Jemds.comCase Report

NEUROFIBROMATOSIS AND NEOPLASMS–TWO INTERESTING CASES

Preethi Dinesh1, Nithun Reddy2, Jyothi Anantharaj3

1Post Graduate, Department of Pathology, Rajarajeswari Medical College and Hospital.

2Post Graduate, Department of Pathology, Rajarajeswari Medical College and Hospital.

3Professor, Department of Pathology, Rajarajeswari Medical College and Hospital.

ABSTRACT

Neurofibromatosisisaninheriteddisorderwithvariedsystemicmanifestationsinthesofttissues,nervoussystemandskin.Cutaneousmanifestationsincludemultipleneurofibromas,café-au-laitmacules,Lischnodulesandintertriginousfreckling.Hematopoieticneoplasmslikelymphomasandleukemiashavebeenreported.Wereportheretwointerestingneoplasmsassociatedwithneurofibromatosis.Thefirstcaseisabenignchondroidsyringomaoftheskin,occurringasacollisiontumorinsynchronywithneurofibroma.Thesecondreportisofacaseofchronicmyeloidleukemiainanadultwithneurofibromatosis.Bothcasesarepresentedherefortheirrarity.

KEYWORDS

Neurofibromatosis,ChondroidSyringoma,ChronicMyeloidLeukemia.

HOW TO CITE THIS ARTICLE:Dinesh P, Reddy N, Anantharaj J.Neurofibromatosis and neoplasms– two interesting cases. J.Evolution Med. Dent. Sci. 2016;5(10):442-445,DOI: 10.14260/jemds/2016/101

J. Evolution Med. Dent. Sci./eISSN- 2278-4802, pISSN- 2278-4748/ Vol. 5/ Issue 10/ Feb.04, 2016 Page 1

Jemds.comCase Report

INTRODUCTION

Neurofibromatosistype1(NF1)isacommonautosomaldominantinheriteddisorderwithaprevalenceof1in2500to3300individuals.AlsoknownasvonRecklinghausendiseasetype1,themostimportantcomponentofthisdisorderisthemultipleneurofibromas.Thesepatientsarealsopredisposedtodevelopavarietyofnon-neoplasticmanifestationsandtumorsincludingvascularlesions,lipoma,gastrointestinalstromaltumor,pheochromocytoma,Wilms’tumorandmelanoma.1,2

CharacteristicskinlesionsinNF1includecafé-au-laitmacules,skin-foldfrecklesandneurofibromas.Chondroidsyringomaisararebenignappendagealtumoroftheskinofeccrineorapocrineorigin.Itisalsocalledamixedtumorofskinbecauseofthepresenceofbothepithelialandmesenchymalcomponents.Ithasanincidenceof0.01–0.098%ofallprimaryskintumors.3,4Synchronousoccurrenceofchondroidsyringomainapatientwithneurofibromatosisisrare.

PatientswithNF1areatincreasedriskforchronicmyelomonocyticleukemia,acutelymphoblasticleukemiaandnon-Hodgkinlymphoma.ChronicmyeloidleukemiaisacommonhematopoieticclonalstemcelldisordercharacterisedbyproliferationofmyeloidcellsandthePhiladelphiachromosome.Childrenwithneurofibromatosisare500timesmorepronetomyeloidneoplasmsthannormalchildren.Occurrenceofchronicmyeloidleukemiainassociationwithneurofibromatosisinanadultisrare.5,6

CASEREPORTS

Case 1

A60-year-oldmalepresentedwithmultiplepainlessswellingsalloverhisbodysincechildhood.

Financial or Other, Competing Interest: None.

Submission 20-12-2015, Peer Review 14-01-2016,

Acceptance 21-01-2016, Published 04-02-2016.

Corresponding Author:

Dr. Jyothi Anantharaj,

255, 11th B Cross, 20th Main,

JP Nagar 2nd Phase, Bangalore-560078.

E-mail:

DOI:10.14260/jemds/2016/101

Onesuchswellingoverhisforeheadontherightsideshowedrapidgrowthover4to5monthsandwasassociatedwithpain.Theforeheadlesionwasexcisedandsentforhistopathologyexamination.

Gross

Theexcisedspecimenwasaskincoveredglobularsofttissuemassmeasuring3.3x2.2x2.0cms.Cutsectionshowedgrey-whiteandmyxoidareas.[Figure1].

Fig. 1: Collision tumor-neurofibroma with chondroid syringoma: gross specimen of a skin covered soft tissue mass (Left) with grey white and myxoid areas on cut surface (Right)

Microscopy

Twosynchronousbenignneoplasmswerenotedinthedermis[Figure2].Onewasaneurofibroma,composedofproliferatingspindlecellswithinterspersedfibroblasts,capillariesandsparsemononuclearcellinfiltrate[Figure3].Adjacenttothiswasawellcircumscribedmixedtumorofskinwithfeaturesofchondroidsyringoma.Thetumorcomprisedoftubulesofvaryingsizesandshapes,somecysticallydilatedandwerelinedbybenignbilayeredepithelium[Figure4].Theluminaoftubulesshowedeosinophilicmaterial.Cholesterolcleftswerenotedinthesesecretions.Theductswereseendispersedinamucoidandchondroidmatrix[Figure5].Adiagnosisofcollisiontumorofneurofibromawithchondroidsyringomawasmade.

Fig. 2: Neurofibroma with chondroid syringoma-photomicrograph shows collision of two synchronous benign neoplasms (4x, H&E)

Fig. 3: Neurofibroma-photomicrograph shows proliferation of spindle cells with wavy nuclei, interspersed with fibroblasts, capillaries and sparse mononuclear cell infiltrate in a collagenous and myxoid stroma (10x, H&E)

Fig. 4: Chondroid syringoma-photomicrograph shows a tumor comprising tubules lined by benign bilayered epithelium with intervening chondromyxoid matrix (20x, H&E)

Fig. 5: Chondroid syringoma-Photomicrograph shows ducts dispersed in chondroid matrix. Also seen is a cyst filled with secretions and cholesterol clefts (4x, H&E)

Case 2

Aforty-year-oldmalepresentedwithhistoryofmultiple(4)softtissueswellingsofsixmonthstooneyearduration.Thelargeroneonthebackmeasured3x2cmsandthesmalleronesontheleftforearmmeasured1cmindiametereach.Theswellingswerefirm,mobileandnon-tender.Aclinicaldiagnosisofneurofibromatosiswasmadeandconfirmedwithfineneedleaspirationcytology[Figure6].Patient’speripheralbloodwasexaminedasaroutineworkup.Hishemogramwasasfollows:Hb-9.7gm%,totalleucocytecount-morethan4.0lakhs/cummwithimmaturegranulocytesandplatelets-1.9lakhs/cumm.PeripheralsmearshowedmacrocyticRBCs,shifttoleftinthemyeloidserieswith02%myeloblasts,03%promyelocytes,25%myelocytes,10%metamyelocytes,46%bands/stabs/neutrophils,06%eosinophilsand08%basophils[Figure7].Adiagnosisofchronicmyeloidleukemiainchronicphasewasmade.

Fig. 6: Neurofibroma-aspirate smear shows a tissue fragment with spindle cells trapped in collagenous stroma (20x, H&E). Inset shows comma-shaped nuclei in some cells (40x, H&E)

Fig. 7: Chronic myeloid leukemia-peripheral blood smear shows increased granulocytes with numerous myeloid precursors and neutrophils. A basophil and a normoblast are also seen in the field (100x, Leishman).

DISCUSSION

NeurofibromatosisisclassifiedasNeurofibromatosistype1(NF1)andtype2(NF2)basedonthegenesinvolved.NF1isalsoknownasvonRecklinghausen’sdiseaseandisthemostcommonform.7,8Itisacommonautosomaldominantneurocutaneousdisorderwithapredispositiontodevelopbenignandmalignanttumors.PatientswithNF1areattwotofivetimesincreasedriskfordevelopingneoplasmscomparedtonormalpopulation.TheseincludeCNS,hematopoieticandskinneoplasms.7,9

ThediseaseiscausedbylossoffunctionmutationsinNF1gene,atumorsuppressoronchromosome17q11.2,thatencodesneurofibromin.Neurofibrominisaguanosinetriphosphatase-activatingproteinandanegativeregulatorofRASproto-oncogene.ThisproteincontainsafunctionalGAPdomainthatactsonRAS-GTP,therebyplayingaroleinregulatingRASfunction.LossofneurofibrominleadstoexcessRASactivityanduncontrolledcellproliferationandtumorigenesis.1RASactivationinducescellproliferationinresponsetoextracellularstimuli.IncreasedlevelsofRAS-GTParefoundinNF1-associatedleukemiasandsuchleukemiccellsshowhypersensitivitytoGM-CSFandother cytokines.10,11

Dermatologicmanifestationsofneurofibromatosisarecharacterizedbycafé-au-laitmacules,Lischnodules,intertriginousfrecklingandmalignantneoplasmsincludingmalignantmelanoma,basalcellcarcinomaandMerkelcellcarcinoma.7,8Chondroidsyringomaisabenignmixedtumoroftheskinwithepithelialandmesenchymalcomponents.Itpresentsassubcutaneousmass,typicallylocatedintheheadandneckregion.2Acollisiontumorisdescribedasassociationoftwodifferentneoplasmsinthesamepatient.12Neurofibromatosiscolludingwithchondroidsyringomaisarareoccurrence.

Hematopoieticmalignanciesknowntobeassociatedwithneurofibromatosisincludelymphomas,chroniclymphoidleukemias,juvenilechronicmyelomonocyticleukemiaandmyelodysplasticsyndrome.10Childrenwithneurofibromatosishave500timesgreaterriskofdevelopingamalignantmyeloiddisorderthanthenormalchildren.However,thisassociationhasrarelybeendemonstratedinadults.13Veryfewcasesofchronicmyeloidleukemiahavebeenreportedtoco-existwithneurofibromatosis.10

Chronicmyeloidleukemiaisapluripotentialstemcelldisordercharacterisedbyanemia,markedlyelevatedleucocytecountwithshifttoleftinthemyeloidseries,basophilia,oftenthrombocytosisandsplenomegaly.Thehematopoieticcellscontainareciprocaltranslocationbetweenchromosomes9and22inmorethan95%ofpatients,referredtoasthePhiladelphia(Ph)chromosome[t(9;22)(q34;q11),abbreviatedast(Ph)].ThefusionproductexpressedbytheBCR-ABLgeneleadstomalignanttransformationbecauseoftheabnormallyregulatedenzymaticactivityofthechimerictyrosineproteinkinase.14

Olayemietal.5intheirreportonanadultwithneurofibromatosistype1whodevelopedchronicmyeloidleukemiasuggestapossiblesynergisticactionbetweentheabsenceofneurofibrominandthepresenceoftyrosinekinaseactivityofBCR/ABLgene.

CONCLUSION

Neurofibromatosisisageneticallydistinctandcommondisorderwithaknownassociationwithneoplasmsandnon-neoplasticpathology.However,itsassociationwithchondroidsyringomaandchronicmyeloidleukemiaisrare.Thiscoexistencecouldbeincidentalorresultingfromageneticdefectassociatedwithneurofibromatosis.Cliniciansmanagingpatientswithneurofibromatosisshouldbeawareoftheseassociations.

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J. Evolution Med. Dent. Sci./eISSN- 2278-4802, pISSN- 2278-4748/ Vol. 5/ Issue 10/ Feb.04, 2016 Page 1

Jemds.comCase Report

J. Evolution Med. Dent. Sci./eISSN- 2278-4802, pISSN- 2278-4748/ Vol. 5/ Issue 10/ Feb.04, 2016 Page 1

Jemds.comCase Report

J. Evolution Med. Dent. Sci./eISSN- 2278-4802, pISSN- 2278-4748/ Vol. 5/ Issue 10/ Feb.04, 2016 Page 1