“Attenuated” Pulmonary Tumor Thrombotic Microangiopathy on Anti-Vascular Endothelial Growth Factor Treatment: A Case Report Open Access

Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal complication of advanced cancers. It was first described in 1990 by von Herbay et al. [1] as a condition in which tumor cells cause fibrocellular intimal proliferation, resulting in the occlusion of pulmonary arteries. Patients with PTTM typically present with a cough and rapidly worsening dyspnea and have a poor prognosis due to severe respiratory failure. In a previous review, the average time from the onset of symptoms to death was 9.5 weeks [2]. This highly progressive nature makes it challenging to diagnose antemortem PTTM. The review also reported that 79% of patients with PTTM were diagnosed during postmortem examination [2]. Vascular endothelial growth factor (VEGF) is one of the cytokines associated with the pathogenesis of PTTM [2]. However, the clinical picture of PTTM in patients with cancer receiving anti-VEGF treatment is unknown. Herein, we report a case of advanced gastric adenocarcinoma in a patient undergoing treatment with a VEGF inhibitor who developed PTTM with mild respiratory symptoms.

A 40-year-old man with no significant medical or family history was diagnosed with human epidermal growth factor receptor 2-negative progressive gastric adenocarcinoma with multiple metastases to intra-abdominal lymph nodes. The patient was started on first-line chemotherapy with S-1 plus oxaliplatin. Five months later, with enlargement of the lymph node lesions, he switched to second-line chemotherapy with paclitaxel plus ramucirumab. After three cycles of paclitaxel plus ramucirumab, the patient developed shortness of breath (SOB) on exertion, prompting consultation at our hospital. He had a 2-month history of dry cough but denied fever, chills, chest pain, and sick contacts. He was hemodynamically stable, with a pulse oxygen saturation (SpO₂) of 97% in room air. Physical examination results were generally unremarkable, with no signs of heart failure or venous thromboembolism. Laboratory tests revealed thrombocytopenia (platelet count 130,000/µL) and elevated levels of D-dimer (7.8 µg/mL), brain natriuretic peptide (327.2 pg/mL), and lactate dehydrogenase (LDH) (300 U/L). Anemia (hemoglobin 14.5 g/dL) and significant elevation of white blood cell count (9,400/µL) and C-reactive protein (0.45 mg/dL) were not observed. Laboratory tests also revealed no significant autoimmune antibodies, such as antinuclear antibodies, rheumatoid factor, antineutrophilic cytoplasmic antibodies, and anti-glomerular basement membrane antibodies. Blood and sputum cultures were both negative. Electrocardiography showed inverted T waves in leads V1–V4. Bilateral diffuse patchy ground-glass opacities (GGOs) were seen on a chest computed tomography (CT) scan (Fig. 1a); however, no pulmonary embolism (PE) was observed on a contrast-enhanced chest CT scan. The primary tumor and the metastatic lymph nodes were stable in size. Transbronchial lung biopsy (TBLB) revealed alveolar hemorrhage and occlusion of the small pulmonary arteries with fibrocellular intimal proliferation; however, no tumor cells were found within the arteries (Fig. 2). Tumor cells were also not evident in the lymphatic vessels or the pulmonary parenchyma. At this point, we suspected the patient to have mild chemotherapy-induced lung injury; hence, we discontinued paclitaxel plus ramucirumab. His symptoms were cough and dyspnea without desaturation; thus, he was monitored carefully without treatment.

However, his dyspnea worsened, with SpO₂ as low as 93% in room air. A follow-up chest CT scan revealed deteriorating bilateral GGOs (Fig. 1b) and dilation of the right atrium and pulmonary arteries (Fig. 1c), without changes in the size of the primary and metastatic tumors. Ultrasound cardiography showed decreased right ventricular function with moderate-to-severe pulmonary regurgitation and mild tricuspid regurgitation. Lung perfusion scintigraphy confirmed numerous small bilateral defects (Fig. 3). Deep vein thrombosis was not evident on venous ultrasonography of the lower extremities. A right heart catheterization revealed pulmonary hypertension (mean pulmonary arterial pressure, 37–40 mm Hg) and normal pulmonary capillary wedge pressure (9 mm Hg). Although no tumor cells were detected on pulmonary wedge aspiration cytology, the patient was diagnosed with PTTM.

After 3 weeks of SOB, he was started on nivolumab as third-line therapy. After 1 week on nivolumab, the patient developed mild respiratory failure on exertion, which was confirmed through a 6-min walk test with a minimum SpO₂ of 90% in room air. As further deterioration of his respiratory condition was expected, he was started on home oxygen therapy at 1 L/min on exertion. However, after 4 weeks of nivolumab treatment, he no longer had dyspnea, and thus, oxygen therapy was discontinued. Ultrasound cardiography revealed normal pulmonary arterial pressure (mean pulmonary arterial pressure, 12 mm Hg), with improvements in pulmonary regurgitation and tricuspid regurgitation. Additionally, almost all GGOs on the chest CT scan disappeared (Fig. 1d), with some lymph nodes shrinking.

After two cycles of nivolumab, the patient developed myositis and hypothyroidism as immune-related adverse events. The patient then discontinued nivolumab and initiated systemic corticosteroid and thyroid hormone replacement therapy. Six weeks after the discontinuation, the follow-up chest CT scan captured re-exacerbation of bilateral patchy GGOs and enlargement of lymph node lesions, suggesting a relapse of PTTM. In 2 weeks, he resumed nivolumab but developed dyspnea again the next day. Five days later, he visited the emergency department, and a CT showed worsening of GGOs and re-dilation of the right atrium/ventricle and pulmonary arteries. With the diagnosis of right-sided heart failure due to exacerbation of PTTM, he was immediately hospitalized but died of respiratory failure on the same day.

We identified three important clinical issues in the current case study. First, PTTM symptoms can be attenuated by VEGF inhibitors. Second, the absence of tumor cells on TBLB cannot exclude the possibility of PTTM. Finally, an immune checkpoint inhibitor (ICI) was found to be effective for PTTM resulting from gastric cancer.

VEGF inhibitors can attenuate symptoms of PTTM. PTTM generally causes acute progressive dyspnea [3], and 95% of patients with PTTM present with hypoxemia at their initial visit [2]. The deterioration of hypoxemia is so rapid that most cases cannot be accurately diagnosed before death [2, 3]. However, no hypoxemia was observed at the presentation in the current case. Before the discontinuation of nivolumab, the progression of dyspnea was relatively slow, requiring temporary oxygen therapy at only 1 L/min on exertion. Although the pathogenesis of PTTM is not fully understood, VEGF is considered to play a role [2]. VEGF is a mitogen that specifically acts on vascular endothelial cells and is thought to induce pulmonary hypertension via endothelial cell proliferation and subsequent pulmonary arterial occlusions [4]. In an autopsy case series of 30 patients with PTTM, tumor cells in the tumor emboli were positive for VEGF in 28 of 29 (96.6%) cases [3]. Additionally, some case reports have also documented the normalization of VEGF levels after treatment for PTTM [5, 6]. VEGF inhibitors demonstrated clinical efficacy in several cases of PTTM [6‒9], which are summarized in Table 1. More than half of patients with PTTM have gastric adenocarcinoma as an underlying malignancy [2]. Ramucirumab, an anti-VEGF receptor-2 monoclonal antibody, is an established second-line or later chemotherapeutic agent for advanced gastric cancer. Therefore, in patients with advanced gastric cancer on ramucirumab, as in the present case, symptoms of PTTM can be attenuated because of VEGF inhibition, resulting in slower development of pulmonary arterial occlusions. In a previous report, 1 patient with relapsed colorectal adenocarcinoma on bevacizumab who developed PTTM demonstrated rapidly worsening dry cough and dyspnea after discontinuation of bevacizumab [6]. After the diagnosis of PTTM, bevacizumab combined with imatinib and S-1 was readministered, and there was a decrease in VEGF levels (from 165 to 76.5 pg/mL) as well as significant improvement in symptoms. “Attenuated” PTTM like these cases cannot be recognized easily due to its slow progression.

The absence of tumor cells in TBLB cannot exclude the possibility of PTTM. A definitive diagnosis of PTTM requires pathological evidence of tumor cells in the lung tissue or pulmonary arterial blood. Although pulmonary arterial blood cytology has a sensitivity of 80–88% and a specificity of 82–94% for PTTM [10], the diagnostic power of TBLB is not known. One review found that tumor cells in the lung tissue were detected in all patients who were finally diagnosed with PTTM through lung biopsy or autopsy [2]. Another autopsy case of PTTM revealed that lesions of fibrocellular intimal proliferation in the pulmonary arteries were not always accompanied by tumor emboli [11]. Thus, TBLB can show only intimal hyperplasia without tumor cells, as in the current case. As PTTM exhibits non-specific CT scan findings and laboratory abnormalities, it is difficult to make a right diagnosis of PTTM. Especially in cases of gastric cancer, since lung injury resulting from paclitaxel plus ramucirumab is not rare, distinguishing it from PTTM is a clinical matter of importance [12]. In the current case, we made a clinical diagnosis of PTTM for the following reasons. According to the 2022 European Society of Cardiology/European Respiratory Society guidelines for the diagnosis and treatment of pulmonary hypertension, a finding of diffuse small defects on lung perfusion scintigraphy can narrow down the differential diagnoses to PTTM and diseases categorized under Group 4 (pulmonary hypertension associated with pulmonary artery obstructions) [13]. Group 4 consists mainly of chronic thromboembolic pulmonary hypertension and some rare diseases clearly unfit for this case, such as arteritis without connective disease, congenital pulmonary artery stenoses, hydatidosis, and pulmonary tumor embolism, which, by definition, does not accompany intimal thickening of the pulmonary arteries. As chronic thromboembolic pulmonary hypertension is a chronic complication of acute PE, no prior history of acute PE or deep vein thrombosis can exclude the diagnosis. Moreover, only PTTM can explain resolution of GGOs with nivolumab and progressive respiratory failure after its discontinuation. Even in the absence of pathological evidence, PTTM should be included in the differential diagnosis when patients with cancer develop dyspnea. Pulmonary hypertension and ventilation-perfusion imbalance are key to the clinical diagnosis of PTTM.

An ICI may be effective against PTTM resulting from gastric cancer. No standard treatment for PTTM is established, primarily because of difficulty in antemortem diagnosis [2]. Some reports have documented cases of PTTM successfully treated with platelet-derived growth factor receptor inhibitors (imatinib), VEGF inhibitors, chemotherapy, corticosteroids, vasodilators, or their combinations [2]. Considering some PTTM cases responded to chemotherapy, anti-cancer therapies targeting a primary tumor are a reasonable approach to expect therapeutic effects also on PTTM. In the present case, we chose nivolumab as third-line therapy for gastric cancer and observed a clinical response to PTTM. In previous studies on macrovascular tumor thrombosis in patients with hepatocellular carcinoma and renal cell carcinoma, ICIs showed shrinkage of tumor thrombi [14, 15]. Another case report documented a patient with locally advanced renal cell carcinoma with inferior vena cava tumor thrombus who achieved a complete response of the thrombus with nivolumab plus ipilimumab and underwent radical nephrectomy and inferior vena cava thrombectomy [16]. Pathologic analysis on the tumor thrombus remnant showed higher stromal expression of PD-L1 and more evident infiltration of CD8⁺ T cells and Batf3⁺ dendritic cells than the primary tumor. ICIs can inhibit the progression of PTTM via activation of CD8⁺ T cells in tumor thrombi occluding pulmonary arteries and subsequent elimination of cancer cells that promote intimal thickening. Antemortem diagnosis and appropriate treatment can improve the prognosis of PTTM. Establishing optimal therapies for PTTM is an important matter that requires immediate attention.

VEGF inhibitors may attenuate PTTM symptoms. Even if the respiratory symptoms are mild, oncologists should consider PTTM in patients with cancer receiving VEGF inhibitors.

Written informed consent was obtained from the patient’s next of kin for publication of this case report and any accompanying images. Ethical approval is not required for this study in accordance with local guidelines. The CARE checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000543930).

The authors have no conflicts of interest to disclose.

There was no funding for this case report.

Haruka Ozaki wrote the article. Rika Kizawa cared for the patient. Takeshi Yamaguchi, Yuko Tanabe, Koichi Suyama, and Yuji Miura helped preparing this manuscript. All authors read and approved the final manuscript.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.