Benign follicular tumors - Birt-Hogg-Dubé Syndrome · PDF fileBenign follicular tumors* ... centric cell layers are identifiable ... 6 The wall recapitulates the infundibular epithelium

Continuing mediCAl eduCAtion

Benign follicular tumors*

Oscar Tellechea1 JoséCarlosCardoso1

JoséPedroReis1 Leonor Ramos1

AnaRitaGameiro1 Inês Coutinho1

AntónioPoiaresBaptista1

DOI: http://dx.doi.org/10.1590/abd1806-4841.20154114

Abstract: Benign follicular tumors comprise a large and heterogeneous group of neoplasms that share a common histogenesisanddisplaymorphologicalfeaturesresemblingoneorseveralportionsofthenormalhairfollicle,orrecapitulate part of its embryological development. Most cases present it as clinically nondescript single lesions and essentially ofdermatological relevance.Occasionally, however, these lesionsbemultiple and represent acutaneousmarkerofcomplexsyndromesassociatedwithanincreasedriskofvisceralneoplasms.Inthisarticle,the authors present the microscopic structure of the normal hair follicle as a basis to understand the type and level of differentiation of the various follicular tumors. The main clinicopathological features and differential di-agnosisofbenignfolliculartumorsarethendiscussed,includingdilatedporeofWiner,pilarsheathacanthoma,trichoadenoma, trichilemmoma, infundibuloma,proliferating trichilemmalcyst/tumor, trichoblastomaand itsvariants,pilomatricoma, trichodiscoma/fibrofolliculoma,neurofollicularhamartomaand trichofolliculoma. Inaddition,themainsyndromespresentingwithmultiplefolliculartumorsarealsodiscussed,namelyCowden,Birt-Hogg-Dubé,RomboandBazex-Dupré-Christolsyndromes,aswellasmultipletumorsof follicular infun-dibulum(infundibulomatosis)andmultipletrichoepitheliomas.Althoughthediagnosisoffolliculartumorsreliesonhistologicalexamination,wehighlighttheimportanceoftheirknowledgefortheclinician,especiallywheninpresenceofpatientswithmultiplelesionsthatmaybethecutaneousmarkerofacancer-pronesyndrome.Thedermatologist is therefore inaprivilegedposition torecognize these lesions,which isextremely important toprovidefurtherpropedeutic,appropriatereferralandgeneticcounselingforthesepatients.Keywords: Birt-Hogg-Dubesyndrome;Hairfollicle;Hamartomasyndrome,multiple;Neoplasms,adnexalandskinappendage

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INTRODUCTIONBenignhairfollicletumors(BHFT)encompassa

largenumberofrelativelyrareneoplasmsdefinedbythe type and degree of hair follicle differentiation as seen on their histologic examination.

Theygenerallyoccuron theheadandneckofadults as a nondescript slow-growing solitary papule ornodule, andaremostlyof exclusivedermatologicrelevance. However they can possess peculiar clinical featuresenablingthediagnosisand,mostimportantly,theymaybethefirstclinicalmanifestationofcomplexvisceral cancer-prone syndromes. In addition, some

Received on 15.10.2014.ApprovedbytheAdvisoryBoardandacceptedforpublicationon23.03.2015.* StudyperformedatCentroHospitalarUniversitáriodeCoimbra–Coimbra,Portugal. Financial Support: None ConflictsofInterest:None

1 CentroHospitalarUniversitáriodeCoimbra–Coimbra,Portugal.

©2015byAnaisBrasileirosdeDermatologia

canmimicprimarymalignantskinneoplasmsorpos-sess a malignant counterpart from which they should be distinguished. Occasionally they can be misdiagno-sed as benign or malignant sweat gland tumors.

Diagnostic criteria for BHFT are well establi-shedand,fromapracticalpointofview,themainis-sue about these neoplasms concerns their differential diagnosis, i.e. the distinction among different BHFTdepicting some type of hair follicle differentiation and the distinction between certain types of BHFT and ba-sal cell carcinoma.1,2

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Their pathogenesis remains largely unknown.Lossofheterozygosityofmutated tumorsuppressorgenes has been implicated in the genesis of some spo-radic cases of BHFT in an analogous manner to their respective hereditary counterparts. 3Additionally, insome cases a relationship with viral infection has been suggested.4

Astheprecisediagnosisofthesetumors,requi-redbythereasonsexplainedabove,dependsonthesi-milarity of their histologic phenotype to the microsco-picfeaturesofthenormalhairfollicle,ashortreviewof the latter is provided emphasizing thedistinctivecharacteristics of the different anatomical regions of the adnexal.

MICROSCOPIC ASPECTS OF HAIR FOLLI-CLE DIFFERENTIATION

The mature anagen hair follicle can be divided indifferentsegments:infundibulum,isthmus,“stem”andbulb,distinguishable fromeachotherbytheor-ganizationandmorphologyofthecellsthatcomposethem,aswellas their relativedisposition (Figure1).Beyond these regions that correspond to a vertical sec-tionofthehairfollicle,twosheaths,resultingfromahorizontalsectionofthehairfollicle,canbealsodefi-ned:i)anouterhairsheath(ORS)extendingfromthebaseofthebulbtothebaseoftheinfundibulum,whi-ch lays on a basement membrane that in some areas isthickenedandhyaline(vitreousmembrane);andii)aninnerrootsheath(IRS)thatiscontinuousalongthebulbandthestem,disappearingattheisthmus.ORSiscomposed of pale cells that are similar along the entire ORS. In contrast, IRS ismore complex as three con-centriccelllayersareidentifiable:Henlelayer,Huxleylayerandcuticle.Themoreperipheral,Henlelayerisa single row column that encloses the double row Hu-xley layer. These layers extend vertically from the bulb to the stemand are composedof cells characterizedby the presence of conspicuous eosinophilic trichoh-yalin granules (the hair equivalent to keratohyalin).Thesecellsundergocornificationnearthelevelwhe-rethesteminitiates,resultingincompactcorneocytescharacterizedbytheirgray-bluehue.Cornificationisseenearlier(beforethebeginningofthestem)inHenlelayer than in Huxley layer. Cuticle is the most central layerofIRSandconsistsofaxiallyorientedflatminutepale cells.

Signs of infundibular differentiationThe infundibular epithelium is indistinguisha-

ble from that of the adjacent epidermis (Figure 1A),consisting in:

(i)abasallayer;(ii)aspinouslayerwithconspicuousintercellu-

lar bridges;

(iii)agranular layerofgranularcellswithkera-tohyalin granules identical to those of the epidermis; and

(iv)abasket-weavestratumcorneum.Itshouldbe noted that the infundibulum is not a constituent of theouterrootsheath(ORS).

Signs of Outer Root Sheath differentiation (is-thmus; stem)

TheORS(trichilemma)consistsofrowsofkera-tinocyteswithpale,abundantPAS-positivecytoplasm,which cornify horizontally and abruptly without agranularcelllayer,originatingthecompacteosinophi-lic stratumcorneum(Figures1Band1C).The thick-ness and hue of ORS changes along its length: thin and clear at the bulb, thicker andmore eosinophilic(pink)at thestem,andagainthinnerat the isthmus.AlthoughORScellsareboundbydesmosomes,inter-cellular bridges are seldom conspicuous.

Signs of ORS differentiation include:(i)pale/clear,PAS-positivecellswithnoconspi-

cuous intercellular bridges;(ii)absenceofgranularlayer;and(iii)acompacteosinophilicstratumcorneum.

Some phenotypic differences between the upper (isthmus) and lower (stem) segments ofORSexist(morestrikingnuclearpalisadingandpinkercy-toplasm with higher content of glycogen of ORS cells inthestem).

Signs of Inner Root Sheath differentiation:(i) Cells with conspicuous bright eosinophilic

trichohyalin(atthebulb);(ii)Compactblue-graycorneocytes(stem).

Signs of differentiation to the bulb and papilla(i)Invertedcupdispositionofmatricalcellsin-

volved by(ii)thelower(bulbar)segmentofIRS,i.e.twoto

three columnar rows of cells with conspicuous bright eosinophilictricohyalin,thatis,inturn,surroundedby

(iii)themostinferiorportionofORS(athinla-yerofpalePASpositivecells).

Signsofhairmatrixdifferentiation(Figure1D)(i)Smallcellswithascantbasophiliccytoplasm

and voluminous round nuclei with prominent nucleo-lus,occurringincrowdedaggregates;

(ii)Mitoticfigures;(iii)Necrosisofisolatedcells(karyorrhexisand

picnosis);(iv)Dendriticmelanocytes(occasionally).

Benign follicular tumors 781

782 Tellechea O, Cardoso JC, Reis JP, Ramos L, Gameiro AR, Coutinho I, Poiares-Baptista A

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Signs of hair shaft differentiation(i) Ghost cells (anucleated polygonal eosino-

philic cells centered by an empty space replacing the nucleus);

(ii)Refractileyellow-orangecornifiedcells;(iii)Truehairshaft(rarelyobservable).

Signs of differentiation towards the perifolli-cular sheath

(i) Loosely arranged, thin collagen fibers in amucinous matrix;

(ii)Scatteredfibroblastswithroundorovalnu-cleus;

(iii)Numerouscapillarybloodvessels.

Signs of differentiation towards the follicular germ

Crescent-shaped, oval or round aggregates ofcellswithovalnucleus,andscant,intenselybasophiliccytoplasm(basaloidcells)withperipheralpalisading,recapitulating the follicular hair germ.

CLASSIFICATIONTheclassificationofthebenignfollicularprolife-

rations is histogenic and based on the set of microsco-pic similarities between lesions and normal hair follicle structures to which they can be contiguous and that are recapitulatedatdifferentdegreesinthetumor(Chart1).

Figure 1: Different segments of the hair follicle. A. Infundibulum. Keratinization simi-lar to theepidermis,including a granu-lar layer and bas-ket-weave orthoker-atosis. B. Isthmus. Trichi-lemmal keratiniza-tion, characterizedby absence of granu-lar layer and abrupt compact orthokera-tosis. C. Stem. Pale outer root sheath cells surrounded by a hyaline membrane. D. Bulb. Closely packed basophil-ic keratocytes andinterspersed pig-mented melanocytes characteristic of the hair matrix

Chart 1: Classificationofbenignfolliculartumors

Infundibular and/or isthmic differentiationDilatedpore(Winer)Pilar sheath acanthomaTrichoadenomaTrichilemmomaDesmoplastic trichilemmomaInfundibuloma(tumoroffollicularinfundibulum)Pilartumor(proliferatingtrichilemmalcyst)

Germinative cell differentiationTrichoblastomaAdamantinoidtrichoblastomaTrichoepitheliomaTrichogerminomaPanfolliculoma

Matrical differentiationPilomatricoma

Mesenchimatous follicular differentiationTrichodiscoma/FibrofolliculomaNeurofollicular hamartomaPerifollicularfibromaTrichofolliculomaFolliculosebaceous cystic hamartoma

A

C

B D


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Dilated pore (Winer)It occurs as a small solitary papule centered by

afollicularporeontheface,neckorback,mimickingagiantcomedo.Itcanbemultipleand,exceptionally,it is agminated with a linear distribution (dilated pore nevus).5

Histologically it is a small vertically oriented in-fundibulocysticlesion,filledwithlamellarortokerato-sis. 6 The wall recapitulates the infundibular epithelium and contains regularly spaced elongated rete ridges,slightly thicker than those of the adjacent epidermis.Theseinfundibularradiarycrestsdonotcontainkera-tinousmicrocystsorsebaceousducts,asisthecaseofpilarsheathacanthoma(seebelow).Inserialsectionsasubjacentinfundibularcystmaybeoccasionallyfound.

Although it has been suggested that dilatedpore of Winer merely corresponds to an infundibu-larcystopeningtotheskinsurfacewithreactivewallhyperplasiasurroundedbyfibroticadventitialdermis,the identity of the lesion within the follicular tumours hasbeenreaffirmed.7

Differential diagnosisPilar sheath acanthoma: See below.Comedo: Itisanoperculizeddilatedinfundibular

cavityfilledwith lamelarortokeratosisandlimitedbyinfundibular epithelium with no elongated rete ridges.

Pilar sheath acanthomaIt is a rarely reported diagnosis presenting clini-

callyasasolitarypapulecenteredbyakeratoticplugon the upper lip or central area of the face.

Microscopically,itisawell-circumscribed,ver-tically oriented epithelial cystic proliferation of the dermis,openingontheskinsurfaceandfilledbyla-mellarkeratin.8 Peripheral lobules of infundibular or isthmic(pale,PAS+)cellsirradiatefromtheacanthoticandhyperplastic cystwall (Figure 2).Within the ra-diatelobules,wherethecellsofthemostperipheralla-yercommonlydisplaynuclearpalisading,smallhorn

cystsand,lessfrequently,sebaceousducts,sebocytesortinysquamouseddiesmaybeseen.

Thus, the lesion isconsideredtobemadeofamoresuperficialinfundibulocysticportionandadee-per lobulated and radiary region with isthmic diffe-rentiation.1

Differential diagnosisDilated pore (Winer): The peripheral radial ridges

ofdilatedporeare regular,evenlyspacedandmadeofinfundibularratherthanisthmickeratinocytesanddonotcontainkeratinouscysts.Distinctioncanbelessstraightforwardinobliquesections.

Trichofoliculoma:Aspilarsheathacanthoma,tri-chofolliculoma has a vertically oriented well-circums-cribedinfundibulocysticsilhouette.However,smallerinfundibula rather than pale cell lobules irradiate from themainwall,resultinginminutedystrophicormorematurevellushairs,featuresthatcontrastwiththelessfloridpatternofpilarsheathacanthoma.

Due to the occasional extension to deep der-mis/hypodermis and to the radiate projections, thetreatment of choice is surgical excision with a 2 mm margin from the ostium.

Trichoadenoma (Nikolowski)It is a rare lesion occurring in adults with no

genderpredilection,presentingasa3-15mmnondes-criptpapule/noduleontheface,neckortrunk.

Histologically it corresponds to a well-circums-cribed,horizontallyoriented,dermalnodule,withnocontinuity with the overlying epidermis. The tumor is composedofnumerous,relativelylarge,roundoroval,infundibulocysticstructures,separatedbyapoorlyde-veloped fibrous stroma (proportion epithelium/stro-ma: “10:1”).The epithelial cysts areoccasionally con-tiguous,andsolidcordsprojectingfromthethincysticwall,whichmayappear“isolated”inthestroma,canoccur.Calcificationsaretypicallyabsent.9,10

Figure 2: Pilar sheath ac-anthoma.A. Thisis a particularly large and solid example; note the multilobular architecture. B. Predominant ly isthmic differenti-ation with abrupt compact keratini-zationA B


Differential diagnosis:Trichoepithelioma: Astrichoadenoma,it isaho-

rizontalintradermalwell-definedtumorcomposedofkeratinousinfundibulocystsdepictinggranularlayer.However,nestsofgerminativecellsinnodular,trabe-cular and cribriform arrays coexist in different propor-tions.Also,contrastingwithtrichoadenoma,folliculargerm, papillar or bulb differentiation and retractionclefts within the stroma are characteristically seen in trichoepithelioma.

Desmoplastic trichoepithelioma: It displays a ge-neral picture similar to trichoadenoma but possesses a characteristic central depression and a much more developedanddenserstroma.Inaddition,mostcellshave features of germ cells rather than infundibular differentiation,andcalcificationisoftenseen,afeaturecharacteristically absent in trichoadenoma.

Trichilemmal cyst nevus:Althoughatlowmagni-ficationtrichilemmal nevus mayevokethediagnosisoftrichoadenoma,theformerconsistsofisthmicstructu-res,withnogranularlayer(“agminatedtrichilemmalcysts”),contrastingwiththeinfundibulardifferentia-tion phenotype of trichoadenoma.11

Microcystic adnexal carcinoma: Can be distingui-shed from trichoadenoma by its irregular, asymme-trical silhouette, deep extension, abundant scirrhousstroma and characteristic perineural invasion.

TricholemmomaTwo types of clinical presentation of trichile-

mommaarerecognized.The more common type occurs as a solitary pa-

puleonthefaceofadults,generallymisdiagnosedasaverrucouspapilloma,aviralwartorabasalcellcarci-noma. Rarely does it correspond to a cutaneous horn.12

Inexceptionalcases thepatientpresents, typi-cally after the second decade of life, with multiplepapulesoftheface(nasolabialfolds,upperlip,front,ears).Inthisvariant,cutaneouslesions(trichilemom-mas) coexist with small papules on the oral cavity(gums, tongue),which tend tocoalesce inacobbles-tonepatterncorrespondingtofibromas.This“florid”clinical picture constitutes the classic mucocutaneous presentation of Cowden’s syndrome, which showsmultiple extracutaneous neoplasms (breast, kidney,intestine)anddependsongermlinemutationsofthetumour suppressor gene PTEN. It is generally admit-ted that the presence of 3 or more histologically pro-ven trichilemommas constitutes a major criteria fordiagnosis of Cowden’s syndrome. 13However,morerecently, in thenewproposeddiagnosticcriteria, thepresenceof at least 3 trichilemmomas,oneofwhich

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mustbebiopsy-proven,isconsideredenoughtofulfilonemajorcriterion.14

It is likely that other entities characterized bysimilargermlinePTENmutationsincluding:(i)Lher-mitte-Duclos disease (hamartomatous cerebellar dys-plasticgangliocytoma);(ii)BannayanRileyRuvacalbasyndrome (pediatric hamartomatous syndrome dis-playing multiple subcutaneous lipomas, hemangio-mas,intestinalpolypsandmacrocefaly);and(iii)seg-mentarformsofaProteus-likesyndrome,constitute,withtheCowden’ssyndrome,polesofasymptomaticspectrum depending of germline PTEN mutations and generically designated as PTEN Hamartoma Tumor Syndrome(PHTS).15,16

Microscopically the aspect is identical in solitary and Cowden’s associated variants: a folliculocentric lobularproliferationofpolygonal,clear,PAS-positiveisthmic cells with nuclear palisading of the peripheral cellsthatcharacteristicallylayonathickenedhyalineeosinophilicbasementmembrane(Figures3Aand3B).Squamous eddies are frequently seen, occasionallycentered by foci of infundibular keratinization. Pig-mentation,necrosisorcalcificationmayoccur.Rarelythe overlying epidermis is hyperplastic.

Some cases of solitary trichilemmoma (as well asdesmoplastictrichilemomma,seebelow)couldre-presentareorganizedviralpapilloma,astestifiedbythe occasional presence in these cases of signs of cy-topathogenicHPVeffect.Howeverthisinterpretation,aswellasthemolecularfindingofHPVintrichilem-momas,remainscontroversial.17,18

In Cowden’s syndrome, beyond trichilemmo-mas,follicularinvertedkeratosis,infundibularhyper-plasia, or tumor of the follicular infundibulum (seebelow)havebeenreported.Inaddition,acrokeratosisverruciformis-likelesionscanoccur.OralfibromasofCowden’s syndrome are indistinguishable microsco-picallyfromthecommonoralfibroma.

Differential diagnosisInfundibuloma:Astrichilemmoma,itismadeof

infundibularcells,largerandpalerthantheperiphe-ral basaloid cells, displaying nuclear palisading andlayingatthedermalborderofthelesion.However,incontrast to trichilemmoma, infundibulomahas a su-bepidermal plaque-like general arrangement andnoperipheralhyalinemembrane,butinstead,acharacte-ristic reinforcement of the elastic tissue.

Epidermal panfolliculoma: This acanthotic in-traepidermal follicularproliferation, although contai-ningareasoftrichilemmaldifferentiation,recapitulatesbothupperandlowerhairfolliclesegmentsexhibiting,inaddition,germinative,matrix,bulb,papilla,andin-ner root sheath microscopic phenotypical features.


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Other intraepidermal clear cell neoplasms. Clear cell acanthoma: lower limb localization, well circumscri-bedacanthotic lesionofpaleandlargekeratinocytescovered with a psoriasiform scale, distinct demar-cation from intraepidermal adnexal epithelium and surroundingkeratinocytes.Clear cell poroma: absence of both peripheral palisading and hyaline peripheral membrane, sharp contrast with neighboring epider-mis,dermalextension,ductaldifferentiation.Clear cell squamous cell carcinoma in situ:nuclearatypia,absenceof basement membrane.19

Desmoplastic trichilemmoma (DT)DT constitutes a type of solitary tricholemmo-

macharacterizedbyapseudoinvasivesilhouetteim-parted by the disposition of the stroma that dissects the epithelial tumor lobules (Figure 3C). Peripheralpalisading of nuclei may be absent.20,21

Differential diagnosisBasal cell carcinoma: In DT no clefts between the

epitheliumandstroma,norcellularatypiaorapopto-sis, are found. In superficial biopsies the distinctionmay be less obvious and in these cases the differential expressionofBerEP4(present inCBC,absent inDT)andCD34(absentinCBC,presentinDT–Figure3D)may be helpful.

Tumor of follicular infundibulum (infundi-buloma)

Two clinical variants occur.22,23 More commonly thelesionisasolitarykeratoticpapuleoftheface,neckoruppertrunkinelderlypatients,judgedasasebor-rheickeratosisorbasalcellcarcinoma.Exceptionally,multiple (<20 to >100) lenticular, hypopigmented orskin-colored,maculopapularorslightlyatrophicele-mentsareseenontheface,neckanduppertrunkofyoungadults, simulatingplanewarts,pityriasisver-sicolor, guttate hypomelanosis or vitiligo (Figure4A).24Atrophiclesionsmaybeconfusedasacnescarsanderythematousonesmayresembleactinicporoke-ratosis.Althoughthe lesionsarebenign, thepossibi-lity of “transformation” into basal cell carcinoma as well as its occurrence within the spectrum of the cuta-neous lesions of Cowden syndrome have been descri-bed,makingfollow-upofthesepatientsadvisable.25,26It can also arise within nevus sebaceous.

Histologically,thetumorconsistsofawellcir-cumscribed,subepidermal,horizontal,plate-likepro-liferationofpale-staining,PAS-positivekeratinocytes(Figures4Band4C).Cellsaremonomorphouswithnoatypia; peripheral palisading of nuclei is a common feature.Theperipheralcellsmaylieonathickenedba-sementmembrane,andsmallkeratinouspseudocystsmayoccur.Auniquefeature,peculiartothetumorof

Figure 3: Trichilemmoma. A. Typical lobular ar-chitecture in close re-lation with the neigh-boring hair follicles. B. Detail of the pale cells with a hint of peripheral palisading and surrounding hya-line membrane. C. Detail of a desmo-plastictrichilemmoma,with sclerotic stroma andapparentlyinfiltra-tive architecture. D. CD34 immunohis-tochemistry, demon-strating positivity in the tumor cells

A

C

B

D


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follicularinfundibulum,isthepresenceofanetworkofelasticfiberssurroundingthelowermarginofthetumor(Figure4D).

Immunohistochemically the lesion stains for MNF-116andCK5/6,andisnegativeforBer-EP4,Bcl-2,CK7andCK20.

Differential diagnosis:Superficial basal cell carcinoma: Pale cells are sel-

domprominent;thepatternis“multicentric”innests,ratherthaninplaque;cleftsareobviousbetweentheepithelium and the underlying stroma; tumor cells are frequentlyatypical,andshowBerEP4andBcl2immu-noreactivity, features that sharply contrast with thefindingsininfundibuloma.24,27

Trichilemmoma: Infundibuloma lacks the lo-bular folliculocentricpattern,andperipheralhyalinebasementmembranetypicaloftrichilemomma,depic-tingasubepidermalanastomosingplaque-likepatternandreinforcementoftheperipheralelastictissue,fea-tures not found in trichilemmoma.

Epidermal panfolliculoma:infundibularplatelikeareasmadeofpalecellsmayoccur,butonly focally,the lesion being characterized by a recapitulation ofthe entire spectrum of hair follicle.

It should be noted that cases described as “Mul-tiple infundibular tumors of the head and neck” bear no resemblance with infundibulomatosis and exhibit his-tologicalfeaturesakintothoseofprurigonodularis.28

The putative relationship between infundibu-loma and basal cell carcinoma (BCC) aswell as theeventuality of “transformation” of infundibuloma into BCC,althoughcontroversial,mayjustifytheremovalof solitary lesions. 29 Ininfundibulomatosis,cryothera-py,CO2laser,topicalretinoids,orkeratolyticsmaybeattempted.

Pilar tumor (proliferating trichilemmal cyst)Typicallypilartumor(PT)isalarge(2-25cm),

exophyticnodule/tumorwithasmooth,oftenulcera-tedsurface,present foryearson the scalpofelderlywomen,andclinicallyinterpretedasasquamouscellcarcinoma. 30 It may occur de novo or arise on a pre--existingtrichilemmalcyst,anditmayhaveanextra--cephaliclocalization.Recurrenceisrareandmetasta-ses occur exceptionally. 31

The diagnosis requires the identification, atleast focally,ofa trichilemmal cystand thepresenceofsignificantcytologicalatypia.Itresidesontheder-mis and/or hypodermis and may be contiguous with the hair follicle. It corresponds to a well-circumscri-bed,large,roundedsolid/cystictumorwithasmooth

Figure 4: Multiple tumors of follicular infundib-ulum (infundibulo-matosis).A. Multiple hy-popigmented mac-ular or slightly papular lesions in the submandibular region. B. Plate-like pro-liferation of mono-morphous pale k e r a t i n o c y t e s ,well-demarcated from the adjacentepidermis. C.PASstainispos-itive in the cells. D. Condensation of elastic fibersaround the base of the proliferation (arrow)

A B

DC


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border surrounded by a dense pseudocapsule that is separated by clefts from the adjacent tissue. Irregu-lar anastomosing strands of keratinocytes irradiatecentripetally from the tumor wall. These strands are successivelycomposedof:i)basallayer;ii)cellswithabundant eosinophilic cytoplasm similar to the outer root sheath at the isthmus; and iii) a horny layer indirectcontactwiththeisthmiccells,withoutinterpo-sition of a granular layer (Figure 5). These cornifiedfocioccurfrequentlyasscatteredislandssurroundedbytheisthmiccells.Mitoticfiguresaswellasdyske-ratotickeratinocytesmaybeobservedandcytologicalatypiaischaracteristicallyprominent.Calcificationiscommon. The epithelial strands may lie on a periphe-ralhyalinethickenedbasementmembrane.

Differential diagnosis:The intensity of cytologic atypia and the presen-

ceofmitoticfiguresanddysketatosisinanepithelialtumor of eosinophilic cells that is only partially cystic mayarisethesuspicionofsquamouscellcarcinoma.However,theasymmetric,irregularandinvasivebor-der,focalcontiguity/replacementoftheepidermisofthelattercontrastwiththelowandhighermagnifica-tion features of PT that additionally exhibits “trichi-lemmal”ratherthanepidermalcornification.

Despite the intensity of the atypical cytological features,PTbehavesmostoften inabenign fashion.The rarities of regional lymph node metastases as well as the local symptoms warrant a complete surgical ex-cision.

TrichoblastomaIt is a benign neoplasm made of germinative hair

follicle cells with a differentiation generally restricted

towards the hair germ and papilla. It is relatively in-frequentexceptinthesettingoforganoidnevus.Cli-nically it presents as a dermal or dermo-hypodermal noduleoftheheadorneck.Whenitoccurswithinanorganoid nevus it may be clinically felt to be a BCC.

Several forms of trichoblastoma have been re-ported including giant, subcutaneous, pigmentedand clear cell variants. “Cutaneous lymphadenoma” is generally considered an adamantinoid variant of trichoblastoma (see below). Also, trichoepitheliomais thought to correspond to a trichoblastoma with ad-vanceddifferentiation(seebelow).

Typically it corresponds to a dermal and/or hypodermal,well circumscribed, symmetrical tumorwithnocontiguitywiththesurfaceepithelium,com-posedofirregularnestsofsmallbasophilcells,resem-bling a BCC. Within the tumor the cellular aggregates exhibit different patterns: nodular, adenoid, cystic,andtrabecular.Thelattercanbecribriform,racemous,reticulated or “schwannoid” (“rippled”).1

Two cell types constitute the cell aggregates of trichoblastoma: i) basaloid cells,with inconspicuouscytoplasm and appearing to contain solely a basophil nucleus(similartofolliculargerminativecells);ii)cellswithlarger,pinkcytoplasmalikehairstemcells.

In most instances there is a strong predominan-ce of the germinative (basaloid) cells. However therelative proportion of the 2 cell types is somewhat re-lated to the architectural pattern of the cell aggregates (e.g.: essentially germinative cells in the nodular pat-tern;equivalenceofgerminativeandstemcellsinthereticulatedpattern).Hairpapillaandhairgermforma-tion(“limitedhairfollicledifferentiation”)istypicallyfound in trichoblastoma.

Surrounding the epithelial aggregates a conspi-cuous,cellularordensestromaisfound,whichcharac-teristically contains clefts present between the stroma andthesurroundingdermis,butusuallynotbetweenthestromaandtheepithelialaggregates(Figure6).

Melanininthecellnestsisnotrare,namelyintrichoblastomas associated with organoid nevi. Despi-tesomecellularpleomorphism,nocytologicatypiaormitosesarefound.Similarly,pronouncedtumoralne-crosisisabsent,butindividualapoptoticbodieswithoccasionalconfluencemaybeobserved.

Frequently,continuitywiththefollicularinfun-dibulumisseen,andinfundibulocysticdifferentiationmay occur within the nests of eosinophilic cells. When thelatterisprominentandthelesionissuperficial,thehistologic picture is indistinguishable from that of tri-choepithelioma(seebelow).

Differential diagnosis:Themostcommondifficultyinthedifferential

diagnosis is to distinguish trichoblastoma from BCC.

Figure 5: Proliferating trichilemmal cyst/tumor. Partially cystic and solidlesionwithkeratinocytesincreasinginsizefromthebasallay-ertothelumen,displayingabruptkeratinizationwithoutgranularlayer


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Inmostinstancestheasymmetricsilhouette,cytologicatypia,occasionalmitoses,presenceofcleftsbetweenthe cellular nests and the stroma with its mucinous cha-racter,allowthediagnosisofthelatter.Inpartialorsu-perficialbiopsies,andoccasionallyinparticularcases,thedistinctionmaybemoredifficult.Whenthewho-le lesion is not available for microscopic examination and if immunohistochemistry is performed in these cases,CK15immunoreactivityofthecellularaggrega-tes as well as the presence of scattered CK20-positive cells would favour the diagnosis of trichoblastoma. In thesameway,thedifferentialexpressionofCD10andBcl2(CD10positiveonthestromaoftrichoblastoma,but not on BCC cells; and Bcl2 immunoreactivity posi-tiveinBCCcells,butnegativeintrichoblastomacells)may be helpful in the distinction.32,33

Trichoepithelioma would correspond to a su-perficialvariantoftrichoblastomawithprominentin-fundibulocysticdifferentiation(seebelow).

Trichoblastoma is a benign tumor and the com-plete surgical excision (often necessary for a correct histologicdiagnosis)isthepreferabletreatmentmoda-lity. Rarely it can have malignant evolution secondary to the sarcomatous transformation of the stroma or coexistwithothermalignantadnexalneoplasm(s)wi-thin an organoid nevus. 34

Adamantinoid trichoblastoma (Lymphoepite-lial cutaneous tumour; cutaneous lymphadenoma)

It is an uncommon neoplasm with differentia-tiontowardsthehairgermcharacterizedbytheper-meation of the tumoral tissue by a conspicuous lym-phocytic infiltrate, a feature reflected on the initialdesignations of “lymphoepitelial cutaneous tumour” and “cutaneous lymphadenoma”. Currently the tu-mor is considered a variant of trichoblastoma.

Clinically, it corresponds to a slowly growingsolitary non-descript nodule on the face or lower limb of adults. Pediatric cases are exceptional.

Microscopic examination generally discloses a well-circumscribed dermal tumor made of epithelial nestsandstrands,variableinsizeandshape,inwhichtwo cell types are readily identifiable: (i) basophilic,germinative cells with a tendency for nuclear palisa-ding at the periphery of the epithelial aggregations; and (ii) loosely arranged cellswithmore prominentand paler cytoplasm occupying the centre of the tu-mornests.Typically,smallmaturelymphocytescons-picuously infiltrate the tumor epithelium.As a rulethe epithelial aggregations are embedded in a dense stroma(Figure7).35,36

Figure 6: Tricho-blastoma. A. Basa-loid proliferation with dense stroma separated by clefts from the adjacentdermis. B. Detail of the cellular stroma forming condensa-tions near the basa-loid islands (papil-lary mesenchymal bodies)

Figure 7: Tricho-blastoma. A. Basa-loid proliferation with dense stroma separated by clefts from the adjacentdermis. B. Detail of the cellular stroma forming condensa-tions near the basa-loid islands (papil-lary mesenchymal bodies)

A B

A B


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The (i) cytoarchitectural compartmentalizationofthetumornests,withbasaloidperipheralcellsandlooselyarrangedpale,glycogen-richcentralcells,ob-servablefromlowmagnification;(ii)thelymphoidcellinfiltration;and(iii)thepresenceofscatteredS100andCD1a-positivedendritic cells, arehighly characteris-tic and distinctive of adamantinoid trichoblastoma,which seldom poses problems in terms of differential diagnosis.

Distinctionfromtrichogerminoma,anotherhairgerm tumor considered by some as another variant of trichoblastoma (see below), is based on the typicalconcentricarrangementofthecells(“cellballs”)onthecentreofthetumornestsintrichogerminoma,which,in addition, lacks the characteristic lymphocytic cellpermeation of adamantinoid trichoblastoma.

TrichoepitheliomaTricoepithelioma is thought to correspond to a

superficial (intradermal) trichoblastoma with promi-nent infundibulocystic differentiation.

Besides the more common solitary, clinicallynondescript,sporadictypeoccurringinadults,lesionsmaybemultiple,presenting in childhoodoradoles-cence with autosomal dominant inheritance (epithe-liomaadenoidescysticum-OMIM601606).Inthelat-ter type the patient presents with multiple 2-10 mm papules occasionally coalescing on the face (nasolabial folds)or scalpandneck.Linearblaschkoiddistribu-tion may occur. Coexistence with cylindromas or less frequentlyspiradenomahasbeenreported,inthecon-textofCYLDgenemutations.37 Multiple trichoepithe-liomasare, inaddition, characteristicofRombosyn-dromeandBazex-Dupré-Christol syndrome (BDCS).In both of these syndromes trichoepitheliomas coexist withatrophodermavermiculatum,milia,hypotricho-sis and basal cell carcinoma. Distinction between them dependsoni):localizationoftheatrophodermicchan-ges: malar regions and elbows in Rombo syndrome versusdorsalhandsinBDCS;ii)cyanoticerythemainRombosyndromepresentfrominfancy,notreportedinBDCS,and:iii)X-linkedtransmissioninBDCScon-trasting to the autosomal dominant pattern of inheri-tance of Rombo syndrome.38

Occasionally giant solitary trichoepitheliomas ofthethigh,buttockandperianalregionshavebeenreported.Morefrequentlythesolitaryformsareclini-cally misdiagnosed as a melanocytic nevus or a non--ulcerated BCC.

Histologically, trichopithelioma is a well-de-marcated intradermal tumor with a horizontal longaxis separated from the neighbouring dermis by re-traction clefts. The tumor is composed of nests of basaloid (hair germ) cells in anodular or trabeculararray coexisting with infundibulocystic structures

(Figure8A).Inthelatter,calcificationmaybeseen.Inthebasaloidnests,hairgerm/papillaandbulbardif-ferentiationarepresent.Althoughperipheralnuclearpalisadingandindividualcellnecrosismayoccur,nosignificantatypia,massivenecrosisoratypicalmito-ses are seen. The stroma is loosely collagenous and containselongatedfibroblastsoccasionallyorganizedin small aggregates at the vicinity of the basaloid cell nests (papillarymesenchymalbodies, traducinghairpapilladifferentiation).Withtheexceptionofforeignbodygranulomatousreactiontorupturedkeratocysts,inflammationischaracteristicallyabsent.

Differential diagnosis:Basal cell carcinoma (infundibulocystic). The cel-

lular,fibrocyticnatureof thestroma, thepresenceofclefts within the stroma and between the stroma and surroundingdermis,aswellasthelargerfolliculardif-ferentiationspectrum(infundibularandgerminative,papillary or bulb), all argue for thediagnosis of tri-choepithelioma.

Trichoadenoma:asopposedto tricoepithelioma,trichoadenoma(i)isanstrictlyinfundibular(andnotgerminative) hair tumor, (ii) displays dilated conti-guousinfundibularstructures,and(iii)ascantystro-ma(epitheliumtostromaratioof“10/1”)(iv)thatisdevoid of clefts.

Trichoblastoma: For some authorities trichoepi-theliomaisasuperficialtrichoblastomawithmoread-vanced(infundibular)differentiation(seeabove).

Desmoplastic trichopitheliomaDescribedbyBrownsteinandShapiro,desmo-

plastic trichopithelioma is a variant of solitary trichoe-pitelioma,recognizableforitsclinicopathologicsingu-larities.39

Clinically it is a small annular plaque with acharacteristic depressed centre and raised border oc-casionally presenting scattered tiny milia grains. It can mimic the clinical image of granuloma annulare. In most cases it occurs on the malar region or forehead of adult women. Exceptionally lesions aremultiple,familialornon-familial,occurringas typicalannularplaquesonthefaceandneck.

Histologically it corresponds to a well-circums-cribed,symmetrical,discoidlesiononthesuperficialand mid dermis with a characteristic central depres-sion that can evoke the diagnosis at lowmagnifica-tion. The tumor is made of branching or more linear cords of basaloid cells and keratinous infundibulo-cystic structures (Figure8B).Thecordsare irregular,giving rise to bizarre patterns, occasionally one cellthick.Thekeratinouscystsarefrequentlycalcifiedand

can exhibit centrifugal “tadpole”projectionsof theirwall. The epithelial aggregations are embedded in a conspicuouscompactandhypocellular,desmoplasticstroma. No cytologic atypia or atypical mitoses occur. Focalforeignbodygranulomatousinflammatoryinfil-tratecanoccursurroundingrupturedkeratinouscysts.

Differential diagnosisBasal cell carcinoma: insuperficial(shave)biop-

sies histological distinction between trichoepithelioma andBCCmay be vexing; the localization of cleftingwithinthestroma,orbetweenstromaandneighbou-ringdermis,ratherthanbetweenstromaandepithe-lial aggregates; the more extensive infundibulocystic differentiation; the more superficial and symmetricsilhouette; as well as the absence of necrosis, mito-sisandof inflammatoryinfiltrate,argueinfavourofDT.Additionally,incontrastwithmorpheaformBCC,CK20/Cam 5.2-positive cells are often seen within the epithelial aggregates of DT.2

Syringoma: Syringoma may show keratinouscystswithwallruptureandforeignbodyreaction,andbe misdiagnosed as DT and vice versa.However,syrin-goma ismore superficially located thanDT, exhibitsductaldifferentiation,anddoesnot showgerminati-ve cells or cleftingwithin the stroma.One cell thickstrandsorcordsarenotafeatureofsyringoma.EMAandCEA regularly decorate the luminal border andmoreoccasionallytheluminalcellsofsyringoma,butare not expressed in DT.

Microcystic adnexal carcinoma (MAC): the cha-racteristic features ofMAC that allow itsdistinctionfromDT (deep extension, infiltrative pattern, asym-metry and perineural invasion) are not always pre-sent in small/superficial/shave biopsies, in whichthe distinction between these two neoplasms may not be possible. Immunohistochemical data described in MAC that can assist thedifferentialdiagnosis inclu-

deexpressionofCEA/EMAontheluminalcells,my-oepithelial phenotype (S100 αSMA)oftheperipheralcellsofductalstructures,andabsenceofBerEP4andCK20/Cam5.2 immunoreactivity in tumor strands.

TrichogerminomaTrichogerminoma is an insufficiently known

benign follicular neoplasm described by Sau et al in 1992.40

It is a germinative hair follicle tumor with an intermediate differentiation between trichoblastoma and panfolliculoma (Table 1). From a clinical stan-dpoint it is a nondescript papule or nodule of the head orneck.

Microscopic examination discloses an intrader-mal symmetrical nodule composed by basophilic lo-buleswithinafibrotic stromawelldemarcated fromthesurroundingdermisbyclefts(Figure9A).Withinthe tumor lobules, rounded cell nests (“cell balls”)made of concentrically arranged pale cells, are cha-racteristicallyseen(Figure9B).Thepalecellnestsaresurroundedbyoneormorelayersofsmallbasaloid,germinative cells displaying nuclear palisading at the periphery of the lobules. Hair germ and bulb struc-tures are routinely found. Infundibulocystic, isthmicstructures, sebaceousducts and sebocytes often coe-xist. Immunohistochemically a “zonal” pattern pro-ducedbyexpressionofCK5/6,CK5/8eCAM5.2onthe peripheral germinative cells contrasting with the absence of staining at the cell balls is typical and may be helpful in distinguishing trichogerminoma from the more classic nodular types of trichoblastoma. 41,42

In contrast with adamantinoid trichoblastoma (thatalsoshowscytoarchitecturalcompartmentaliza-tion of the cell aggregates in a peripheral germinative cell and a central pale cell area), no lymphocytes orS100/CD1a-positive dendritic cells are found in tri-chogerminoma.

Trichogerminoma is thought to be a variant of trichoblastomawithspecifichistological(“cellballs”)and immunohistochemical features.

Figure 8: A. Tricho-epithelioma. Basa-loid proliferation with abundant infundibular kera-tinization;note thedense stroma sepa-rated by clefts from the adjacent der-mis. B. Desmoplas-tic trichoepithelio-ma. Thin basaloid strands in a dense stroma, and a fewkeratocystsA B


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PanfolliculomaIn1993Ackermanet al.1 described 6 cases of a

benignhair follicleneoplasmakin to trichoblastomawith a nodular/cystic pattern but characterized byphenotypicmicroscopic features of bulbar, matrical,stem,isthmicandinfundibulardifferentiation.Asthetumor recapitulated all the epithelial components of the mature hair follicle the term panfolliculoma was coined. Panfolliculoma would represent a trichoblas-toma depicting the most wide differentiation spec-trum. Cystic and intraepidermal variants may occur (“epidermalpanfolliculoma”).43,44 In the latter,histo-logic examination discloses an epidermal acanthoma

where features of differentiation for upper and lower hairfollicle,includinggerminativecells,matricalcells,outerrootsheathcells,trichohyalingranulesindicati-veofinnerrootsheathdifferentiation,ghostcellsandlaminatedbasketwavecornification,coexist.

PilomatricomaNotinfrequentinpediatricages,whereitconsti-

tutesthemostcommonadnexalskintumor,itpresentsclinically as a dermohypodermal progressively gro-wingnoduleofthehead,neck,upperlimbsand,lessfrequently,trunkorlowerlimbs(Figure10A).Charac-teristicallyfirm tohardonpalpation, its consistency

Figure 9: Trichogermino-ma. A. Well-cir-c u m s c r i b e d intradermal mul-tinodular lesion separated from the adjacent der-mis by clefts. B. Detail of the “cell balls” com-posed of concen-trically arranged pale cells sur-rounded by an outer layer of darkercells

Figure 10: Pilomatrixoma. A. Nodule on the upper arm of a young patient; le-sions are typically hard upon palpa-tion,andabluishcolor, as seen inthis example, isnot a rare feature. B. Well circum-scribed dermal nodule with a biphasic appear-ance (basaloid and eosinophilic areas).C. Sharp tran-sition between basaloid cells and keratinizedstrands. D. Detail of ghost cells, in whichonly the outline of the nuclei and cytoplasmic bor-ders are discern-ible

A B

A

C

B

D


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dependsonthepresenceandextentofcalcification.Itmaygrowabruptlyattaining large sizemimickingamalignantlesion.Inrareoccasionsitmaybemultiple,occurring in the setting of myotonic muscular dystro-phy or of Gardner syndrome (familiar adenomatous polyposis)associatedwithhighincidenceofcolorectalmalignancy.Morerarely,itcanbethecutaneousmar-kerofRubinstein-Taybisyndromeorofchromossome9 trisomy. 45,46 Occasionally the solitary lesions invo-lutewithanetodermicchangesofoverlyingskin,suf-fer transepidermal elimination or are spontaneously painful.

β-catenin gene mutations have been described inmostcasesstudied,implicatingtheWNT/β-catenin pathwayinthepathogenesisofpilomatricoma,afea-ture in agreement with the association with Gardner´s syndrome,asthisischaracterizedbygermlinemuta-tions of a suppressor allele of this tumor suppressor pathway.47Morerecently,chromosome18trisomyhasbeenidentifiedinpilomatricomacells,ageneticano-maly that could additionally be pathogenically rele-vant via the hyperfunction of the anti-apoptotic gene Bcl-2,thatresidesinthischromosome.48

The histological picture varies with the age of lesions. Typically, it is a well-circumscribed der-mohypodermal rounded nodule, with smooth bor-ders surrounded by a pseudocapsule and constituted byepithelialaggregates(Figure10Band10C).Intheseaggregates two cellular types are regularly found: i)peripherally,cellsaresmallwithscantcytoplasmandadeeplybasophilicelongatednucleus(matricalcells);they occur in multiple layers with no nuclear palisa-ding;ii)inthecentreoftheepithelialaggregates,cellsdisplay an abundant eosinophilic cytoplasm whereas the nucleus disappears and is replaced by an empty space.Theseareknownasghostcells,theyarecharac-teristic of pilomatricoma and correspond to terminal differentiation of the basophilic peripheral cells (ma-tricalcells)(Figure10D).Thetransitionbetweenma-tricalcellsandghostcellsmaybeabruptorgradual,through a variable number of cells whose cytoplasm acquiresprogressiveeosinophiliawhereasthenucleussufferspycnosisandisfinallylost(Figure10C).

In early lesions the architectural pattern is cystic and there is predominance of basophilic matrical cell aggregates. Progressively ghost cells replace the baso-philiccells,andcalcification(“calcifiedepithelioma”)or, lessoften,hemosiderindepositionor evenossifi-cation,may occur. Simultaneously, a granulomatousforeign body inflammatory infiltrate is trigged, pro-gressively replacing the epithelial proliferation. This aspect may dominate the histological picture in late lesions. Melanin granules and dendritic melanocytes may occur within the epithelial aggregates, reinfor-

cing the phenotypic similitude between pilomatrico-maandhairmatrix.Insomeinstances,particularlyinolder patients, the predominance of basophilic cellsmay persist in late lesions, a feature that frequentlycoexists with conspicuous mitosis (“proliferative pilo-matricoma”). The histological picture is so characte-ristic that differentiation from other tumors is rarely put forward. When the basophilic cells are prominent the lesion can be misinterpreted as a “proliferative pilomatricoma” or even a malignant pilomatricoma. “Proliferative pilomatricoma” exhibits brisk mitoticactivity,andpredominanceofmatricalbasophiliccellsoverghostcells,butconservesthewellcircumscribedsmooth border seen in ordinary pilomatricoma and should not be confused with the malignant pilomatri-comathat,besidescytologicalatypia,variablemitoticrateandpredominanceofmatrical cells,displaysanasymmetricalsilhouette,withpoorcircumscribedin-filtrativejaggedborders,centralnecrosisoftheepithe-lialaggregates,andalymphohistiocyticinflammatoryinfiltrateonadesmoplasticstroma.49 In partial super-ficialbiopsiesconfusionwithbasalcellcarcinomamayoccur,butnuclearperipheralpalisadingandcleftingbetween an altered stroma and the epithelial aggrega-tes do not occur in pilomatricoma.

Pilomatricomaisabenigntumor.Nevertheless,locally aggressive and even metastatic examples have beenrarelyreported.Accordingly,surgicalexcisionisadvisable.

Trichodiscoma and FibrofolliculomaThese two follicular neoplasms, characterized

by extensive perifollicular mesenchymatous diffe-rentiation,althoughexhibitingdistincthistologicfea-tures, generally coexist in the samepatient, occasio-nally in identical nearby clinical lesions or in the same lesion (where both pictures can be seen in the same sectionorinserialsections)andarethoughttocorres-pond to different designations of the same entity with different development and topographic orientation of their constituents.

Multiple fibrofolliculomas and trichodiscomasare the main cutaneous manifestations of the rare Bir-t-Hogg-Dubésyndrome(BHDS)(Figure11A).Inthissyndrome, with autosomal dominant inheritance,there is an increased incidenceof kidneyneoplasms(oncocytomas, chromophobe carcinoma, papillarycarcinoma, clear cell carcinoma), and lung disease(spontaneous pneumothorax, pulmonary cysts, bul-lous emphysema). Less often, patient may presentmultiple lipomas and angiolipomas, aswell as neu-ral tumors (neurothekeoma,meningeoma), connecti-ve tissuenevi, facial angiofibromas andparathyroidadenoma. The relationship with colorectal cancer is controversial. The initially reported association with


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medullarycancerof thyroidhasnotbeenconfirmedand was instead associated with the presence of coe-xistent dominant hereditary multiple endocrine neo-plasia type 2.50

The susceptibility gene for SBHD has been lo-calizedin17p11.2and17p12-q11.2,andsubsequentlyidentifiedasa“new”supressortumorgenedesigna-tedasfolliculin(FLCN).Itispresentin60%to80%ofthe patients

Exceptional cases of multiple trichodiscomas without any other cutaneous or extracutaneous ma-nifestation as well as observations of localized/cir-cumscribed SBHD have been reported. 51,52Fibrofolli-culoma/trichodiscoma can also occur in exceptional occasions as a sporadic solitary lesion of exclusive dermatologic relevance.

Fibrofolliculoma: Histologic examination dis-closes a vertically oriented dermal papule centred by a follicular infundibulum from which anastomo-sing thin cellular cords, that may contain sebocytesor sebaceous lobules, irradiate into the surroundingabundantstroma(Figure11B).Cysticdilatationofthecentrally located infundibulum may occur. Stroma is readilyconspicuousatlowmagnification,withastri-kingmucinouscharacter,containingparallelfibresoffibrillarycollagen,fibroblastsandoccasionaldendriticcells.

Trichodiscoma: The classic histologic picture of trichodiscomadiffersfromthatoffibrofolliculomabythe relative proportions and disposition of the stromal andepithelial components, aswell as thehorizontalrather than vertical general orientation of the lesion. In trichodiscoma there is a greater development of the stroma and tendency to a more peripheral disposition of theepithelial component,whichkeeps its radiarydisposition and tends to exhibit a more pronounced maturesebaceouscontent,recapitulatingmantlehairdifferentiation(Figure11C).Thestroma,peripherallylimited by the infundibulo-sebaceous cords, domi-natesthepicture.Itsnatureissimilartothatoffibro-folliculoma and is characteristically devoid of elastic fibres.

As seen, the distinction between fibrofollicu-loma and trichodiscoma is not always possible and,duetothepresenceofmantlehairdifferentiation,thelesionsarealsoknownundertheterm“mantleoma”.

Differential diagnosis:Fibrofilliculoma/trichodiscomahasadistincti-

ve, easily recognisablehistologicalpicture (Chart 2).Trichofoliculomas(seebelow)withawell-developedstromamaybeconfoundedwithfibrofolliculoma.Ho-wever,intheformernoradiatecordscontainingsebo-cytesemanate fromthemain infundibularwall,andin turn, fibrofolliculoma does not depict secondaryinfundibula from which vellus hair emanate.

Figure 11: A. Birt-Hogg-Dubésyndrome. Multiple papules distribut-ed on the face and a larger nodular lesion on the right nasal ala. B. Trichodiscoma. Papule containing a centrally located dense stroma that pushes the epitheli-al component to the periphery; note the small sebaceous lob-ules(arrows).C. Fibrofolliculoma. Vertically orienteddistorted follicu-lar structure with thin anastomosing strands surrounded by a dense stroma

A

CB


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Neurofollicular hamartoma,describedbyBarr etal,isthoughttorepresentavariantoffibrofilliculoma/trichodiscoma with a prominent spindle cell stroma. 53-

55 It should be noted that neurofollicular hamartoma is a solitary papule of the nose of strict dermatologic re-levance whereas fibrofolliculoma/trichodiscoma areingeneralmultipleandamajorsignofBHDS.

Perifollicular fibromaPerifollicularfibromapresentsassingleormul-

tiple papules most commonly located on the head and neck.Someauthorshaveregardeditasahamartoma-tous lesion and a possible variant of angiofibroma/fibrouspapule,whereasothershaveaffirmeditsrela-tion to the spectrumoffibrofolliculoma/trichodisco-ma. In fact, the association ofmultiple perifollicularfibromasandcolonicpolyps is called theHornstein--Knickenbergsyndrome,whichiscloselyrelatedtoorevenpartofthespectrumofBirt-Hogg-Dubésyndro-me.56,57Inaddition,lesionswithoverlappingfeaturesbetween fibrofolliculoma and perifollicular fibromahave been documented in the setting of Birt-Hogg-Du-bésyndrome.58

Histologically, it consists of cellular fibroustissue arranged concentrically around one or several normalhairfollicleswithan“onion-skin”appearance.Frequently,acleftseparatesthefibroustissuefromtheadjacentdermis.

Differential diagnosisFibrofolliculoma: the fibrous tissue surrounds

and is closely intermingled with a distorted hair fol-liclethatdisplaysthinanastomosingprojectionsthatfrequentlycontainsebocytesorsmallsebaceouslobu-les; in contrast, in perifollicular fibroma, the fibroustissue surrounds normal follicular structures.

Angiofibroma/fibrous papule: perifollicular fibro-sistendstobelessprominent,anangiomatouscom-ponentisevident,andthepresenceofspindle-shapedorstellatefibroblastsisusuallyeasytoidentify.


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Chart 2: Differential diagnosis between trichodisco-maandfibrofolliculoma

Trichodiscoma Fibrofolliculoma

Horizontallyoriented Verticallyoriented

Epithelial+ Epithelial+++

Peripheral location Central location

Stroma+++ Stroma+++

Cysticpattern-to+ Cysticpattern++

TrichofolliculomaThe diagnosis may be clinically elicited in the

presence of a smooth hemispheric papule with a cen-traldepressionfromwhichmultiplethinhairemerge,located on the centrofacial area in adults.

Histologically it corresponds to single or mul-tipleverticallyoriented infundibulocystickeratinousstructure(s)drainingtotheskinsurfacebyanostiumand resulting from one or multiple dilated infundi-bula. From their wall smaller infundibula emanate centrifugallythat,inturn,giverisetomatureordys-trophicvellushairfollicles(Figure12).Thefollicularelementsareembeddedinaconnectivetissue,whichmay be poorly developed or, in contrast, abundantandfibrous, separated from the surroundingdermisby retraction clefts.59

Differential diagnosisThe distinction from pilar sheath acantho-

ma, dilated pore and tricoepithelioma is generallystraightforward.Neitherperifollicularfibromanorfi-brofolliculoma/trichodiscoma,which share a stromasimilar to that of tricofolliculoma, showvellus hairsirradiating from dilated infundibulocystic structures that are characteristic of the latter.

The difference between trichofolliculoma and folliculosebaceous cystic hamartoma (HQFS) would rely on the operculized indundibulocystic silhouettewithirradiatingvellushairfolliclesintheformer,andthe sebaceous differentiation and development of the stroma with obligatory mesenchymal changes (adi-pocytes)inthelatter.However,thefactthatbothcan

Figure 12: Trichofollicu-loma. Cystic cavity from which nu-merous vellus hair follicles radiate


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sharethesamearchitecturalpattern,thepossibilityofsebaceous differentiation in trichofolliculoma (“seba-ceoustricofoliculoma”)andthereportofcaseswheredistinction between these tumors is virtually impos-sible,mayindicateacloserelationshipbetweentheselesions and/or a common pathogenic basis.60

Folliculosebaceous cystic hamartomaClinically it is a slow growing solitary nodule

oftheheadandneck,asarulefirstnoticedinthe5thor 6th decades. Congenital forms are not exceptional. Lesioncanattainalargesizeandbecerebriform.

Thehistologicalcharacterizationofthefollicu-losebaceous cystic hamartoma has been thoroughly precised in the initial description: a dermal infundi-

bulocystic structure into which merge sebaceous ducts attachedtosebaceouslobules,surroundedbyafibro-plasic lamellar stroma that incorporates mesenchymal elements, including adipocytes, separated from thesurrounding dermis by clefting. 61 The individuali-zation of folliculosebaceous cystic hamartoma as anentity distinct from trichofolliculoma is controversial. The prominence and character of the stroma as well asthenon-operculizedgeneraldispositionandmag-nitude of the sebaceous differentiation would assist the diagnosis of folliculosebaceous cystic hamartoma ratherthansebaceoustrichofolliculoma(seeabove)

It should be noted that folliculosebaceous cys-tic hamartoma bears no relationship with Torre-Muir syndrome. q

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18. Leonardi CL, Zhu WY, Kinsey WH, Penneys NS. Trichilemmomas are not associated with human papillomavirus DNA. J Cutan Pathol. 1991;18:193-7.

19. Al-Arashi MY, Byers HR. Cutaneous clear cell squamous cell carcinoma in situ. J Cutan Pathol. 2007;34:226-33.

20. Hunt SJ, Kilzer B, Santa Cruz DJ. Desmoplastic trichilemmoma: histologic variant resembling invasive carcinoma. J Cutan Pathol. 1990;17:45-52.

21. Tellechea O, Reis JP, Domingues JC, Baptista AP. Desmoplastic trichilemmoma. Am J Dermatopathol. 1993;15:452-5.

22. Mehregan AH, Butler JD. A tumor of follicular infundibulum. Arch Dermatol. 1961;83:924-7.

23. Kossard S, Kocsard E, Poyzer KG. Infundibulomatosis. Arch Dermatol. 1983;119:267-8.

24. Cardoso JC, Reis JP, Figueiredo P, Tellechea O. Infundibulomatosis: a case report with immunohistochemical study and literature review. Dermatol Online J. 2010;16:14.

25. Schnitzler L, Civatte J, Robin F, Demay C. Tumeurs multiples de l’infundibulum pilaire avec dégénérescence baso-cellulaire. Ann Dermatol Venereol. 1987;114:551-6.

26. Starink TM. Cowden’s disease; analysis of fourteen new cases. J Am Acad Dermatol. 1984;11:1127-41.

27. Tellechea O, Reis JP, Domingues JC, Baptista AP. Ber EP4 distinguishes basal cell carcinoma from spinous cell carcinoma of the skin Am J Dermatopathol. 1993;15:452-5.

28. Findlay GH. Multiple infundibular tumors of the head and neck. Br J Dermatol. 1989;120:633-8.

29. Weyers W, Hörster S, Diaz-Cascajo C. Tumor of follicular infundibulum is basal cell carcinoma. Am J Dermatopathol. 2009;31:634-41


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Mailing address:Oscar TellecheaCentro Hospitalar Universitário de CoimbraServiço de DermatologiaPraceta Prof. Mota Pinto3000-075 CoimbraPortugalEmail: [email protected]

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31. Batman PA, Evans HJ. Metastasizing pilar tumor of scalp. J Clin Pathol. 1986;39:757-60.

32. Misago N, Satoh T, Miura Y, Nagase K, Narisawa Y. Merkel cell-poor trichoblastoma with basal cell carcinoma-like foci. Am J Dermatopathol. 2007;29:249-55.

33. Córdoba A, Guerrero D, Larrinaga B, Iglesias ME, Arrechea MA, Yanguas JI. Bcl-2 and CD10 expression in the differential diagnosis of trichoblastoma, basal cell carcinoma, and basal cell carcinoma with follicular differentiation. Int J Dermatol. 2009;48:713-7.

34. Rosso R, Lucioni M, Savio T, Borroni G. Trichoblastic sarcoma: a high-grade stromal tumor arising in trichoblastoma. Am J Dermatopathol. 2007;29:79-83.

35. Betti R, Alessi E. Nodular trichoblastoma with adamantinoid features. Am J Dermatopathol. 1996;18:192-5.

36. Baptista AP, Tellechea O, Reis JP. Tumor linfo-epitelial cutâneo. Acta Med Port. 1998;11:555-8.

37. Tellechea O, Reis JP, Freitas JD, Poiares Baptista A . Multiple eccrine spiradenoma and tricoepiteliomata. Eur J Dermatol. 1991;1:111-115

38. Parren LJ, Frank J. Hereditary tumour syndromes featuring basal cell carcinomas Br J Dermatol. 2011;165:30-4.

39. Brownstein MH, Shapiro L. Desmoplastic trichoepithelioma. Cancer. 1977;40:2979-86.

40. Sau P, Lupton GP, Graham JH. Trichogerminoma. Report of 14 cases. J Cutan Pathol. 1992;19:357-65.

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42. Tellechea O, Reis JP. Trichogerminoma. Am J Dermatopathol. 2009;31:480-3.43. Hoang MP, Levenson BM. Cystic panfolliculoma. Arch Pathol Lab Med.

2006;130:389-92.44. Harris A, Faulkner-Jones B, Zimarowski MJ. Epidermal panfolliculoma: A report of

2 cases. Am J Dermatopathol. 2011;33:e7-10.45. Cribier B. Maladies associées aux tumeurs annexielles. I- Tumeures folliculaires.

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50. Reese E, Sluzevich J, Kluijt I, Teertstra HJ, De Jong D, Horenblas S, Ryu J. Birt Hogg Dubé syndrome. in Riegert-Johnson DL, Boardman LA, Hefferon T, editors. Cancer Syndromes [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2009. [cited 2015 Jun 11]. Available from http://www.ncbi.nlm.nih.gov/books/NBK45326/?report=reader#!po=2.27273

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52. Schulz T, Ebschner U, Hartschuh W. Localized Birt-Hogg-Dubé Syndrome With Prominent Perivascular Fibromas Am J Dermatopathol. 2001;23:149-53.

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55. Kutzner H, Requena L, Rütten A, Mentzel T. Spindle Cell predominant Trichodiscoma: A Fibrofollicular/Trichodiscoma variant considered formerly to be a Neurofollicular Hamartoma Am J Dermatopathol. 2006;28:1-8.

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57. McKenna DB, Barry-Walsh C, Leader M, Murphy GM. Multiple perifollicular fibromas J Eur Acad Dermatol Venereol. 1999;12:234-7.

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How to cite this article: TellecheaO,CardosoJC,ReisJP,RamosL,GameiroAR,CoutinhoI,Poiares-BaptistaA.Benignfolliculartumors.AnBrasDermatol.2015;90(6):780-98.


An Bras Dermatol. 2015;90(6):780-98.

Questionss

1. Which one of the following is correct about follicular tumors? a) Most cases are clinically distinctive. b) They occur more commonly as multiple lesions. c) The diagnosis is based on histology. d) They occur more commonly on the limbs.

2. Which one of the following is not characteristic of outer root sheath differentiation? a)Basket-weaveorthokeratosis. b) Cells with pale cytoplasm. c) Peripheral palisading. d) Thickenedhyalinebasementmembrane.

3. Which one of the following does not belong to the group of tumors with germinative (hair germ) differentiation? a) Trichoblastoma. b) Pilomatricoma. c) Trichogerminoma. d) Tricoepithelioma.

4. Which one of the following tumors, when multiple, can be associated with increased risk of visceral neoplasms? a) Pilar sheath acanthoma. b) Dilated pore of Winer. c) Proliferating trichilemmal tumor. d) Trichilemmoma.

5. Which one of the following is not a feature of Birt-Hogg-Dubé syndrome? a) Multiple tumors of follicular infundibulum. b) Multiplefibrofolliculomasandtrichodiscomas. c) Increasedriskofrenalcancer. d) Spontaneous pneumothorax.

6. Which one of the following is true about trichoblastoma? a) The histological differential diagnosis with basal cell car-

cinomaisstraightforward,eveninsmallbiopsies. b) Artifactualcleftsaretypicallyseenbetweentheepithe-

lial nests and the stroma. c) The presence of CK20-positive cells is consistent with

the diagnosis of trichoblastoma. d) It is a rare occurrence in organoid nevus (nevus seba-

ceous).

7. Which one of the following syndromes is not usually associated with multiple pilomatricomas? a) Myotonic dystrophy. b) Rombo syndrome. c) Gardner syndrome. d) Rubinstein-Taybi syndrome.

8. Which gene is associated with Birt-Hogg-Dubé syn-drome? a) PTEN. b)CYLD. c) FLCN. d) WNT.

9. Which one of the following is not usually included in the histological differential diagnosis of desmoplastic trichoepithelioma? a)Infiltrativebasalcellcarcinoma. b) Squamouscellcarcinoma. c) Microcystic adnexal carcinoma. d) Syringoma.

10. Which one is not usually found in pilomatricoma? a) Foreign body giant cell reaction. b) Ghost cells. c) Mitotic activity. d) High-grade nuclear atypia.

11. Which one is true about proliferating trichilemmal tu-mor/cyst? a) It is more common in men. b) It is usually multiple. c) Theuppertrunkisthemostcommonlocation. d)Themaindifferentialdiagnosisissquamouscellcarci-

noma.

12. Which one is false about trichogerminoma? a) It belongs to the group of tumors with germinative

(hairgerm)differentiation. b) It usually presents with multiple lesions. c) Itismorecommononthehead/neck. d) Thecharacteristichistologicalfindingisthepresenceof

“cell balls”.

13. Regarding the tumor of follicular infundibulum (in-fundibuloma), which one is false? a)In its multiple form (infundibulomatosis) the lesions

can be confusedwith pityriasis versicolor, vitiligo orporokeratosis.

b)In its multiple form (infundibulomatosis) there is awell-documented association with visceral malignan-cies,particularlyofthethyroidandbreast.

c) Whensingle,itisusuallynotclinicallydistinctiveandcanbeconfusedwithaseborrheickeratosisorabasalcell carcinoma.

d) Histologically,itisasubepidermalplaque-likeprolifer-ationofpalekeratinocytesthatmaydisplayperipheralpalisadingandstromalcondensationofelasticfibers.


An Bras Dermatol. 2015;90(6):780-98.

14. Which one is false about trichofolliculoma? a)Itoccursmorecommonlyonthehead/neck. b)A typical presentation is a papule with protruding

hairs. c) The distinction from pilar sheath acanthoma is usually

not problematic. d) The distinction between sebaceous trichofolliculoma

and folliculosebaceous cystic hamartoma is straight-forward.

15. Which one is false about adamantinoid trichoblastoma? a) Itisalsoknownascutaneouslymphadenoma. b) It is typically seen in the pediatric population. c) It is usually well-circumscribed. d) The nests of cells are infiltrated by lymphocytes and

dendritic cells.

16. Which one of the following favours clear cell poroma over trichilemmoma? a) Peripheral palisading. b) Hyaline basement membrane. c) Folliculocentricity. d) Ductal differentiation.

17. Which one of the following features in not seen in trichilemmoma? a) Lobular architecture. b) PAS-positivecells. c) Ghost cells. d)CytopathogeniceffectofHPV.

18. Which one of the following proteins is thought to have a pathogenic role in pilomatricoma? a) CD34. b) Beta-catenin. c) CK20. d)EMA.

19. Which tumor is seen both in Rombo and Ba-zex-Dupré-Christol syndromes? a) Trichilemmoma. b) Trichoepithelioma. c) Trichoadenoma. d) Pilar sheath acanthoma.

20. In addition to tricoepitheliomas, mutations in the CYLD gene can be associated with which combination of adnexal neoplasms? a) Sebaceomas and sebaceous adenomas. b) Syringomas and hidradenomas. c) Spiradenomas and cylindromas. d) Trichilemmomas and tumors of follicular infundibulum.

Answer keyCoccidioidomycosis and the skin: a compre-hensivereview.2015;90(5):610-21.

1. C2. B3.A4. B5. B

6. C7.A8. D9. D10.C

11. D12. B13. D14. B15. C

16. A17. D18. B19. A20. A

PapersInformation for all members: The EMC-D

questionnaireisnowavailableatthehome-pageof theBrazilianAnnalsofDermatolo-gy: www.anaisdedermatologia.org.br. The deadlineforcompletingthequestionnaireis30 days from the date of online publication.

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Benign follicular tumors - Birt-Hogg-Dubé Syndrome · PDF fileBenign follicular tumors* ... centric cell layers are identifiable ... 6 The wall recapitulates the infundibular epithelium