Cancer Immunology Miniatures

Melanoma Brain Metastasis Pseudoprogressionafter Pembrolizumab TreatmentJustine V. Cohen1, Ahmed K. Alomari2, Alexander O. Vortmeyer2, Lucia B. Jilaveanu1,Sarah B. Goldberg1, Amit Mahajan3, Veronica L. Chiang4, and Harriet M. Kluger1

Abstract

The role of immunotherapy in treatment of brain metas-tases is unknown because most trials exclude patients withactive brain lesions. As new immunomodulating agents gainapproval for many malignancies, it is important to knowif they have unique effects in the central nervous system(CNS). Here, we present a case of a patient with progressingbrain metastases treated with a single cycle of pembrolizu-mab, who presented with mental status changes 11 daysthereafter. MRI of the brain showed enlargement of CNS

lesions with intense central enhancement and diffuse perile-sional edema. Histologic evaluation of a resected lesionrevealed isolated clusters of tumor cells surrounded by reac-tive astrocytosis, scattered inflammatory cells, and an abun-dance of microglial cells. Given the increasing use of immunecheckpoint inhibitors in patients with brain metastases frommelanoma and other diseases, recognition of pseudoprogres-sion and management with immune suppression are essential.Cancer Immunol Res; 4(3); 179–82. �2015 AACR.

IntroductionTen to 40% of patients withmetastatic melanoma develop brain

metastases (1). Standard management of brain metastases involvessurgery or radiotherapy, depending on size and number of tumors(2). Although systemic therapy might have a role in treating brainmetastases, the ability of newer systemic therapies to cross theblood–brain barrier (BBB) remains unknown and is the subject ofongoing investigations (1, 3). Most systemic therapy trials excludepatients with active brain metastases due to their expected poorprognosis, concerns about confounding neurologic symptoms,and possible inability of drugs to cross the BBB (4, 5). In recentyears, a few systemic therapy trials have been tailored specificallyto brain metastasis patients (6–11). All of these studies were small,with the exception of the BREAK-MB trial (dabrafenib in patientswith Val600Glu or Val600Lys BRAF-mutant melanoma meta-stastic to the brain), which enrolled 172 patients.

Drugs with known ability to cross the BBB, fotemustine andtemozolomide, both alkylating agents, have shown limited activ-ity, with brain metastasis response rates of 25% and 6%, respec-tively (12–14).Most of the experience in treatingmelanomabrainmetastases with immune therapy has been with ipilimumab.There is evidence that T cells activated by the CTLA-4 inhibitoripilimumab cross the BBB, resulting in intracerebral antitumorresponses. A phase II trial of patients with asymptomatic and

symptomatic brainmetastases showedmedian overall survival of7 and 3.7 months, respectively, with 2-year survival rates of 10%(15). Activity in asymptomatic patients was thus similar to that ofpatients without brain metastases (16).

As immunomodulating antibodies play an increasing role intreatment ofmelanoma and other cancer types, the effects of theseagents on brain metastases need to be assessed. Magnetic reso-nance imaging (MRI) is the most commonmodality for assessingresponse of brain metastases, but the range of imaging responsesof brain metastases to immunotherapy is not well studied. Wepresent a case ofmetastaticmelanoma to thebrain associatedwithsignificant pseudoprogression after treatment with the PD-1inhibitor pembrolizumab.

Case PresentationA 56-year-old woman presented with BRAFV600E-mutant meta-

static melanoma to subcutaneous tissues, axillae, and adrenalglands 4 years after excision of a 2.13 mm, nonulcerated primarylesion. Shewas treatedwith vemurafenib for 4monthswithdiseaseprogression in the brain. She received whole-brain radiation fol-lowed by induction of ipilimumab without response and wasswitched to dabrafenib and trametinib (BRAF andMEK inhibitors,respectively), to which she had a mixed response. She then devel-oped innumerable new small brain metastases, seen on surveil-lance MRI, for which radiosurgical salvage was not easily achiev-able. To facilitate safe management, one of her intracranial lesionswas resected. She was enrolled on a trial of pembrolizumab formelanoma patients with active brain metastases (NCT02085070),receiving her first dose of 10 mg/kg of pembrolizumab. She pre-sented to the emergency room 11 days later with mental statuschanges. MRI showed significant worsening of cerebral edemasurrounding all of her brain lesions, many of which were largeron post-gadolinium T1 imaging. The enlarging lesions showedunusual target-like appearances (Fig. 1). Given the MRI and thespeed of imaging growth that was atypical for tumor progression,we resected a representative accessible small left parietal–occipital

1DepartmentofMedicine, SectionofMedicalOncology,YaleUniversitySchool of Medicine, NewHaven, Connecticut. 2Department of Pathol-ogy, Yale University School of Medicine, New Haven, Connecticut.3Department of Diagnostic Radiology,Yale University School of Med-icine, New Haven, Connecticut. 4Department of Neurosurgery, YaleUniversity School of Medicine, New Haven, Connecticut.

Corresponding Author: Harriet M. Kluger, 333 Cedar Street, PO Box 208028,New Haven, CT 06520. Phone: 203-737-2572; Fax: 203-785-3788; E-mail:Harriet.Kluger@Yale.edu

doi: 10.1158/2326-6066.CIR-15-0160

�2015 American Association for Cancer Research.

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lesion. Histopathology of this second lesion showed small clustersof tumor cells surroundedby an admixture of hemorrhage, reactiveastrocytosis, scattered inflammatory cells, and an abundance ofmicroglial cells, as identified by CD68 immunostaining—allchanges consistent with response to treatment rather than tumorgrowth (Fig. 2). CD45 staining highlighted scattered inflammatorycells, of which surprisingly few were CD8þ T cells. Sparse tumorcells showed reactivity to S100, HMB45, and Melan A. The pati-ent passed away 3 weeks later. No autopsy was done, and thepathologic disease status could not be determined.

DiscussionImmune checkpoint inhibitors, alone and in combination, are

currently the focus of intense study for a wide range of malig-

nancies, including melanoma and lung cancer—diseases thatmetastasize to the brain frequently. Patientswith brainmetastaseshave previously been excluded from these trials, and literaturedescribing effects of immunomodulating antibodies on brainlesions and microenvironment consequently remains sparse.There is evidence that T cells activated by ipilimumab may crossthe BBB, enabling an intracerebral antitumor response (17, 18).Several studies have shown a positive effect of ipilimumab onselected patients with small asymptomatic brain metastases notrequiring steroid therapy (7, 15, 16, 19–22). Hodi and colleagues(23) described 1 patient with brain metastases from melanomawho did not respond to ipilimumab. Pathologic review of aresected brain metastasis following treatment with ipilimumabshowed focal necrosis with marked tumor infiltration by lym-phocytes and an abundance of melanophages and CD8þ tumor-

Figure 1.MRI before and after treatment withpembrolizumab. A, post-contrast T1-weighted image revealed severalenhancing metastatic lesions withinthe brain parenchyma prior toinitiation of treatment. B, post-contrast T1-weighted image acquired11 days after the onset of treatmentwith pembrolizumab revealedincrease in the size of many of themetastatic lesions with a target-likeappearance. The lesions show acentral densely enhancing area with aground glass zone surrounding it.C and D, post-contrast T1-weightedimaging before and on therapy. Thearrows show the lesion that wasresected.

Cohen et al.

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infiltrating lymphocytes with a paucity of FoxP3þ regulatory cells.The lesion in our patient showedonly small clusters of tumor cellswith similar reactive brain changes. The inflammatory infiltrate in

our patient was composed predominantly of activated microglialcells and scattered CD8þ T cells. While the effects of pembroli-zumab on normal brain and brain metastases are largely

Figure 2.A, a representative hematoxylin and eosin (H&E)section fromoneof the patient's brain lesions priorto pembrolizumab treatment showing diffuse areaof malignant cells (�10). B, HMB-45immunostaining of the lesion depicted in Ashowing diffuse positivity consistent withmetastatic melanoma (�10). C, a representativeH&E section post-pembrolizumab treatmentshowing small clusters ofmelanoma cells admixedwith areas of hemorrhage (�20). D,immunohistochemical staining with HMB-45 ofthe lesion depicted in C highlighting scattered fociof melanoma cells (�20). E, reactive astrocytosisand infiltration of macrophages in surroundingbrain tissue of the lesion in part C (�40). F, CD45immunohistochemical staining showing scatteredperivascular and interstitial inflammatory cells aswell as activated microglial cells (�20). G and H,CD8 immunostaining highlighting infiltration ofcytotoxic lymphocytes (�40 and �20). I, CD4immunostaining showing only rare helper Tlymphocytes (�20). J, CD68 immunostainingshowing microglial/macrophagocytic cells (�20).

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Brain Pseudoprogression after Pembrolizumab

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unknown, itmight cause an inflammatory response similar to thatof ipilimumab, as supported by our pathology.

Many studies have investigated effects of radiosurgery on braintumors. Interpretation of imaging after radiosurgery may bedifficult even without additional effects of immunotherapy. Inpatients treated with gamma knife stereotactic radiosurgery(GKRS), re-increase in size of enhancing lesions on T1 MRI isthought to be due to tumor regrowth. Our institution reportedthat regrowth of lesions on MRI after GKRS can histologicallyshow either tumor recurrence or post-radiation inflammation(24) and often it is impossible to differentiate these entities usingMRI. Rauch and colleagues (25) reported histopathologic changesin 10 patients with symptomatic growing lesions 8 to 17 monthsafter GKRS and increased FLAIR signal on MRI. They observedradiation-induced leukoencephalopathic changes (inflammatoryinfiltrate, demyelination, coagulative necrosis, and reactive astro-cytosis) and vasculitic pathology, without evidence of tumor,indicative of treatment-related changes.

Our case demonstrates that lesion enlargement on gadolinium-enhanced T1 MRI associated with increased perilesional FLAIR onMRI in a patient treated with pembrolizumab may not necessarilyreflect true tumor progression, but can also be an inflammatoryeffect. Patients may become symptomatic from this inflammation,and management of the inflammation with corticosteroids mightbe necessary despite diminishing the immune effect. Recognition

of the possibility of pseudoprogression is therefore crucial formanagement of these patients. Moreover, correct interpretation ofeffects of immunomodulatory agents such as pembrolizumab onbrain metastases and correct classification of patients by clinicaltrial response criteria (RECIST or RANO) remain a challenge.

Disclosure of Potential Conflicts of InterestS.B. Goldberg reports receiving commercial research support from

AstraZeneca. No potential conflicts of interest were disclosed by the otherauthors.

Authors' ContributionsConception and design: J.V. Cohen, A.K. Alomari, V.L. Chiang, H.M. KlugerDevelopment of methodology: J.V. Cohen, A.O. Vortmeyer, V.L. ChiangAcquisition of data (provided animals, acquired and managed patients,provided facilities, etc.): J.V. Cohen, A.K. Alomari, A.O. Vortmeyer, A.Mahajan,V.L. ChiangAnalysis and interpretation of data (e.g., statistical analysis, biostatistics,computational analysis): J.V. Cohen, S.B. Goldberg, A. Mahajan, V.L. ChiangWriting, review, and/or revision of the manuscript: J.V. Cohen, A.K. Alomari,L.B. Jilaveanu, S.B. Goldberg, V.L. Chiang, H.M. KlugerAdministrative, technical, or material support (i.e., reporting or organizingdata, constructing databases): J.V. Cohen, A.K. Alomari, A.O. VortmeyerStudy supervision: H.M. Kluger

Received July 2, 2015; revised September 24, 2015; accepted October 23,2015; published OnlineFirst December 23, 2015.

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2016;4:179-182. Published OnlineFirst December 23, 2015.Cancer Immunol Res   Justine V. Cohen, Ahmed K. Alomari, Alexander O. Vortmeyer, et al.   Pembrolizumab TreatmentMelanoma Brain Metastasis Pseudoprogression after

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