A Cautionary Note on Pembrolizumab use in Patients with Ascending Aortic Aneurysms

Abstract

Case description: We describe a case of a patient treated with pembrolizumab (an immune checkpoint inhibitor) for metastatic scalp melanoma. He had a previous history of colorectal cancer, prostatic cancer and chronic polymyalgia rheumatica. The patient was known to have a stable ascending aortic aneurysm of 4.5 cm. However, he developed a rapid expansion of the ascending aortic aneurysm with the size crossing the threshold for surgery. The patient was referred to the cardiothoracic surgery service for intervention and he subsequently underwent surgery. The patient was electively admitted one week later for resection of aortic aneurysm, aortoplasty and external graft fixation. Pathologically, gross evidence of dissection was not identified; however, the histological analysis of the media showed laminar medial necrosis, multifocal in nature, with occasional clusters of histiocytic cells appreciated at their edge reminiscent of that seen in an inflammatory aortitis (granulomatous/giant cell type).

Discussion: Immune checkpoint inhibitor-induced aortitis is becoming increasingly evident, and its presentation can vary. It has been discovered incidentally on surveillance imaging with the use of nivolumab. In other cases, patients have been symptomatic to severely symptomatic. Atezolizumab with carboplatin and etoposide has been reported to cause abdominal aortitis which was responsive to corticosteroids and subsequent discontinuation of atezolizumab. Pembrolizumab has been linked to a case of transverse aortic arch aortitis. In our case, the inflammatory aortitis due to pembrolizumab was the cause of the rapid expansion of the ascending aortic aneurysm.

Conclusion: Patients with known aortic aneurysms should undergo careful surveillance when commencing immune-checkpoint inhibitor therapy.

Learning points: Immune checkpoint inhibitors are being increasingly used in the treatment of metastatic malignancy. However, they are a relatively new group of medications, and the side effect profile of each is yet to be fully recognised. Aortitis has occurred with several different immune checkpoint inhibitors.Patients with known aortic aneurysms should undergo careful surveillance when commencing immune checkpoint inhibitors.All interventional therapeutic options should be considered early in these patients on the development of aneurysmal expansion.

Keywords: Immune checkpoint inhibitors; aortitis; ascending aortic aneurysm; melanoma; pembrolizumab.

Figure 1

Serial surveillance CT imaging over 22 months from diagnosis to operation. A) Initial CT; B) CT at 6 months; C) CT at 13 months; D) CT at 18 months; E) CT at 22 months.

Figure 2

Timeline of ascending aortic aneurysm size as discovered during surveillance computerised tomography scans, showing a rapid increase in aneurysm size post-commencement of pembrolizumab treatment (red line at 15 months).

Figure 3

A) Transthoracic parasternal long axis view demonstrating mild central aortic incompetence with dilated aortic root (13 months); B) Transthoracic parasternal long axis view demonstrating significantly dilated aortic root and ascending aorta (13 months); C) Long axis view transoesophageal echo demonstrating worsening aortic root dilation with moderate to severe aortic incompetence (20 months); D) Transoesophageal echo demonstrating rapid progression of ascending aortic aneurysm (20 months). Credit: Dr. Barry Hennigan

Figure 4

A) and B) Giant cells medium power, giant cells higher power, medium (10×) and higher power (20×) view of H&E stained sections of the media showing laminar medial necrosis, multifocal in nature, with occasional clusters of histiocytic cells appreciated at their edge reminiscent of that seen in an inflammatory aortitis (granulomatous/giant cell type); C) Elastic stain –- Elastic van Gieson’s special stain highlights collapse of elastic fibres in the giant cell rich areas; and D) Gross aorta - pieces of aortic wall as received in the histopathology department showing focal yellowing of the intima with no evidence of dissection.