Pulmonary Tumor Thrombotic Microangiopathy in Platinum-Resistant Ovarian Cancer – A Case Report

Abbreviations

CABG, Coronary artery bypass graft surgery

CT, Computed tomography

CTPA, CT pulmonary angiogram

LAD, Left anterior descending

LIMA, Left internal mammary artery

LVEF, Left ventricular ejection fraction

PH, Pulmonary hypertension

PTTM, Pulmonary tumor thrombotic microangiopathy

TTE, Transthoracic echocardiogram

INTRODUCTION

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare and rapidly fatal complication of metastatic cancer resulting in tumor cell embolization to pulmonary arterioles.¹ This results in increasing pulmonary hypertension (PH) eventually causing right heart failure. Despite typically following gastric cancer, PTTM is also a rare complication of ovarian cancer with abysmal prognosis. This case report describes a 59-year-old female with platinum-resistant recurrent high-grade serous ovarian carcinoma who developed PTTM. The patient, with a BRIP1 mutation conferring homologous recombination deficiency, initially presented with progressive dyspnea. Despite her benign presentation, she experienced a precipitous clinical decline culminating in right heart failure and death within two weeks. This case underscores the importance of recognizing PTTM in patients with ovarian cancer, as it is infrequently reported compared to its occurrence in gastric cancer.² The findings highlight the need for heightened awareness and consideration of PTTM in the differential diagnosis of PH in patients with advanced ovarian cancer.

CASE

A 59-year-old Chinese female with recurrent platinum-resistant ovarian cancer (BRIP1 c.2218C>T, HRD+) presented with 1-month progressive dyspnea.

Medical background

Ten years prior, the patient experienced an anterior ST-elevation myocardial infarction with a reduced left ventricular ejection fraction (LVEF) of 40-45%. She underwent coronary artery bypass graft surgery (CABG) for triple-vessel disease, utilizing the left internal mammary artery (LIMA) to bypass the left anterior descending (LAD) artery and a radial artery graft for the diagonal artery. Subsequent transthoracic echocardiogram (TTE) demonstrated successful revascularization, with LVEF improving to above 60%.

Nine years later, the patient was diagnosed with International Federation of Gynecology and Obstetrics stage III high-grade serous ovarian carcinoma, presenting with a markedly elevated CA-125 level of 1,530 U/mL. Treatment involved a multimodal approach, including neoadjuvant chemotherapy with carboplatin and paclitaxel, followed by cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Maintenance therapy with niraparib, a poly ADP-ribose polymerase inhibitor, was initiated but discontinued due to recurrent neutropenia.

In August of the same year, biochemical relapse was detected through rising CA-125 levels. Four months later, positron emission tomography scans revealed abdominal nodal and serosal metastases, indicating platinum-resistant recurrence. The patient was counseled regarding palliative chemotherapy with liposomal pegylated doxorubicin. However, being asymptomatic at the time, she opted to defer treatment, preferring watchful waiting.

Current case

The patient presented with progressive dyspnea over one month, with significant functional limitation. Initial workup revealed elevated cardiac biomarkers (Troponin I 78 → 143 ng/L, N-terminal pro-Brain Natriuretic Peptide 1,500 pg/mL)

While post-CABG heart failure was initially considered, computed tomography (CT) coronary angiogram on day 3 showed a patent LIMA-LAD graft, ruling out ischemic heart disease as a cause of heart failure. The occluded radial artery graft to the diagonal branch was noted but deemed insufficient to explain the acute presentation. An electrocardiogram (Figure 1A) on day 3 also showed no severe abnormalities pointing to heart failure. There were premature ventricular complexes and T inversion in V1-V3 with deep R waves indicating possible right heart strain.

Figure 1.

(A) Electrography (ECG) on day 3 showing normal sinus rhythm, left axis deviation, premature ventricular complex and T inversion in V1-3 with deep R waves. (B) Transthoracic echocardiogram (TTE) (short axis view) on day 6 showing straightening of interventricular septum. (C) TTE on day 6 of apical 4 chambers showing dilated right ventricle. (D) TTE on day 6 of Doppler interrogation showing tricuspid regurgitation.

TTE (Figure 1B, C, D) on day 6 demonstrated severe PH (PASP 84 mmHg), right ventricular dilation, and systolic dysfunction. CT pulmonary angiogram (CTPA) (Figure 2A, B) confirmed cardiomegaly and signs of pulmonary hypertension, without evidence of pulmonary embolism.

Figure 2.

(A) Computed tomography pulmonary angiogram (CTPA) on day 6 revealing a dilated pulmonary artery. (B) CTPA on day 6 with iodine map indicating small mild perfusion defects in the peripheries.

Right heart catheterization on day 8 revealed pre-capillary PH (mean pulmonary arterial pressure 38 mmHg, pulmonary capillary wedge pressure 2 mmHg), excluding left heart disease. The absence of a right-to-left shunt on bubble study ruled out intracardiac shunts. The bubble study did not show any significant intracardiac or extracardiac shunts. The dual energy CT also showed scattered subpleural defect but no significant evidence of pulmonary emboli.

Given the patient’s history of platinum-resistant ovarian cancer and lack of alternative explanations, PTTM was suspected. Pulmonary artery wedge cytology on day 9 confirmed the presence of malignant cells in pulmonary arterial blood, establishing the diagnosis of PTTM.

Despite the initiation of pulmonary vasodilators (iloprost, sildenafil, ambrisentan) and inotropic support (levosimendan), the patient’s condition rapidly deteriorated. She developed refractory hypoxemia and hypotension, transitioning to comfort measures after goals of care discussion. The patient ultimately succumbed to right heart failure secondary to PTTM on day 12.

This case highlights the importance of considering PTTM in cancer patients presenting with unexplained pulmonary hypertension, particularly those with ovarian malignancies and absent active chemotherapy.

DISCUSSION

PTTM is categorized under Group 5 PH, which encompasses PH due to multifactorial or unclear mechanisms, including malignancy-associated vascular complications.³ The pathogenesis of PTTM is distinct from that of pulmonary arterial hypertension (Group 1 PH) and is characterized by widespread microscopic tumor emboli, fibrocellular intimal proliferation, and subsequent occlusion of small pulmonary arteries and arterioles.⁴ This leads to rapidly progressive PH and right heart failure. Importantly, PAH-specific therapies, such as endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs, have not shown therapeutic efficacy in PTTM, likely due to the underlying obstructive and proliferative vascular pathology rather than vasoconstriction.³ As such, treatment remains largely supportive and directed at the underlying malignancy. The prognosis is poor, and early pathological or cytological diagnosis is critical for clinical decision-making.⁶

This case highlights the challenges in diagnosing and managing PTTM in a patient with platinum-resistant recurrent ovarian cancer. The patient’s initial presentation with progressive dyspnea was initially attributed to post-CABG heart failure, underscoring the nonspecific nature of PTTM symptoms and the importance of maintaining a high index of suspicion in cancer patients with unexplained cardiopulmonary symptoms.⁶

Currently, there is no internationally recognized framework for diagnosing PTTM. In this case, a systematic approach to rule out other diagnoses proved efficient in narrowing the diagnosis down to PTTM. This approach included CT pulmonary angiography to exclude large vessel thromboembolism, echocardiography to assess for PH, right heart catheterization to confirm pre-capillary PH, and pulmonary artery wedge aspiration cytology for definitive diagnosis. Such a systematic approach is crucial due to PTTM’s overlapping symptoms and nonspecific presentation. The absence of obvious pulmonary lesions on CT further emphasizes the necessity of direct vascular sampling for confirmation.

The management of PTTM presents significant challenges. In this patient, the presence of lupus anticoagulant and anti-cardiolipin immunoglobulin M antibodies increased thrombotic risk, while concurrent thrombocytopenia, possibly due to thrombotic microangiopathy, complicated anticoagulation management which is a common issue in treatment of PTTM.⁷ This necessitated extreme caution in anticoagulation administration due to the patient’s compounded symptoms. Furthermore, conventional therapies such as vasodilators and anticoagulants primarily target symptoms and fail to address the underlying structural obliteration caused by tumor-mediated vascular remodeling.

The rapid clinical deterioration observed in this case is characteristic of PTTM, with most patients succumbing within weeks of diagnosis. This underscores the need for early recognition and prompt initiation of multidisciplinary management.⁷ While targeted therapies have shown promise in isolated cases,⁸ their overall role in PTTM management remains limited, highlighting the need for further research into novel therapeutic approaches targeting the tumor-endothelial axis.

This case emphasizes the importance of considering PTTM in the differential diagnosis for cancer patients presenting with unexplained PH and right ventricular dysfunction, particularly in those with ovarian, gastric,⁹ or lung malignancies. Early integration of palliative care is crucial, as prognosis remains poor once PTTM is diagnosed, even with targeted therapies. Further research is needed to develop effective screening protocols for high-risk oncology patients and to explore innovative treatment strategies that may improve outcomes in this challenging condition.

The patient’s history of platinum-resistant ovarian cancer with a BRIP1 mutation, which confers homologous recombination deficiency, adds complexity to the case. This genomic profile may have implications for tumor behavior and treatment response, potentially influencing the development and progression of PTTM.

In conclusion, this case underscores the complex interplay between advanced cancer and cardiopulmonary complications, exemplified by PTTM. It highlights the need for increased awareness, prompt diagnosis, and innovative treatment strategies to improve outcomes in this rare but devastating condition.

LEARNING POINTS

• A high index of suspicion for PTTM is important for cancer patients not currently under treatment. This is especially so for those with ovarian & gastric malignancies that present with unexplained respiratory symptoms and pulmonary hypertension.

• A systemic approach involving CTPA and pulmonary artery wedge cytology is necessary to rule out other differentials and confirm PTTM diagnosis timely.

DECLARATION OF CONFLICT OF INTEREST

All the authors declare no conflict of interest.

FUNDING

None.