Clinical decision making in the era of immunotherapy for high grade-glioma: report of four cases

Abstract

Background: Immune checkpoint inhibitors (ICPIs) are being investigated in clinical trials for patients with glioblastoma. While these therapies hold great promise, management of the patients receiving such treatment can be complicated due to the challenges in recognizing immune-related adverse events caused by checkpoint inhibitor treatment. Brain imaging changes that are the consequence of an inflammatory response may be misinterpreted as disease progression leading to inappropriate premature cessation of treatment. The aim of this study was to, by way of a series of cases, underscore the challenges in determining the nature of contrast-enhancing masses that develop during the treatment of patients with glioblastoma treated with ICPIs.

Case presentation: We reviewed the clinical course and management of 4 patients on ICPIs who developed signs of tumor progression on imaging. These findings were examined in the context of Immunotherapy Response Assessment in Neuro-Oncology (iRANO) guidelines. Although all 4 patients had very similar imaging findings, 2 of the 4 patients were later found to have intense inflammatory changes (pseudoprogression) by pathologic examination.

Conclusions: A high index of suspicion for pseudoprogression needs to be maintained when a patient with brain tumor on immunotherapy presents with worsening in an area of a pre-existing tumor or a new lesion in brain. Our findings strongly suggest that pathological diagnosis remains the gold standard for distinguishing tumor progression from pseudoprogression in patients receiving immunotherapy. There is a large unmet need to develop reliable non-invasive imaging diagnostic techniques.

Trial registration: ClinicalTrials.gov NCT02311920. Registered 8 December 2014.

Keywords: CTLA-4; Immune checkpoint inhibitors; Immunotherapy; Ipilimumab; Nivolumab; PD-1; Pseudoprogression; iRANO.

Conflict of interest statement

Ethics approval and consent to participate

All the patients reported above were enrolled in a clinical trial approved by the National Cancer Institute institutional review board and the National Cancer Institute ethics committee of the National Institutes of Health. A written informed consent was obtained directly from all patients who participated in this study.

Consent for publication

All 4 patients provided written informed consents for publication of their medical data, images and histopathology slides in this article.

Competing interests

The authors declare that that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Tumor histology of patient P1. At initial diagnosis, H&E stain (a, 200X) shows a high grade glioma with increased cellularity, pleomorphic tumor cells (arrows), increased mitotic figures (arrowheads) and areas of necrosis (stars). Histiocytes are minimal in number as stained by KP-1 (b, 200X), and a high proliferative rate is detected by MIB-1 stain (c, 200X). At 3.5 months after initiating nivolumab treatment, a tumor biopsy shows on H&E stain (D, 200X) a much less cellular lesion with fewer atypical cells and marked histiocytic infiltration highlighted by KP-1 (e, 200X), suggesting reactive changes. MIB-1 stain (f, 200X) shows a much lower proliferative rate index. At 7 months, a new biopsy shows similar findings: on H&E (g, 200X) there is some increase in cellularity and cell atypia, still much less than prior to treatment. KP-1 stain (h, 200X) highlights a large number of histiocytes, and MIB-1 (i, 200X) continues to demonstrate a low proliferative rate index. Scale bar for all panels measures 150 μm

Fig. 2

Tumor histology of patient P3. At initial diagnosis, H&E stain (a, 200X) reveals a high-grade glioma with pleomorphic tumor cells (arrows), increased mitotic figures (arrowheads), and areas of necrosis (stars). Histiocytes are minimal in number as stained by KP-1 (b, 200X). MIB-1 shows a high proliferative rate index (c, 200X). At 8.5 months after the initiation of ipilimumab, a new biopsy of the tumor still shows on H&E (d, 200X) a high-grade glial neoplasm with increased cellularity and mitotic figures. Reactive changes are present and abundant histiocytes are identified with KP-1 stain (e, 200X). MIB-1 demonstrates a high proliferative rate index, up to 40% in some areas. Scale bar for all panels measures 150 μm

Fig. 3

MRI images of P1 at initial diagnosis (A and a), at 2 months of initiation of nivolumab when a new enhancing lesion was noted in the centrum semiovale of the left frontal lobe (B and b), at 3.5 months of initiation of nivolumab prior to biopsy showing an increase in size of the enhancing lesion and mass effect on the left lateral ventricle (C and c) and at 7 months of initiation of nivolumab prior to second craniotomy illustrating a continued increase in size of the enhancing left frontal lesion and left frontal edema (D and d)

Fig. 4

MRI images of the patients P2, P3 and P4 at 4 weeks post-chemoradiation (A and a) and at the time of biopsy or resection (B and b)