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An Uncommon Presentation of Brain Metastases in a Lung Cancer Patient

      Immunotherapy is a promising treatment option for non–small-cell lung cancer patients. Immunotherapy clinical trials include for example PD-(L) 1 and CTLA4 blockers, but also activating interleukins (IL). The related adverse events are different from that of chemotherapy-based treatment and new lesions can be the result of so called pseudo-progression instead of real tumor progression.
      • Fecher LA
      • Agarwala SS
      • Hodi FS
      • Weber JS
      Ipilimumab and its toxicities: A multidisciplinary approach.
      • Wolchok JD
      • Hoos A
      • O'Day S
      • et al.
      Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria.
      Differentiation among progressive disease, pseudo-progression, and infectious disease can be challenging, as was the case for the patient described below.
      This patient was diagnosed with metastasized nonsmall-cell lung cancer (adenocarcinoma). At diagnosis, magnetic resonance imaging (MRI) of the brain was normal. First-line treatment consisted of four cycles of chemotherapy (gemcitabin/cisplatin) resulting in a partial response. As a maintenance treatment, she was treated with the immuncytokine Selectikine (modified IL-2 [NHS-IL2]) in a phase I trial (NCT00879866).
      • van den Heuvel MM
      • Verheij M
      • Boshuizen R
      • et al.
      NHS-IL2 combined with radiotherapy: Preclinical rationale and phase Ib trial results in metastatic non-small cell lung cancer following first-line chemotherapy.
      After 2 months, she presented with nausea, vomiting, and an altered mental status. Brain MRI showed extensive supra- and infratentoral perivascular enhancement, with additional leptomeningeal enhancement at the brainstem and pineal gland (Fig. 1). Extracranially, new liver metastases were found. Differential diagnosis of the brain lesions consisted of brain metastases, an (opportunistic) infection or polyoma JC virus causing progressive multifocal leukoencephalopathy (PML) as part of an immune reconstitution syndrome (IRIS) due to the immunotherapy, and pseudoprogression. Serum viral serology and cerebrospinal fluid cultures for polyoma JC, HIV, toxoplasma, CMV, HSC, VZV, mycobacteria, cryptococcus, and yeasts were negative. Cerebrospinal fluid cytology showed malignant cells. After 3 weeks she died; brain obduction showed extensive adenocarcinoma metastases (Fig. 2). Additional staining did not show an intracranial immune response (no influx of B-cells, T-cells, or macrophages).
      Figure thumbnail gr1
      FIGURE 1Brain MRI. Transverse T2-weighted images (A) and transverse (B) and coronal (C) contrast enhanced T1-weighted images show numerous punctiform hyperintense lesions at T2-weighted imaging, with enhancement after administration of gadolinium. The lesions follow a more or less curved pattern, consistent with perivascular distribution, without lesions at the gray-white matter interface.
      Figure thumbnail gr2
      FIGURE 2Brain autopsy. A and B, Macroscopic aspect of brain tissue show multiple millimetric nodules located along the perivascular spaces; (C) microscopy shows moderately differentiated tubuli with mucin-forming cilindric cells, consistent with adenocarcinoma metastases.
      In this patient, MRI findings were not equivocal. Brain metastases are located mostly at the border of gray and white matter and extensive perivascular enhancement is not a typical finding for brain metastases although some cases are described.
      • Ruppert AM
      • Stankoff B
      • Lavolé A
      • Gounant V
      • Milleron B
      • Seilhean D
      Miliary brain metastases in lung cancer.
      • Iguchi Y
      • Mano K
      • Goto Y
      • et al.
      Miliary brain metastases from adenocarcinoma of the lung: MR imaging findings with clinical and post-mortem histopathologic correlation.
      Brain MRI findings in PML-IRIS are consistent with the findings in our patient. Typical PML lesions are diffuse, with variable size and shape, mainly subcortical located and hyperintensive in T2-weighted images. They are found almost exclusively in the white matter with sparing of the periventricular white matter.
      • Sahraian MA
      • Radue EW
      • Eshaghi A
      • Besliu S
      • Minagar A
      Progressive multifocal leukoencephalopathy: A review of the neuroimaging features and differential diagnosis.
      Contrast enhancement can be seen in PML-IRIS due to local inflammation and breakdown of the blood–brain barrier.
      • Sahraian MA
      • Radue EW
      • Eshaghi A
      • Besliu S
      • Minagar A
      Progressive multifocal leukoencephalopathy: A review of the neuroimaging features and differential diagnosis.
      PML-IRIS has been increasingly diagnosed in patients treated with immunomodulation when T-cell function is restored after removal of immunosuppression.
      • Major EO
      Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies.
      In conclusion, miliary brain metastases are rare and remain a diagnostic challenge especially in the era of immunomodulation.

      ACKNOWLEDGMENT

      The authors thank K. Monkhorst, Department of pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands for the evaluation for an immune response in the brain obduction tissue.

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