Case Report: Pseudomeningeosis and Demyelinating Metastasis-Like Lesions From Checkpoint Inhibitor Therapy in Malignant Melanoma

Schmidt, Teresa; Kebir, Sied; Livingstone, Elisabeth; Junker, Andreas; Zülow, Stefan; Lazaridis, Lazaros; Oster, Christoph; Chorti, Eleftheria; Pierscianek, Daniela; Pul, Refik; Keyvani, Kathy; Sure, Ulrich; Stuschke, Martin; Kleinschnitz, Christoph; Scheffler, Björn; Zimmer, Lisa; Glas, Martin

doi:10.3389/fonc.2021.637185

Cited by 3 publications

(1 citation statement)

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“…Until now, only single case reports or case series of cerebral pseudoprogression have been published and the incidence of cerebral pseudoprogression after ICI treatment is unknown. Imaging patterns of cerebral pseudoprogression reported so far are diverse and include an increase in MRI contrast enhancement in metastatic lesions with an increase of adjacent edema (9)(10)(11), small dotted cerebral bleedings (12) and new FLAIR hyperintense lesions (13) distant from cerebral metastases. The FLAIR hyperintense lesions have been interpreted as inflammatory central nervous system (CNS) demyelination in one case (14) and as immunemediated cerebellitis in another case (15).…”

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Inhibitor-Induced Cerebral Pseudoprogression: Patterns and Categorization

et al. 2022

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BackgroundThe 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.MethodsWe 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.ResultsWe 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.ConclusionCerebral 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.

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Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Inhibitor-Induced Cerebral Pseudoprogression: Patterns and Categorization

et al. 2022

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Immune Checkpoint Inhibitor-Related Cerebellar Toxicity: Clinical Features and Comparison with Paraneoplastic Cerebellar Ataxia

Dentoni,

Florean,

Farina

et al. 2024

Cerebellum

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AbstractImmune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, and the association with immune-related adverse events (irAEs) is well-established. However, cerebellar irAEs are poorly defined and their relationship with paraneoplastic disorders remains unclear. Our aim was (i) to characterize cerebellar irAE; (ii) to compare it with paraneoplastic cerebellar ataxia (PCA). We performed a multicenter, retrospective, cohort study of patients developing new-onset, immune-mediated, isolated/predominant cerebellar dysfunction after ICI administration. In addition, a systematic review following PRISMA guidelines was performed. Cerebellar irAE cases were compared with a consecutive cohort of patients with PCA. Overall, 35 patients were included, of whom 12 were original cases (males: 25/35 (71%), median age: 65 [range: 20–82]). The most frequent tumor was non-small cell lung cancer (12/35, 34%). Anti-PD1 were adopted in 19/35 (54%). Symptoms developed at a median of 11 weeks after ICI onset. Neuronal antibodies were detected in 15/31 patients tested (48%). Cerebrospinal fluid was inflammatory in 25/30 (83%). Magnetic resonance imaging showed cerebellar hyperintensities in 8/35 (23%). Immunotherapy was applied in 33/35 cases (94%), and most patients improved with residual disability (16/35, 46%). When compared with a series of PCA (n = 15), the cerebellar irAE group was significantly more associated with male sex, lung cancer (rather than gynecological/breast cancers), isolated ataxia, and a better outcome. We provide a detailed characterization of cerebellar irAE. Compared to PCA, differences exist in terms of tumor association, clinical features, and outcome. Clinical presentation-antibody-tumor triad in the ICI group only partially reflects the associations described in paraneoplastic disorders.

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Ipilimumab/nivolumab

2021

Reactions Weekly

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A 47-year-old man developed demyelinating diseases during treatment with ipilimumab and nivolumab for malignant melanoma. The man, who had malignant melanoma, presented with an ulcerated melanoma of the occipital scalp. The molecular analysis showed a BRAF V6000E mutation, NRAS wild-type and KIT wild-type. He underwent left-sided neck dissection (level 2-4) without any signs of tumour spread. As per the American Joint Committee on Cancer (AJCC), the staging at diagnosis was IIc and switched to IIIc after sentinel lymph node biopsy. Hence, he started receiving combinatorial treatment arm with nivolumab 240mg, every 2 weeks and ipilimumab 1 mg/kg, every 6 weeks [routes not stated]. After 5 weeks of treatment, he developed evidence of cerebellar disease with pathologic heel-to-shin exam, gait ataxia and dysmetria. Over time, his symptoms worsened.Hence, the man's treatment was discontinued after 3 cycles of nivolumab and 2 cycles of ipilimumab. The brain MRI showed several spot-shaped periventricular, parenchymal and leptomeningeal contrast enhancements, indicative of parenchymal and predominantly leptomeningeal metastasis. The spine MRI was consistent with leptomeningeal metastasis with nodular enhancement tracking, along with the thoracic and cervical segments and conus terminalis. The CSF examination revealed mild elevation of protein level and a moderate elevation of lymphomononuclear pleocytosis. However, the tumour cells were absent. No melanoma cells were observed, and no signs of lymphoma were observed in a clonality analysis for T and B-cell receptors. The neuropathologic examination revealed white matter tissue with reactive gliosis and abruptly demarcated demyelinated areas, positive staining for myelin protein CNPase and MBP, dense macrophagocytic infiltrates and perivascular accentuated lymphocytic CD45+ infiltrates including CD3+ and CD20+ cells of low to moderate density. The tissue showed negative results for lymphoblastoid B or T-cells, clonality analysis and melanosomal antigens (Melan A and HMB45). Also, no IDH-1 R132H mutationspecific stainability, p53 accumulation or alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss were observed. His findings were considered pseudomeningeosis. Based on findings, a diagnosis of ipilimumab and nivolumab-induced demyelinating diseases was made. Hence, he received corticosteroid treatment, which resulted in prompt clinical improvement. Six weeks later, the CSF and MRI examination showed a near-complete remission. He did not receive any other tumour directed treatment. At the latest follow-up (on May 2020), no signs of tumour progression were observed. He remained progression-free for 22 months.

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Case Report: Pseudomeningeosis and Demyelinating Metastasis-Like Lesions From Checkpoint Inhibitor Therapy in Malignant Melanoma

Cited by 3 publications

References 10 publications

Immune Checkpoint Inhibitor-Induced Cerebral Pseudoprogression: Patterns and Categorization

Immune Checkpoint Inhibitor-Induced Cerebral Pseudoprogression: Patterns and Categorization

Immune Checkpoint Inhibitor-Related Cerebellar Toxicity: Clinical Features and Comparison with Paraneoplastic Cerebellar Ataxia

Ipilimumab/nivolumab

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