Immune Checkpoint Inhibitor-Induced Cerebral Pseudoprogression: Patterns and Categorization

Abstract

Background: The inclusion of immune checkpoint inhibitors (ICIs) in therapeutic algorithms has led to significant survival benefits in patients with various metastatic cancers. Concurrently, an increasing number of neurological immune related adverse events (IRAE) has been observed. In this retrospective analysis, we examine the ICI-induced incidence of cerebral pseudoprogression and propose a classification system.

Methods: We screened our hospital information system to identify patients with any in-house ICI treatment for any tumor disease during the years 2007-2019. All patients with cerebral MR imaging (cMRI) of sufficient diagnostic quality were included. cMRIs were retrospectively analyzed according to immunotherapy response assessment for neuro-oncology (iRANO) criteria.

Results: We identified 12 cases of cerebral pseudoprogression in 123 patients treated with ICIs and sufficient MRI. These patients were receiving ICI therapy for lung cancer (n=5), malignant melanoma (n=4), glioblastoma (n=1), hepatocellular carcinoma (n=1) or lymphoma (n=1) when cerebral pseudoprogression was detected. Median time from the start of ICI treatment to pseudoprogression was 5 months. All but one patient developed neurological symptoms. Three different patterns of cerebral pseudoprogression could be distinguished: new or increasing contrast-enhancing lesions, new or increasing T2 predominant lesions and cerebral vasculitis type pattern.

Conclusion: Cerebral pseudoprogression followed three distinct patterns and was detectable in 3.2% of all patients during ICI treatment and in 9.75% of the patients with sufficient brain imaging follow up. The fact that all but one of the affected patients developed neurological symptoms, which would be classified as progressive disease according to iRANO criteria, mandates vigilance in the diagnosis and treatment of ICI-induced cerebral lesions.

Keywords: brain metastases; cerebral pseudoprogression; immune checkpoint inhibitors (ICI); immune related adverse events (irAE); immunotherapy; neurological complication; neurological side effects.

Figure 1

Consort Flow-diagram.

Figure 2

Cranial MRI scans of a 54-year-old patient with single, cerebellar metastasis of non-small-cell lung carcinoma. The MRI scan shows an excellent response of the cerebellar metastasis to the radiation therapy [(A): T1-weighted, contrast enhanced images]. At the same time, new tubular contrast enhancements with adjacent edema and diffusion restrictions have appeared in the left frontal lobe distant to the irradiated cerebellar metastasis [(B): T1-weighted, contrast enhanced images, (C): Fluid-attenuated inversion recovery (FLAIR), (D): Diffusion-weighted images (DWI, b1000)].

Figure 3

Cranial MRI scans of a 61-year-old patient with Hodgkin’s lymphoma in the thoracic and abdominal lymph nodes. Recurrent lymphoma had been treated with pembrolizumab since 12/2018. Initial CT scan of the brain as part of a whole body FDG-PET scan had shown no cerebral manifestations of the lymphoma (not shown). The patient had no neurological symptoms at the start of ICI therapy. The patient was admitted in 05/2019 with dizziness and nausea. First MRI (upper row) showed small nodular, cortical contrast enhancement (A) with corresponding hyperintense signal in fluid-attenuated inversion recovery (FLAIR) imaging (B) and diffusion-weighted imaging (DWI, b1000) (Arrows mark the biopsy site), (C) as well as small bleedings in susceptibility-weighted imaging (SWI) (D). Cerebrospinal fluid was not indicative for cerebral lymphoma or bacterial or viral encephalitis. Histological evaluation of biopsy samples (E–G) revealed neither cerebral lymphoma nor JC-virus, but reactive CNS alterations with astrogliosis [(E)+(G), arrows: astrocytes with reactive changes] and macrophage clearance (F). First follow-up MRI after the discontinuation of pembrolizumab (middle row) showed a further progression of the lesion. Treatment with high-dose methylprednisolone and tapering dose of prednisolone in combination with everolimus was administered. First control under the immunosuppressive treatment (lower row) showed an improvement with regressive contrast enhancement.

Figure 4

Cranial MRI scans of a 76-year-old patient with melanoma of the vulva. The patient had been treated with nivolumab and ipilimumab, which had been discontinued due to autoimmune hepatitis and switched to pembrolizumab in 03/2018. Routine staging revealed a new, contrast-enhancing tumor next to the right posterior cerebral artery (second column, red arrow). Repetitive cerebrospinal fluid analysis did not show meningeal carcinomatosis. Treatment with oral prednisolone was started in 12/2018 (third column) and the next MRI one month later showed shrinkage of the tumor, which was retrospectively diagnosed as pseudoprogression (fourth column). In 05/2019 the patient showed a meningeosis carcinomatosa in before normal appearing localizations.

Figure 5

Cranial MRI scans of a 64-years-old with a metastasis malignant melanoma. The patient had been treated with radiosurgery of one metastasis (second row with contrast agent) and nivolumab after the radiation. After clinical deterioration within 4 weeks of starting checkpoint therapy, the patient showed a marked increase in T2 changes outside the radiation field.

Figure 6

Cranial MRI of a 44-year-old female patient with NSCLC and pembrolizumab therapy. (A) Shows vascular imaging with no evidence of vasculitis-type changes in the large cerebral vessels. (B) Transversal gadolinium enhanced T1 weighted MRI with the remains of the occipitally located brain metastasis, as well as periventricular contrast medium accumulations suspicious for vasculitis (arrow). (C) A frontal gadolinium enhanced T1 weighted MR of the same patient. Again, the arrow indicates suspicious contrast agent accumulations. (D–F) Cranial MRI Scans and vertebral column MRI of a 72-year-old patient with melanoma. The Patient had been treated with nivolumab for 15 months. The patient then developed a headache and paraparesis. Cerebral angiography showed caliber changes of the left middle cerebral artery and the basilar artery. Due to vasculitis, the patient developed prolonged bleeding with siderosis-associated myelopathy. (D) Cerebral angiography with caliber changes of the cerebral vessels. (E) Cranial MRI of the lower spinal cord with bleeding in the caudal region. (F) Cranial MRI with bleeding of the metastasis and blood in the liquor system.