Immunotherapy Brings Three-Year Survival in Rare, Usually Fatal Lung Vascular Cancer Syndrome

A 64-year-old man with a heavy smoking history has survived more than three years after developing one of the deadliest and least understood complications of cancer, according to a case report published in Respirology Case Reports. The condition, pulmonary tumour thrombotic microangiopathy, or PTTM, occurs when tumour cells shed into the bloodstream and lodge in the smallest vessels of the lungs, triggering clotting and inflammation that progressively choke off blood flow. Most patients die within weeks, and the majority of cases are only identified after death during autopsy. The Japanese patient, treated with the immune checkpoint inhibitor nivolumab, is now believed to be among only a handful of people worldwide to achieve durable, long-term survival after the syndrome took hold, offering a striking example of how rapid clinical detective work and modern immunotherapy can change the trajectory of a disease that has historically been considered an automatic death sentence.

The patient’s story began deceptively. He had been managed for bronchial asthma for two years, but over the six months before presentation he developed worsening breathlessness on exertion and wheezing. He had no cough and no coughing up of blood, and there were no laboratory signs of disseminated intravascular coagulation, the catastrophic clotting disorder that often accompanies advanced malignancy. When his symptoms suddenly accelerated, imaging became the first clue that something far more sinister than an asthma flare was underway. A computed tomography scan of the chest revealed diffuse centrilobular nodules distributed throughout both lungs, a so-called tree-in-bud pattern, and mild bilateral ground-glass opacities, the hazy areas that suggest partial filling or thickening of the air spaces.

That tree-in-bud appearance is classically the signature of infectious bronchiolar disease, particularly tuberculosis and nontuberculous mycobacterial infection, and it initially steered clinicians toward an infectious explanation. The patient was treated for a presumed asthma exacerbation with infection, but his respiratory status continued to deteriorate. Laboratory testing added a crucial piece of the puzzle: there was no marked inflammatory response, yet his serum carcinoembryonic antigen, or CEA, a tumour marker, was dramatically elevated at 34.7 nanograms per millilitre against a normal ceiling of 5.0. Microbiological and serological investigations, including tests for tuberculosis, failed to support any infectious cause. Together, the elevated tumour marker and the atypical radiology pointed toward a noninfectious, malignant vascular process.

Positron emission tomography using fluorodeoxyglucose showed mild tracer uptake in a pulmonary ground-glass lesion, with no abnormal activity elsewhere in the body to suggest a primary tumour outside the chest. Within two weeks, the man’s breathing had deteriorated so severely that he required urgent hospitalisation for hypoxaemia, a dangerous drop in blood oxygen. Contrast-enhanced CT found no large pulmonary artery thrombi, which might have suggested ordinary clot embolism, but lung perfusion scintigraphy revealed widespread bilateral perfusion defects, meaning large regions of lung tissue were receiving little or no blood flow. Echocardiography demonstrated mild pulmonary hypertension with strain on the right ventricle, the chamber that must pump blood through the lungs and which fails early when pulmonary vessels become obstructed.

On hospital day four, bronchoscopy with bronchoalveolar lavage and transbronchial lung biopsy was performed. Cultures of the lavage fluid were negative for bacteria and mycobacteria, further excluding infection. The biopsy revealed adenocarcinoma, but critically, the histopathology showed preserved vascular architecture without definitive tumour emboli, so PTTM could not be confirmed under the microscope. Right heart catheterisation on day five showed pressures that, while abnormal, had not yet crossed the formal diagnostic threshold for pulmonary hypertension, likely because the procedure was performed early in the course. Faced with a patient in rapid decline, the clinical team made the judgment call to diagnose PTTM associated with carcinoma of unknown primary on clinical grounds alone and to begin treatment before completing a full diagnostic workup, a decision that almost certainly saved his life.

After discussion with the patient and his family, the team selected nivolumab monotherapy, an immune checkpoint inhibitor that blocks the PD-1 receptor and unleashes T cells against tumour cells, initiated on hospital day eleven. Molecular testing had shown no EGFR mutation and no ALK or ROS1 rearrangements, ruling out targeted therapies, but PD-L1 immunostaining revealed strong expression in more than 75 percent of tumour cells, a biomarker associated with responsiveness to checkpoint blockade. Immunohistochemistry showed nuclear positivity for thyroid transcription factor-1, suggesting the tumour likely originated in the lung, though the small biopsy specimen could not definitively establish the primary site, and upper gastrointestinal endoscopy, performed because gastric cancer is the malignancy most often linked to PTTM, found nothing.

The early course was harrowing. Despite starting nivolumab, the man’s respiratory condition continued to worsen, and by day fourteen he needed high-flow nasal cannula oxygen. By day twenty-six he had developed severe disturbance of consciousness, likely reflecting the combined effects of profound hypoxaemia and the metabolic strain of a failing pulmonary circulation. Then, remarkably, both his consciousness and his oxygenation improved by day twenty-nine, and he was discharged on day fifty-four without any neurological or respiratory after-effects. Serial CEA measurements told the story of the tumour’s retreat: the marker fell progressively from 34.7 nanograms per millilitre before treatment to within the normal range two months after discharge, and it has remained normal throughout follow-up. Serum BNP, a marker of cardiac strain, transiently rose and then normalised, mirroring the resolution of right ventricular stress seen on serial echocardiography.

The treatment was not without cost. During follow-up the patient developed a series of immune-related adverse events, the flip side of a successfully activated immune system, including thyroid dysfunction, renal dysfunction and hepatic dysfunction. These were managed with close monitoring, and nivolumab was continued until after seven cycles, when treatment had to be stopped because of grade 3 pneumonitis, a significant inflammation of the lung tissue itself. Despite that complication, the underlying disease has never returned. The patient remains progression-free more than three years after symptom onset, joining only two previously reported patients who survived longer than three years with PTTM, one with stage IV breast cancer treated with chemotherapy and another with ROS1-rearranged lung cancer treated with crizotinib under extracorporeal membrane oxygenation.

The authors of the report argue that the case carries two broad lessons. First, the vascular tree-in-bud pattern, in which neoplastic emboli rather than infected secretions produce the characteristic branching nodules on CT, deserves wider recognition as a potential marker of PTTM, particularly when accompanied by rising tumour markers, absent inflammatory response and rapidly progressive hypoxaemia. Because transbronchial biopsy specimens are small and subject to sampling error, pathological confirmation of PTTM is often impossible in life, and clinicians may need to act on integrated clinical, radiological and haemodynamic evidence rather than waiting for a definitive histological diagnosis. Second, and perhaps more importantly, the case suggests that when PTTM is strongly suspected, prompt systemic treatment of the underlying malignancy may be justified even before the primary tumour is identified. No standard therapy exists for PTTM, and reported approaches, from anticoagulation and corticosteroids to pulmonary vasodilators and imatinib, rest on little more than case reports. But in all three long-term survivors to date, including this one, durable control of the underlying cancer was accompanied by resolution of the pulmonary vascular catastrophe. The exceptionally high PD-L1 expression in this patient may have contributed to the response to nivolumab, and the authors suggest that early recognition of PTTM combined with effective anticancer therapy may be the key to converting a disease measured in weeks into one measured in years.

Subject of Research: Long-term survival in pulmonary tumour thrombotic microangiopathy treated with nivolumab for cancer of unknown primary

Article Title: Long‐Term Survival Following Nivolumab Treatment in Pulmonary Tumour Thrombotic Microangiopathy Associated With Cancer of Unknown Primary: A Case Report

Article References: Fujishima, K., Osugi, J., Noma, S., Higuchi, M., & Suzuki, H. (2026). Long‐Term Survival Following Nivolumab Treatment in Pulmonary Tumour Thrombotic Microangiopathy Associated With Cancer of Unknown Primary: A Case Report. Respirology Case Reports, 14(10), Article e70763. https://doi.org/10.1002/rcr2.70763

Image Credits: AI Generated

DOI: 10.1002/rcr2.70763

Keywords: pulmonary tumour thrombotic microangiopathy, nivolumab, cancer of unknown primary, immunotherapy, pulmonary hypertension, PD-L1, CEA, tree-in-bud pattern, checkpoint inhibitor, case report, lung adenocarcinoma, immune-related adverse events