Black Hairy Tongue After Immune Checkpoint Inhibitors in NSCLC: A Case Report and Review of the Literature

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JID:CLLC [mNS;April23,2021;6:41]

Case

Report

Black

Hairy

Tongue

After

Immune

Checkpoint

Inhibitors

in

NSCLC:

A

Case

Report

and

Review

of

the

Literature

Cristina

Cecchi,

Annapaola

Mariniello,

Simona

Carnio,

Marco

D. Delcuratolo,

Silvia

Novello

Clinical

Practice

Points

•Immunecheckpointinhibitors(ICIs)areassociatedwith the development of unique immune-related adverse events(irAEs), which emerged primarily during post-marketingsurveillance.Oral irAEshavealreadybeen reported,withthemostcommonmanifestationsbeing mucositisandxerostomia.Ithasbeensuggestedthata T-cellactivation,similartothatobservedinautoimmune conditions,mayplayarole.

•Here,wereportacaseofblackhairytongue(BHT)ina patientreceivingﬁrst-linepembrolizumabforadvanced non–small-celllungcancer(NSCLC).AlthoughtheBHT wassymptomaticforburningmouthanddysgeusia,ICI usewascontinueddue to its clinicaland radiological beneﬁt,whichpersistedforalongtime.

•BHTischaracterizedbyhypertrophyandlengtheningof theﬁliformpapillae.Despitebeingararebenign condi-tion,itcanoftenresultinasigniﬁcantburdenonquality oflife.

•Manypredisposing factorshavebeen described,and cancer patients represent a population particularly at risk.Basedonthetemporalassociationandexcluding possible alternativecauses, weproposed that,in our patient, BHTwaslikely ICIrelatedthrough the devel-opmentofxerostomia,whichrepresentsakeyfactorin BHTpathogenesis.

•To the best of our knowledge,this is the ﬁrst report ofBHTafterICIuse,suggestingthatitmayrepresent anatypicaloralirAE.Todate, theoralirAEshavenot been well explored, and further studies are needed to elucidate the underlying mechanisms and possi-bleassociationswithanti-tumorresponses,with signif-icant implications on prognosis and quality of life.In thepresentcontext,ourcaseemphasizestheneedto remainvigilantforatypicalandnewirAEs.

Introduction

Over the last decade, immune checkpoint inhibitors (ICIs) have emergedasa novelandeffective treatmentstrategythathas produced unprecedented results in several solid tumors, includ-ing non–small-cell lung cancer (NSCLC).1 _In _contrast _to _other anti-cancer therapies, ICIs are associated with the development of unique immune-related adverse events (irAEs).2 _Whereas _the mostcommonirAEs,suchasrash,diarrhea,arthritis,hepatitis,and endocrinopathies, werereportedinclinicaltrials,rareirAEshave

DepartmentofOncologyatSanLuigiGonzagaUniversityHospital,Universityof Torino,Turin,Italy

Submitted:Jan29,2021;Revised:Feb27,2021;Accepted:Mar18,2021;Epub:xxx Addressforcorrespondence:CristinaCecchi,DepartmentofOncologyatSanLuigi

Gonzaga UniversityHospital,UniversityofTorino, RegioneGonzole,10,10043 Orbassano,Torino,Italy.

E-mailcontact:annapaola.mariniello@unito.it

emergedduringpost-marketingsurveillance.3 _Dermatologic_irAEs upontheuseof ICIsarefrequentandmayaffectqualityoflife.4 Oralmucosacanalsobeinvolved,withthemostcommon manifes-tationsbeingmucositis andxerostomia.Toourknowledge,black hairytongue(BHT)upontheuseofICIshasnotbeendescribedso far.Here,wereportacaseofICI-inducedBHTinapatientwith advancedNSCLC.

Case

Presentation

A68-year-oldmanwhowasaformersmokerwithapasthistory of type 1diabetes mellitus, tuberculosis, and myocardial infarc-tion was diagnosed with advanced NSCLC in December2019. Thediagnosticwork-uprevealedapoorlydifferentiatedcarcinoma atstageIIIb(T4N2M0).Themolecularprofilingshowed epider-malgrowthfactorreceptorwild-type,anaplasticlymphomakinase and c-ros oncogene 1 receptor tyrosine kinase non-rearranged,

https://doi.org/10.1016/j.cllc.2021.03.008 ClinicalLungCancer 2021

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Pleasecitethisarticleas:CristinaCecchietal,BlackHairyTongueAfterImmuneCheckpointInhibitorsinNSCLC:ACaseReportandReviewofthe Literature,ClinicalLungCancer,https://doi.org/10.1016/j.cllc.2021.03.008

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Figure1 BlackHairyTongue.

andimmunohistochemistryshowedaprogrammeddeathligand-1 tumorproportionscoreof100%(clone22C3).

According to the medical history and the clinical conditions (EasternCooperativeOncologyGroupperformancestatus1), first-line treatment with pembrolizumab 200 mg every 21 days was given,startingfromJanuary2020.InFebruary2020,dueto uncon-trolledpain,palliativeradiationtherapywasdeliveredontheright chestwall(20Gyin5fractions).Aftertwocyclesofpembrolizumab, the patient reported grade 1 mucositis (according to Common TerminologyCriteriaforAdverseEventsVersion5.0[CTCAE5.0]), associated with xerostomia and burning mouth, initially treated with bakingsodamouthwashesandnystatin,withoutsignificant improvement. The restaging CT scan,after four cycles, showed a partialresponse forshrinkage ofthe lunglesion andassociated lymphnodes.

In May 2020 (after five cycles, about 110 days after pembrolizumabstart),oralmucositisworsenedfromgrade2to3 (CTCAE5.0),forpersistingsymptomsofburningmouth, dysgeu-sia, and severe xerostomia. These symptoms partially interfered withfoodintake,butdidnotdeterminesignificantweightloss.At theobjectiveexamination,theonsetofblackdiscolorationonthe dorsumofthetongue,withhairyelevationofthefiliformpapillae, wasnoted(Figure1).

Diagnosis of BHTwas first madeby a dermatologist inJune 2020.AsecondodontostomatologyevaluationconfirmedBHTand suggestedapossibleassociationwithICI,notwithstandinga possi-bleroleofotherconcomitantmedications,whichincluded

panto-prazole, bisoprolol, candesartan/hydrochlorothiazide, manidipine, cardioaspirin, clopidogrel,simvastatin, fentanyl,paracetamol, and insulin.Good oralhygienewasrecommended,and other topical andsystemic treatmentsforBHTweretried(eg,miconazoleoral gel,fluconazole)withoutclinicalbenefit.

Inagreementwiththepatient,andinconsiderationofthe excel-lentradiological response, ICI usewascontinuedinspite of the qualityoflife(QoL)impairmentduetoBHTandxerostomia.Inthe subsequentmonths,theBHTseverityvaried,alternatingperiodsof remissionandexacerbation;thelattermostlyinthefirstdays follow-ing pembrolizumabinfusion. Ofnote, the patient also reported an immune-related thyroiditis, laboratory confirmed with anti– thyroid-stimulatinghormone receptorantibodies,whichoccurred alongwithBHTinMay2020andrequiredspecifictreatment.As ofJanuary2021,thepatient’slungdiseasewasstableandtherapy withpembrolizumabwasongoing,withtheBHTbeingmanaged withbakingsodamouthwashandgentlebrushingwithgauze.

Discussion

BHT,orlinguanigravillosa,isabenignrarecondition character-izedbyhypertrophyandlengtheningofthefiliformpapillae,witha blacktobrownishdiscolorationcommonlyontheposteriordorsal surfaceofthetongue.Intermsofpathogenesis,predisposing condi-tions,suchaspoororalhygieneanddrymouth,canleadtoa defec-tivedesquamationofthefiliformpapillae,collectingdebris,fungi, andbacteria,whichproducechromogenicporphyrins.5,6

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Table1 ReportedCasesofBlackHairyTongueinCancerPatients

PatientAge (y);Sex Related Comorbidities Oncological Disease

OncologicalTreatment WhenBHTOccurred BHTTreatment;Outcome Ref.

61;male Notknown Lungcancer Erlotinib 28daftererlotinibbegan Drugwithdrawal;complete resolution

10

68;female Notknown Breastcarcinoma Doxorubicin,cyclophosphamide, anddocetaxel

Fewweeks(notspeciﬁed) Notreatment;completeresolution 11 57;female Notknown Breastcancer Cyclophosphamide,

5-ﬂuorouracil,anddoxorubicin

60dafterchemotherapybegan Notreatment;completeresolution 12 75;female Diabetesmellitus Anaplastic

oligoastrocytoma

Temozolomide 9dafterchemotherapybegan Oralcareandbrushing;complete resolution

13

63;male Diabetesmellitus Glioblastoma Temozolomide 1dafterchemotherapybegan Oralcareandbrushing;complete resolution

13

79;male Diabetesmellitus LargeBcelllymphoma Rituximab,methotrexate, procarbazine,andvincristine

9dafterchemotherapybegan Oralcare;completeresolution 13 78;male Hypertension,

dyslipidemia, hypertrophic cardiomyopathy

LargeBcelllymphoma Rituximab,methotrexate, procarbazine,andvincristine

102dafterchemotherapybegan Oralcareandbrushing;complete resolution

13

73;female Appendicitis,lacunar cerebralinfarction,

cataract

LargeBcelllymphoma Rituximab,methotrexate, procarbazine,andvincristine

145dafterchemotherapybegan Oralcareandbrushing;complete resolution

13

68;male None Lungcancer Carboplatinandvinorelbine 15dafterchemotherapybegan Sodiumbicarbonatemouthwash; completeresolution. 14 Clinical Lung Cancer 2021

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P lease cite this ar ticle as: C ristina Cecchi et al, Bl ac k Ha iry To n gu e After Immune Checkpoint In h ib ito rs in NSCL C: A Case Re p or t and R evie w of the Literatur e, Clinical Lun g Cancer , https://doi.org/10.1016/j.cllc.2021.03.008

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Black

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BHTisaclinicaldiagnosis combiningdermoscopicevaluation and clinicalhistory.Despitetypicallyasymptomatic,BHTcanbe associated with gagging, nausea, dysgeusia, xerostomia, burning mouthsyndrome,andhalitosis,resultinginasignificantburdenon QoL,asinthepresentcase.5

Treatments include good oral hygiene, discontinuing habits predisposingtoBHT,andgentlebrushingorscrapingofthetongue. Antifungals, suchas fluconazole ornystatin, canalso beuseful.6 When considering the possible causesof BHT inthis case, our patientpresentedseveralacknowledgedriskfactors,suchasolderage (>60years),smoking,type1diabetesmellitus,andmalignancy.5,7

Infact,asshowninTable1,BHThasbeendescribedincancer patients, primarily after chemotherapy and/or other immune-suppressivetreatments.Ithasbeenreportedthatnumerous medica-tionscanalsopredisposetoBHT,includingantibiotics, anticholin-ergic,antipsychotics,andantihypertensiveagents.8_Our_patient_was onantihypertensivetreatment,butthishadbeenundertakenprior tothestartofimmunotherapy,andthepatienthadnoxerostomia or BHT.Basedonthetemporalassociation andexcluding possi-blealternativecauses,weproposethatinthiscaseBHTwaslikely associated with the useof ICIs, resultinginthe development of xerostomia.

In clinical trials, ICI-inducedoral effects have been reported, mainly consisting of grades 1 and 2 xerostomia observed in melanomapatientsreceivingnivolumab(6.5%)orpembrolizumab (3.5%).9_Indeed,_it_has_been_suggested_that_ICIs_may_induce xeros-tomiaduetoanexcessiveT-cellactivation,similarlytothatobserved in autoimmune conditions.9 _In _its _turn, _dry _mouth _can predis-posetothedevelopmentofBHT.5,6_{Unfortunately,}_biopsy_was_not performedinthepresentcase.Thedescriptionoftissue modifica-tionswouldhaveprovidedbetterinsightintotheBHTpathogenesis andpossiblyclarifiedthecausalrelationshipwithICIuse.

Ofnote,alongwithBHT,thepatientalsodeveloped immune-relatedthyroiditis.Smallretrospectiveserieshavesuggestedthatthe developmentofirAEscanpredictsurvivalbenefitincancerpatients receivingICIs.Infact,theimmunesystemactivationunderlyingthe observedirAEsmayalsoberesponsiblefortheanti-tumorresponse.2

Conclusion

AlthoughBHTisabenignconditionandtheoverallprevalence issmall,itmayconsiderablyaffectQoL.Cancerpatientsrepresenta

populationparticularlyatrisk,becauseofthefrequentlyassociated comorbidities,anti-cancertreatments,andthemalignancyitself.To thebestofourknowledge,thisisthefirstreportofBHTafterICI use,suggestingthatBHTmayrepresentanatypicaloralirAE.To date,theoraleffectsinducedbyICIshavenotbeenwellexplored, andfurtherstudiesarenecessarytoelucidatetheunderlying mecha-nisms and possibleassociation with anti-tumor responses,which havesignificantimplicationsregardingprognosisandQoL.Inthe presentcontext,wheretheuseofICIisrapidlyincreasing,ourcase emphasizestheneedtoremainvigilantfornewandatypicalirAEs.

Disclosure

S. Novello has received speaker bureau or advisor fees from Eli Lilly, MSD,Roche, BMS, Takeda, Pfizer, AstraZeneca, and BoehringerIngelheim.Theremainingauthorshavestatedthatthey havenoconflictsofinterest.

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14.SowML,MoukafihB,BaldeS,etal.Vinorelbineandcarboplatin-inducedblack tongue:Acasereport.Therapie.2020.doi:10.1016/j.therap.2019.05.006.

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