleura, lungs, and myocardium. Following pericardiectomy, the restrictive component of a mixed constrictive-restrictive physiology became apparent, leading to cardiogenic shock requiring venoarterial extracorporeal membrane oxygenation.

Discussion

Radiation-associated malignant mesothelioma is a rare but challenging late complication of thoracic radiotherapy and may contribute to mixed constrictive-restrictive physiology.

Take-Home Message

Survivors of mantle-field radiotherapy for Hodgkin lymphoma remain at risk for both radiation-associated heart disease and secondary malignancies decades after treatment.

Visual Summary

History of Presentation

A 60-year-old woman presented with progressive fatigue, weight loss, night sweats, orthopnea, pleuritic chest pain, lower-extremity edema, and NYHA functional class III dyspnea. She was initially hospitalized in a regional hospital and diagnosed with presumed postviral pericarditis associated with acute decompensated heart failure with preserved ejection fraction.

Despite treatment with colchicine and nonsteroidal anti-inflammatory drugs (NSAIDs), symptoms worsened with recurrent pleural and pericardial effusions, prompting referral to our hospital.

On admission, blood pressure was 147/89 mm Hg, heart rate 106 beats/min, oxygen saturation 98% on room air, and temperature was normal. Physical examination demonstrated a marked cervical muscle wasting, mild jugular venous distension, mild peripheral edema, bibasal hypoventilation, a subtle pericardial friction rub, and a grade 3/6 systolic murmur over the aortic area.

Past Medical History

More than 4 decades earlier, in the 1980s, the patient had been treated for Hodgkin lymphoma with mantle-field radiotherapy and chemotherapy consisting of procarbazine, vinblastine, and corticosteroids. The exact radiation dose was unavailable, however, historical mantle-field protocols typically delivered approximately 40 to 44 Gy.

She subsequently developed radiation-induced pulmonary fibrosis and left diaphragmatic paralysis.

Additional medical history included thyroid carcinoma treated by total thyroidectomy without chemotherapy, moderate aortic stenosis, paroxysmal atrial fibrillation treated by catheter ablation, and hypertension.

Differential Diagnosis

The differential diagnosis included recurrent inflammatory pericarditis, radiation-associated constrictive pericarditis, restrictive cardiomyopathy, lymphoma recurrence, metastatic disease, and malignant mesothelioma. Given the patient's history of mantle radiotherapy and recurrent pleuropericardial effusions, both radiation-associated cardiac disease and secondary malignancy were considered.

Investigations

Laboratory evaluation revealed slightly reduced hemoglobin at 115 g/L, no inflammation with leukocyte count 7.1 G/L, C-reactive protein 6.52 mg/L, platelet count 287 G/L, N-terminal pro–B-type natriuretic peptide was normal at 266 ng/L as for troponin at 12 ng/L. Renal function was normal. Thyroid-stimulating hormone was elevated at 16.9 mU/L with normal T3 and T4 levels. Extensive infectious (syphillis, enterovirus, coxiella, borrelia, parvovirus, herpes simplex virus/HIV/hepatitis B virus/hepatitis C virus/cytomegalovirus/Epstein-Barr virus/human herpesvirus 6/human herpesvirus 8, and tuberculosis) and autoimmune (immunoglobulins, C3/C4, antinuclear factor, anti-neutrophil cytoplasmic antibody, rheumatoid factor, anti-cyclic citrullinated peptide) investigations were negative.

Electrocardiogram demonstrated sinus tachycardia without electrical alternans or features of acute pericarditis (Figure 1).

Figure 1.

12-Lead Electrocardiogram Demonstrating Sinus Rhythm With No Diffuse ST-Segment Elevation, PR-Segment Depression, or Electrical Alternans

Transthoracic echocardiography performed while the patient was in sinus rhythm demonstrated left ventricular ejection fraction of 65%, moderate circumferential pericardial effusion (16 mm), grade II diastolic dysfunction with an E/A ratio of 1.6, septal and lateral e′ velocities of 6.31 and 6.96 cm/s respectively, and an average E/e′ ratio of 16.5, as well as moderate aortic stenosis (peak and mean gradients of 27.5 and 16.0 mm Hg, respectively), without constrictive physiology (Video 1, Figure 2).

Figure 2.

Annulus Reversus

(A) Septal and (B) lateral mitral annular tissue Doppler velocities with preserved lateral predominance (6.96 cm/s vs 6.31 cm/s), demonstrating the absence of annulus reversus. These findings do not support constrictive physiology at this stage.

Subsequent transthoracic echocardiography showed ventricular interdependence with septal shift, annulus reversus (septal e′ 8.36 cm/s vs lateral e′ 5.10 cm/s), expiratory hepatic vein flow reversal with an expiratory retrograde-to-anterograde ratio of 0.87, and inferior vena cava dilation without respiratory variation, all supporting constrictive physiology. (Video 2, Figures 3 and 4). Global longitudinal strain was relatively preserved at −16.1%.

Figure 3.

Pulsed-Wave Doppler of the Hepatic Vein Demonstrating Prominent Expiratory Diastolic Flow Reversal With An Expiratory Retrograde-to-Anterograde Flow Ratio of 0.87, Supportive of Constrictive Physiology

Figure 4.

Annulus Reversus

(A) Septal and (B) lateral mitral annular tissue Doppler velocities with septal predominance (8.36 cm/s vs 5.10 cm/s), demonstrating annulus reversus. These findings support constrictive physiology.

Two pericardiocentesis showed hemorrhagic exudative fluid without evidence of infection or malignancy. Repeated pleural fluid analyses demonstrated sterile lymphocytic exudates with negative cytology.

Positron emission tomography–computed tomography (PET-CT) demonstrated hypermetabolic subcarinal lymphadenopathy, hypermetabolic pericardial nodules, and focal pleural uptake suspicious for neoplastic disease (Figure 5). Thoracoscopy with lymph node biopsy showed sinus histiocytosis consistent with nonspecific physiological reaction typically present in the lymph node draining inflammatory sites without signs of malignancy.

Figure 5.

Positron Emission Tomography–Computed Tomography Demonstrating Hypermetabolic Subcarinal Lymphadenopathy, Hypermetabolic Pericardial Nodules, and Focal Pleural Uptake Suspicious for Neoplastic Disease

Cardiac magnetic resonance demonstrated preserved biventricular function, no myocardial edema, no infiltrative cardiomyopathy, and no pericardial enhancement (Figure 6). Importantly, respiratory-coupling sequences could not be completed because severe pleuritic pain prevented adequate inspiratory maneuvers and the patient was in atrial fibrillation during the study, further impairing image quality.

Figure 6.

Cardiac Magnetic Resonance Imaging

(A) T1 and T2 mapping sequences without evidence of myocardial edema or infiltrative cardiomyopathy. (B) Late gadolinium enhancement sequence showing no pericardial enhancement.

Right and left heart catheterization demonstrated a cardiac output of 4.2 L/min and cardiac index of 2.5 L/min/m². Mild precapillary pulmonary hypertension was present (37/10/24 mm Hg, wedge pressure 14 mm Hg). Although ventricular interdependence and equalization of diastolic pressures were absent, a dip-and-plateau pattern and prominent Y descent appeared after volume loading, supporting early constrictive physiology (Figure 7). This exam also revealed a nonsignificant (<50%) stenosis of the mid–right coronary artery (RCA).

Figure 7.

Hemodynamic Features Supporting Early Constrictive Physiology

(A) Left ventricular pressure tracing demonstrating a dip-and-plateau pattern. (B) Right atrial pressure tracing showing a prominent Y descent after volume loading.

Management

The patient initially received colchicine 1 mg daily for 3 months and high-dose aspirin (1 g 3 times daily). Because she continued to experience symptoms consistent with pericarditis and persistent pleuropericardial effusions, treatment of NSAIDs was maintained for an extended time of 6 weeks. Recurrent symptomatic effusions ultimately required repeated pericardiocenteses. Given the persistence of symptoms and echocardiographic evidence of constrictive physiology, prednisone 20 mg daily was initiated, resulting in temporary clinical improvement and disappearance of constrictive features on follow-up echocardiography, including loss of annulus reversus (septal e′ 3.8 cm/s, lateral e′ 7.4 cm/s) and improvement in inferior vena cava plethora.

Despite this response, progressive congestion recurred. Near-total pericardiectomy was then performed.

Unexpectedly, surgery revealed extensive adhesions caused by dense fibrotic material infiltrating the mediastinum and heart with intramyocardial invaginations, similar to what was found in the left pleura (Figure 8). These findings were inconsistent with isolated constrictive pericarditis and suggested a more diffuse infiltrative process involving both the pericardium and myocardium, raising suspicion for a mixed constrictive-restrictive physiology.

Figure 8.

Gross Surgical Specimen Showing Multiple Fibrotic and Nodular Tissue Fragments Resected From the Pericardium and Mediastinum During Near-Total Pericardiectomy

Histopathological examination revealed high-grade mesothelioma.

Outcome and Follow-Up

Histopathological examination demonstrated high-grade mesothelioma involving the mediastinum, pericardium, pleura, lungs, and myocardium.

Following removal of the constrictive pericardial component, severe restrictive biventricular physiology with right ventricular dysfunction was unmasked, leading to progressive fluid overload, anuric cardiorenal syndrome, and ultimately refractory cardiogenic shock requiring 2 weeks of venoarterial extracorporeal membrane oxygenation support. The coexistence of histologically confirmed myocardial infiltration and severe postoperative restrictive physiology strongly supports a mixed constrictive-restrictive physiology.

Because of advanced disease and profound frailty, systemic oncologic treatment could not be initiated. Following multidisciplinary discussion with the patient and family, palliative management was pursued.

Discussion

This case illustrates an exceptionally late presentation of radiation-associated malignant mesothelioma occurring more than 40 years after mantle radiotherapy for Hodgkin lymphoma. Although high-dose cardiac irradiation (>21 Gy) has a recognized substantial long-term risk of heart failure (13.3% at 25 years),¹ the spectrum of cardiovascular complications depends heavily on the irradiation technique and the year of treatment.² Before the 1980s, mantle radiotherapy (extended mediastinal fields, higher fraction doses, low cardiac sparing) exposed large cardiac and coronary volumes, resulting, decades later, in higher rates of constrictive pericarditis, valvular heart disease, coronary artery disease, and cardiomyopathy. Mesothelioma remains a rare and often overlooked secondary malignancy of historical mantle-field radiotherapy. Previous studies have demonstrated an increased risk of mesothelioma among Hodgkin lymphoma survivors exposed to mediastinal irradiation, even in the absence of asbestos exposure.³ The latency period is typically measured in decades, making diagnosis particularly challenging. In our patient, the marked cervical amyotrophy was a hallmark of the substantial burden of prior mantle-field irradiation and prompted comprehensive evaluation for radiation-induced cardiotoxicity and secondary malignancies (Table 1).

Table 1.

Postradiotherapy Complication Over Time

System or Organ	Acute Toxic Effects (0-12 mo)	Late Toxic Effects 1 y or More	Toxic Effects Very Late 20-30 y or More
Heart	•Acute pericarditis	•Constrictive pericarditisa •Restrictive cardiomyopathya •Heart failure •Valvular heart disease: Stenosis/regurgitationa •Radiation-induced coronary artery disease/myocardial ischemiaa •Cardiac arrhythmias/Conduction blocks
Lungs	•Radiation pneumonitis	•Pulmonary fibrosisa •Pulmonary hypertension •Secondary cancer
Skin and soft tissues	•Radiation dermatitis •Erythema	•Cutaneous fibrosis •Soft tissue necrosis	Amyotrophya
Digestive system	•Radic esophagitis	•Esophageal fibrosis/stenosis
Thyroid		•Hypothyroidoism •Thyroid nodules or thyroid cancera
Oncological risk		Secondary cancers (lymphomas, leukemias)	Malignant mesotheliomaa

^aComplications observed in the present case.

The diagnosis was particularly difficult because recurrent pleuropericardial effusions, ventricular interdependence, annulus reversus, and invasive hemodynamic findings suggestive of constriction initially supported a diagnosis of constrictive pericarditis. Transient improvement with corticosteroids suggested an inflammatory process. Furthermore, biopsy of 8 hypermetabolic lymph nodes on PET-CT demonstrated histiocytosis typical for inflammation drainage sites with no evidence of malignancy. The sensitivity of PET-CT is variable, and false negatives have been reported, particularly because tumor metabolism may be low.⁴

A particularly instructive aspect of this case is that the mesothelioma did not remain confined to the pleura and pericardium. Histopathological examination confirmed myocardial involvement, providing a pathological substrate for the mixed constrictive-restrictive physiology observed throughout the disease course. However, thoracic irradiation itself is a recognized cause of both constrictive pericardial disease and restrictive cardiomyopathy through progressive myocardial fibrosis. Therefore, the restrictive component was likely multifactorial, resulting from the combined effects of radiation-induced myocardial injury and direct myocardial infiltration by mesothelioma.

Following pericardiectomy, severe restrictive biventricular dysfunction became clinically apparent and resulted in cardiogenic shock requiring 2 weeks of venoarterial extracorporeal membrane oxygenation support. This evolution highlights how an underlying restrictive process may remain clinically masked by concomitant constrictive physiology until surgical relief of the constrictive component. Pericardiectomy series show a clear difference in survival depending on the etiology. In the study by Al-Kazaz et al,⁵ postradiotherapy patients had the highest operative mortality (10.1%) and significantly reduced survival (53.4% and 32.1% at 5 and 10 years). This poor prognosis can be explained by the multitissue damage caused by radiation, which can lead to mixed restrictive and constrictive physiology, limiting the benefits of pericardiectomy.

Another important feature is the coexistence of moderate aortic stenosis, a recognized manifestation of radiation-associated valvular heart disease. The patient also had a nonsignificant (<50%) mid-RCA stenosis, also consistent with a radiation origin affecting primarily the RCA. Radiation injury rarely affects a single thoracic structure and often involves the pericardium, myocardium, valves, coronary arteries, lungs, and mediastinum simultaneously.

Even in the absence of symptoms, the European Society of Cardiology guidelines on cardio-oncology⁶ emphasize the importance of performing transthoracic echocardiography screening at regular intervals, generally every 2 to 5 years depending on the patient's risk profile (type of radiotherapy, cumulative dose, cardiovascular comorbidities). Our patient unfortunately did not benefit from such surveillance. Clinicians should remain alert to secondary thoracic malignancies when unexplained pleural or pericardial disease develops decades after treatment.

Conclusions

Radiation-associated mesothelioma is a challenging diagnosis that can present more than 4 decades after mantle radiotherapy and may contribute to a mixed constrictive-restrictive physiology.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Take-Home Message

• •Survivors of mantle-field radiotherapy for Hodgkin lymphoma remain at risk for both radiation-associated heart disease and secondary malignancies decades after treatment.

Appendix

Video 1

Apical 4-Chamber View Demonstrating Normal Interventricular Septal Motion Consistent With the Absence of Ventricular Interdependence

Video 2

Apical 4-Chamber View Demonstrating Septal Bounce, Reflecting Ventricular Interdependence Supporting Constrictive Physiology