A case of pulmonary tumoral thrombotic microangiopathy supported by VA-ECMO and a review of the literature

Abstract

We report a case of pulmonary tumoral thrombotic microangiopathy (PTTM) of pancreatobiliary origin who presented with fulminant right heart failure and was revived by extracorporeal membrane oxygenation-cardiopulmonary resuscitation (ECMO—CPR). Pathology of PTTM was illustrated. This case highlights the notorious difficulty of antemortem diagnosis of PTTM as well as the role of venoarterial-ECMO as a temporizing measure to diagnosis and treatment.

<Learning objective: Pulmonary tumoral thrombotic microangiopathy should be considered in middle-aged patients with pulmonary hypertension with seemingly negative workup results before the diagnosis of idiopathic pulmonary hypertension is accepted. Venoarterial extracorporeal membrane oxygenation is an effective temporizing strategy for this rapidly progressive disease.>

Introduction

Pulmonary tumor thrombotic microangiopathy (PTTM) is an underrecognized cause of rapidly progressive pulmonary hypertension. Being first reported in 1990, it was not until 2006 that PTTM was diagnosed antemortem [1]. PTTM patients typically progress to hemodynamic instability with dismal prognosis [2]. Recent advances include extracorporeal support for hemodynamic compromise, antemortem diagnosis with pulmonary artery wedge blood cytology [3], and lung biopsy as well as a cocktail of treatments including tyrosine kinase inhibitors and systemic steroid [4,5]. We herein report a case of PTTM of pancreatobiliary origin supported by veno-arterial extracorporeal membrane oxygenation (VA-ECMO).

Case report

A 65-year-old Malaysian Chinese woman with good past health was admitted for shortness of breath for 1 week and reduced exercise tolerance for 2 months in April 2020. Her vital signs on admission included blood pressure 105/72 mmHg, pulse rate 115 beats/min, respiratory rate 24, and SpO2 96% on 6 liters of oxygen. Her chest was clear on auscultation. Examination of her lower limbs revealed soft calves and pitting edema bilaterally. An electrocardiogram showed sinus tachycardia at 106 beats per min with S1Q3T3. Arterial blood gas was pH 7.15, PaCO2 4.33 kPa, PaO2 15.01 kPa, bicarbonate 11 mmol/L, base excess −16.7 mmol/L on 6 liters of oxygen. Complete blood picture showed hemoglobin level of 10.2 g/dL and platelet of 52 × 10⁹/L (152–359 × 10⁹/L). D-dimer was elevated at >10,000 ng/ml (<500 ng/ml) while fibrinogen level was 1.2 g/L (1.6–3.3 g/L). Reticulocyte count was 6.14% (<2%). Lactate dehydrogenase was 849 U/L (</= 250 U/L). Blood smear showed occasional schistocytes. Chest radiograph showed prominent pulmonary vasculature. High-sensitive troponin I was elevated at 225 ng/L (<15.6 ng/L). Echocardiogram showed dilated right atrium and ventricle with flattening of interventricular septum. Right Ventricular Systolic Pressure (RVSP) was 67 mmHg (Fig. 1A).

Fig. 1.

(A) 4-chamber view of echocardiography; (B) Pulmonary angiogram.

The patient developed cardiogenic shock with respiratory failure within 18 h of admission and was thus intubated and transferred to the intensive care unit (ICU). Shortly after admission to ICU, she developed profound cardiogenic shock with multiorgan failure requiring escalating vasopressor support. Her condition deteriorated rapidly and culminated in pulseless electrical activity (PEA) cardiac arrest while preparations were being made for an elective cannulation of VA-ECMO. ECMO-cardiopulmonary resuscitation (CPR) was commenced and she was stabilized on VA-ECMO. She was subsequently weaned off vasopressor and extubated to 2 liters of oxygen with full neurological recovery. Heparin was started as anticoagulant for VA-ECMO at 15 units/kg/hour and titrated to achieve an activated partial thromboplastin time of 1.5–2.0 times upper range of normal. Computed tomography (CT) pulmonary angiogram with contrast showed no radiological evidence of acute pulmonary embolism. Coronary catheterization showed healthy right coronary artery, precluding the differential diagnosis of right ventricular infarction.

Right heart catheterization (RHC) was performed on Day 3 of hospitalization showing a systolic pulmonary artery pressure of 62 mmHg and mean pulmonary artery pressure of 42 mmHg. Pulmonary capillary wedge pressure was 11 mmHg. Pulmonary angiogram showed dilated pulmonary trunk but no filling defect (Fig. 1B). Transesophageal echocardiogram (TEE) revealed no intracardiac shunt. Autoimmune markers were negative. Infective workups including human immunodeficiency virus were negative. She was started on iloprost at 2 ng/kg/min which was stepped up incrementally to 4 ng/kg/min, sildenafil 20 mg thrice daily, and macitentan 10 mg daily. Pulmonary artery wedge blood sample was sent for cytologic analysis. The patient's mean pulmonary arterial pressure showed a modest decrease to 32 mmHg with 5 days of treatment with pulmonary vasodilator. She was weaned off VA-ECMO on Day 7 as she showed signs of sepsis with no obvious focus.

At this point her Cancer Antigen 19–9 came back grossly elevated at 56,901 U/mL (normal <= 37 U/mL). CT scan of her thorax, abdomen, and pelvis showed no suspicious lesion. Pulmonary artery wedge blood sent for cytologic analysis showed atypical cells but the amount was not sufficient for immunohistochemical staining. The diagnosis of PTTM was strongly suspected and the patient was started on systemic steroid and anticoagulation [1]. The patient developed respiratory failure with worsening right heart failure. In view of high likelihood of metastatic malignancy, VA-ECMO support was not reinstituted. Transbronchial biopsy was considered but precluded by the patient's poor respiratory status. The patient succumbed to decompensated right heart failure on Day 18 of hospitalization.

Postmortem examination of the lungs confirmed the diagnosis of PTTM. There were multiple lesions within the muscular arteries as well as interalveolar septal arterioles. The lesions were characterized by presence of intimal fibrocellular proliferation and admixed scattered tumor cells and fibrin deposition [6]. Complete to near-complete occlusion of intra-alveolar arterioles was frequently observed whilst eccentric or concentric involvement of muscular arteries with thrombosis and subsequent recanalization was also noted (Fig. 2). There was no interstitial or lymphangitic tumor invasion. At hotspots, there were 32 PTTM-like lesions per cm², satisfying the diagnostic criteria proposed by Sato et al. [7]. Immunohistochemical studies of the malignant cells were positive for cytokeratin 7 (CK7) and cytokeratin 20 (CK20), compatible with pancreatobiliary origin (Fig. 3). A lesion was seen in pancreatic body measuring 2.3 cm across. Sections of the lesion showed autolytic changes precluding further assessment. Further, a 1.5-cm lymph node was noted at the peri-pancreatic soft tissue. Histology of the lymph node showed metastatic carcinoma with the malignant cells staining positive for both CK7 and CK20. Examination of other abdominal and pelvic organs including the stomach was unremarkable.

Fig. 2.

At this scanning magnification, pulmonary tumor thrombotic microangiopathy-like lesions are seen affecting numerous small intra-alveolar septal arterioles (blue arrows) as well as larger muscular arteries (black arrows). Background unaffected intra-alveolar septal arterioles are also present for reference (green arrow). (van Gieson stain for elastic fibers, x20).

Fig. 3.

Medium magnification of one muscular artery with pulmonary tumor thrombotic microangiopathy-like lesion and tumor emboli present. (A) Hematoxylin and eosin stain, x200. (B) von Gieson stain for elastic fibers, x200. (C) CK7 positivity (x200). (D) CK20 positivity (x200).

Discussion

We report a patient with good past health who presented with rapidly progressive pulmonary hypertension with consequent right heart failure and cardiac arrest successfully revived with ECMO—CPR. PTTM is characterized by a combination of rapidly progressive pulmonary hypertension, typically negative CT/ pulmonary angiogram, and raised fibrinogen degradation products such as D-dimer. D-dimer level has been reported to be useful as a surrogate for treatment response [1]. Strong clinical suspicion is warranted in middle-aged adults with no obvious cause of pulmonary hypertension to expedite diagnosis of PTTM. Median age of PTTM patients is 58 years in contrast to idiopathic pulmonary hypertension which primarily affects younger adults [8]. Given its aggressive natural course, prompt diagnosis and treatment are instrumental in improving outcome of patients with PTTM.

This case highlights an unfortunate feature of PTTM: the extraordinary difficulty of antemortem diagnosis. Despite strong clinical suspicion, extensive imaging in this case failed to identify the primary site of malignancy. Lung biopsy obtained by means of CT or bronchoscopic guidance and video-assisted thoracoscopic surgery may be valuable [9]. Finding of PTTM-like lesions with tumor emboli is distinctive and it is not seen in other entities that cause pulmonary hypertension [2]. However, a considerable proportion of PTTM patients present with or rapidly progresses to critical condition rendering them unfit for invasive procedures. Non-diagnostic biopsy due to sampling error is also an inherent limitation. Pulmonary wedge blood cytology has a reported sensitivity of 80–88% and specificity of 82–94% [3]. It is considerably less invasive and could be readily obtained during RHC, which is typically part of the evaluation for pulmonary hypertension. The presence of malignant cells in pulmonary artery wedge blood under cytological examination can be supportive for the diagnosis of PTTM [5]. Depending on the number of malignant cells present, immunohistochemical studies can be performed on cell block preparations which can potentially help elucidate the primary site of the malignancy.

This case demonstrates that VA-ECMO is an effective rescue therapy for PTTM patients with rapid deterioration. Peripheral VA-ECMO is a mechanical circulatory support that drains blood from the right atrium, bypasses the pulmonary circulation, and provides retrograde arterial flow. By allowing right ventricular decompression and maintaining systemic oxygenation and circulation, it provides a therapeutic window for decompensated pulmonary hypertension. Pulmonary vasodilators as well as systemic steroid and anticoagulation were initiated in an attempt to ameliorate pulmonary hypertension. Hemodynamic improvement was once demonstrated on our patient, although it was not sustained. Systemic steroid and anticoagulation were reported in previous case reports to offer clinical benefit [1].

This patient unfortunately deteriorated before a pathological diagnosis could be made. There were previous reports of initiation of treatment for PTTM based on clinical suspicion before a definitive diagnosis of PTTM or the primary source of malignancy was identified [4]. Ogawa et al. reported a case of ECMO-supported PTTM who responded to imatinib that was initiated based on clinical suspicion with subsequent reduction in mean Pulmonary Arterial Pressure and clinical improvement allowing decannulation as well as transbronchial lung biopsy to confirm diagnosis of PTTM [4]. Oshikawa et al. recently reported a case of PTTM from metastatic breast cancer who was started on imatinib based on clinical suspicion and exclusion of alternative diagnoses [5]. Both afore-mentioned cases showed clinical and radiological improvement. It is the limitation of this case report that we could not tell whether initiation of imatinib under ECMO support may translate to clinical improvement. Our experience showed that VA-ECMO could be a temporizing measure to buy time for diagnosis and treatment. Early initiation of empirical imatinib and chemotherapy directed at underlying malignancy under ECMO support may revolutionize PTTM treatment and outcome.

Conclusion

In conclusion, high clinical suspicion with prompt diagnosis where possible are instrumental to management of PTTM patients. VA-ECMO is an effective bridging therapy for PTTM patients with hemodynamic compromise. Antemortem diagnosis of PTTM is challenging and requires a multifaceted approach. Initiation of imatinib based on clinical suspicion has been reported with favorable outcome.

Declaration of Competing Interest

The authors have no conflict of interest to declare.