Fibroepithelioma-like changes associatedwith anogenital epidermotropic mucinouscarcinomaFibroepitheliomatous Paget phenomenon

We describe two patients with crusted perineal ];laques thatwere biopsied and diagnosed as Paget's disease. Resection s]3eei-mens of each contained a dermal mucinous carcinoma withextensive epidermotropism and coexistent epidermal basaloidproliferations elosely resembling fibroepithelioma (Pinkus). The|Dresence of the Paget phenomenon was supported by histochem-ical, immunohistochemical, and ultrastrtielrual evidenee. Noother primary neoplasms were lound in eitlier patient. l'\)llowupat 2 1/2 and 3 1/2 years, res|3e(-tively, has heen negative. Wecoiu-lude that either the fil)roe|jitheliomatous changes may beindueed by or may represent a collision (unlikely) with the epi-detnioUopit- tmicinotis eareinoma. It is proposed tliat the c:on-cvpl ftbtoepitlteliorrtattnis Pcta^el phentnnenon l)e used to s tand for thehistologic changes common lo our eases as well as those ])revi-ously reported.

Hurl MA, Hardarson S, Stadeeker MJ, Santa Cruz DJ. Fibroe-plthelioma-like ehanges associated with anogenital ejiidermo-tropt(- mueinous eareinoma. I'll^roepitheliomatous Paget jjlie-notiienon.J Gutan Patliol 1<.)<)2: 19: 134-141.

Mark A. Hurt,^ Sverrir Hardarson,^Miguel J. Stadeeker,^Daniel J. Santa Cruz,^Departments ot Pathology, 'University of TexasHealth Science Center and Audie L. MurphyVeterans Memorial Hospital, San Antonio,Tutts University - New England MedicaiCenter, Boston, -'Division ot CutaneousPathology, St. John's Mercy IVIedicai Center,St. Louis, Missouri. USA.

Mark A. Hurt, Cutaneous Pathology, St. John'sMercy Medical Center, 615 South New BallasRoad, St. Louis, MO 63141-8221, USA.

Accepted May 7, 1991

In 19,53, Pinkus (1) described an epilhelial-stromal,basaloid, relieular ttimor ihat was loeated primarilyon the trunk. He noted lhe resemblance of the tumorto inlracanalicular llbroadenoma of the breast, butbecause the eutaneous tumors lacked a chiclal com-ponent, he regarded them as morpholofrieal variantsof basal (ell carcinoma ("epithelioma" in his termi-nology). "Fibroepithelial tttniot-'' was the term he(hose to represent the spe(-trum of these lesions.

Ivxlramatiimary Paget's disease is a eoncept thathas evolved simultaneously with mammary Paget'sdisease. It refers to a type ol tnaligtiatil tttmor, usu-ally found in tlie anogenital region, composed ofrandotTtly distributed individual eells, clusteredcells, or both, existing within the epidermis. These(-(•Us exhibit phetiotypie attributes of adeiKxarci-

R c a d itt p a r t at i h c m c e l i i i H d r t h c A t t i c t i ( - an .Society o F D c r t t t a t o -

pathology, November 2!). I99t), iu .AtlalU.i, (Jeorgia.

tioma and may or may nol he associated with asweat gland ot- viseeral eareinoma. Many atithoishave ollered opinions to explain the microseopic(mdings responsible lot- lhe elinical ehanges of stis-pected (muco) eutaneous Paget's disease of any type(trtamtnary or extramammary). In retrospeet, how-ever, unrelated lesions such as superficial basal cellcarcinoma (2), malignant melanoma (3), and spon-giotic dermatitides (4) were |)reviotisly diagnosed assueh. The origin (jl the tiioclern concept of the micro-scopic changes Paget's disease ofany type, as well asits i^roper clitii(-()]:)alh(jl(jgieal contexl, began withJacobaeus in 1904 (,5). However, il was through theitiOuence of authors sueh as Sekiguehi (6), Muir (7),Pautrier et al. (8), Weiner (9), and finally, Pinkusand Gould (10), that the clinical and histologiealchanges, as we know them today, were objectivelydepicted. Pinkus and Gould proposed a special des-ignation lor the histologieal finding ol lhe epidermaladenocareiuoma cells. They termed ll the Pai^fl pite-

134

Fibroepitheliomatous Paget phenomenon

t'i:;. I. (,'tt.u' I. T h e s e t h r e e s e ( - t i o n s o l t l u ' i ; r o s s w e r e a d j a e e n t .

I ' h e w h i t e a r e a s o f e p i d e r m i s ( h i s ^ l i l i n h u - d l i \ a r r o w s ) e o i i c -

s p o i i d t o t h e l i b r o e p i l l i e l i o n i a t o i i s a r e a s . .A s i i i n l e i m K i i i l a k ( -

( a r r o w l i e a d ) i s p i c s e n t i n t h e l o w e s t s e e t i o n .

ttottteitoit. T h i s w a s d o t t e t o ( h s l u i g t t i s h t l a s a t u t ( - t - ( ) -

scopie |X'r(-eptual a t t r ibu te , eomj^at-ed wtth the en-tire e(3uce|:>tual elinicopathologtcal eonlext ol lhebreast , anogeni la l , or visceral tttmors with whieh itmight be assoeiated tn atiy itidix-tdtial case (10).

Mu(-inou.s eare inoma, ocetn-ring as a primai-y eu-taneous maligtiaticy, was lirst deserilK-d hy Letmox,P(-arse, and Ri(-hards in l!) ,^ ( I I ) . Ol the (-utaneousg landula r adne.xal earc inomas , il is usttall) loealedon the head or neck region (12), |)artietilarly theeyelid (13). Additiottally, h is one of the mot-e com-mon mot-|)li()logi(-al ly|)es ol sweat glatul eai-(-inottta

and, geiierally, is assoeiated wtth a good jj iognosis.Al though n-itieinotis eatt-inomas of the anogetiilalregion luu'e l)een illnstrated in the l i terature, manyliaxe dilHered Irom mueinous (a te i t iomas of otherregions. Speeilieall)-, several of the anogeni ta l easeshave been assoeiated wilh the Paget | )henomenon(14—2()) how'ex'er, sueh ehatiges ha\'e tie\-ei- beetidescribed in extraper ineal mueinous eare inoma.

In this jjaper, we shall detail in tw-o pat ients theititersection ot these three nioi-|)hologi(-al i tmior |)at-lerns, i.e. mneinotis eat-eitiotna, the Pagel ])hetiotn-enon, and l ibroepithel ioma. In addi t ion, w-e alsodisetiss these nndings in relalioti to two similat-, btunot identieal , cases previousi) ' deseribed m the liter-a ture . Finally, we oiler a theory to ex|)laiii theni(ii-ph()l()gi(-al (-hanges attd pt-o|)ose lustologi(-al and(-liiiic-opathologieal (otteepts that will ser\-e to tmitethe findings iu the anti(-ipali()n of the diseovery ofnew eases.

Clinical histories

Patieni 1 was a t)7-yeai--old Hisjianie man who yivc-setited al the Att(he L. Mur|:)h\- Memot ia l X'eteratisAdmtnis t ta l ton Hospitai with <i t i-monlh history olan extt(lati\-e, erythemalot ts , inoisl, |)ei-ianal lesionthat exletided onlo lhe |:)ei-ttiettm atul had t-e(-enll\developed ei-(isions and nodules. I he lesion w as sttr-gt(-ally exeised, aflet- se\'et-al separa te j)t-o(-edures,with uegatixe margins, eonlinned by IVcr/en seetion.A .syslemie wotk-up , iti otclet- lo |jttt-stte a possible\-iseet-al ( a i e inoma , was negati\-e. 1 he palietil re-inaitis w(41 2 1/2 years alter hts tttmor was i-emo\-ed.

Patient 2 w^as a 73-yeai--old white womau whoIMcseuled in Ttifts UniversitN- - r\'e\s- lMiglatul Med-ical ( lenter with a liistot-) ol a (-i-ustecl, xat iegated,petitieal |:)laqtie that had beett presetil lot- sexetalmonths . It was surgieally rerno\-ed, and a systemiewdtk-tt]) was negalixe. She has t-etnained diseasefree lot- 1 1/2 vears.

/•'/!;. 2 . C a s e / . T h i s s c a t t i i i i i i ; \ i c - w s e l e i - t i \ - e l \ h i i ; h l i i ; l i t s t h e m u e i n o u s ( a r e i u o i u a l a k e , i i i u i l i o f w h i e h w a s l o s t i n p t - o ( - ( - s s i i i < ; . O n t h e

t t i ^ h t , s e \ - e r a l h \ p e r p l a s l l e l i h r o e p i t h e l i o m a t o t i s l o e i . e o e x i s t i i i L ; w i t h t h e P , i i ; c t p h e n o m e n o n , a r e a p p a r e i i t .

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Hurt et al.

l'ig. 3. Case /. I his seaiinitig view highlights the extensive (ibroepitheliomatous changes. The Paget plieiiomeiiou eoexists within the(Mitite epidermis, but eannot be visualized at this power.

Material and methods

In both eases, routine hematoxylin & eosinstains were obtained on 10% neutral-bulfered, for-malin-fixed tissues. Speeial hist(jchemical stains oncase I included periodic acid-Schilf (PAS) — aleianblue (pH 2..5 and 1.0), and PAS with and withouthyalurouidase. Immunoperoxidase slains on botlicases ineluded carcinoembryonie anligen (CEA,l:.')t) monoclonal, ZYMED).

Speeimens from Case 1 were laken from formalin-lixed tissue and proeessed for electron microscopy in0.1 M phosphate bufTer, \°k^ osmium tetroxide, em-bedded in epon, then sectioned and |)hotograi:)hedwith a J E O E 100 CX eleetron microscope.

Pathology

dross — The exeision Irom Case I measttred14 X 7.5 X 1 em within whieh was a 10 X 5 X f).b cmirregular, variegated placitie. In multiple adjaeentsections, there was a broad zone of epidermal hy-

perplasia (l'ig. 1, arrows) that giadttally tapered toepidermis of normal thiekness. In one seetion (l'ig.1, arrowhead), there was a mucin lake. The excisionfrom Case 2 had similar features, bul the lesion wasmore extensive, measuring- 7 X 7 x 1 em, with aprominent nodular sitrfaee and obvious tntt(-tu lakeson eut section.

Linht ttiicroscopy ~ Eow-|3ower views of the seetionsform Case 1 revealed that the hyjierplaslic areaseorresp(jnded to fibroepitheliomatous ehanges,whereas the n-ttuin lake was a small mucinotis carci-noma (Fig. 2), Itidividual and aggregates of adeno-careinoma eells were found within the nitiein |:)ool.A few aggregates had an aeinar conligutatiou. Cyt-ologieally, the typical tumor eell contained abtm-dant eyto]:)lasm with large muein va(-uoles, althoughsome were euijoidai and devoid ol obvious muem. Asection adjaeenl to lhe mueitious lake was charae-terized ain-tost exelusively by libroei)itheli(3matouschanges (I'ig. 3). In these areas, the lesion wasreticular, extending into the superluial relieular

l ' i g . 'I. Ca.se 2 . S c a n t i i t i e ; m a g t i t l t t a l i o u o l l h e l a t - g c ( a p p r o x i m a t e l y 2 ( - i n ) i i i i i ( - i n o t i s ( a r i - i n o m a . N o l e t h a t l l u ' t c i s t t o p a n ( - t ( ) i ( l s p t c a di i U o t h e e p i d e r m i s i n t h i s l i e l d .

136

Fihroepitheliomatous Paget phenomenon

't r '

Fig. ."). Case 'J. . A p p r o x i m a t e l y 2 c t u a w a y Troni t h e t u m o r | i r o p e i - . l i b r o e p i t h e l i o m a t o i i s ( - l i a i iges a s s o c i a t e d w i t h P a g e t ' s p h e i i o t u e i i o i i . i r e

p r e s e n t .

dermis. Cylologieally, il contained basaloid cellswith n-tinin-ial eyto|jlasm and lujinogenous nuelei.The mucinotis carcinoma of Case 2 was similarhistologically, but was approximately twice as largeas that of Case 1 (l''ig. 4). Like Case 1, the fibro-epitheliomatous ehanges of C'ase 2 were separatedfrom the mueinous cat-einoma by 1 to 2 cm (Fig. 5).In the epidermis above the mucinous eareinoma,few Paget (ells were present in either case; however,several millimeters to several (-entimeters distal tothe tumors, the intraepidermal cells of the Pagetphenomenon were observed. Iu several areas ineach case, the Pagel eells coexisted with fibroepithe-liomatous areas and were best visualized with thePAS-alcian blue stain at pH 2.5 (Fig. 6). 'Fhe typicalPaget cell contained abundant amphophilie cyto-plasm with a large muein vacuole and was 3 to 4times the size of an adjacent keratinocyte. Free mu-cin pools were present in the dermis under someareas of the fibroepitheliomatous lesion. Some of thefibroepitheliomalous loci had mesenchymal compo-

nents similar lo hairmal bodies (Fig. 7).

:'rnis or pa|3illai-\ mesenchy-

l staitts - In C'ase 1, the nitiein in the tntteinouseareinoma, as well as in areas of the Pagel phenom-enon, was ]xxsitive for PAS-aleian bltie at j^H 2.5(purple), b(tl negative al pH 1.0 (red) as PAS posi-tivity was present at both pH levels. In certaintumor cells, either PAS (red) or alciau blue (blue)positi\-e muein was ijresent (i^H 2.5). Additionally,the mucin in this lesion was resistant to hyaluroni-dase digestion. In both cases, CEA was present inthe mticinous careiuoma, as well as the Paget plu^-nometion (Eig. 8), either alone or eo(?xisteul wilh ihefibroepitheliomatotis lesion.

Ultrastrticttire - By ultrastructural observation of for-malin-fixed tissue from case 1, one could dilleren-tiate epidermal keratinocytes as well as several largeepithelial cells containing cytoplasmic mucin \-aeu-oles. In some areas, the mucin was diffuse, whereas

F"ig. 6. Case I. This area ofribrocpilhcliomatoii.s (contains numerous individual

Paget cells. PAS-alcian blue,pH 2..5.

i^\\:

137

Hurt et al.

Fio. 7A. Ca.sc I. A (S: H. ' I ' h c i r is

h ; i i r t^crii i s i m i h i n U ' in l l i c s c i w o

foci (ll l l i c I i l ) i ' ( K ' p i t l u ' l i i ) i n ; i t o u s

c o n i p o i u ' t i l .

itt othei- a tcas , small tnu(-itt aggregates wete presenl(l''ig. 9). The remainder ol th(- (-yto|ilasm contained

few otgatielles, notably dilated tottgh endoplasimc

fir > ^

I f

•., • < l

,.•

/ ' ( [ ; /; C r t K / C a l l m o ( m i l l \ o m i a i i t i g ( i i i s ( \ I I I I M \ < H I t h e

P , i g e t ( c l l s w t t h t t i t i n l l b i o e p i t l K I m i i h i t o i i s i o m p o i i i n l l i o t l i

( ,is< s \s e ! e s i m i l . i l

/'Vi;. i). ('use I. In ihc iow-powcr

iihra.striKl iirai \ lew ol a .siiii^ic

Pagi ' l ccli. t l icrc ;ni ' luimcrdu.s,

c i r cu la r , iiuu in .sphrri 's williiii n

l a i n c i iUraryl( i | ) lasmi( \ iniiciii

iakc. i IK' cell is .siirrouiKJc'd by

kcnUiiuK ytcs .

Fibroepitheliomatous Paget phenomenon

/y

\

Discussion

Historically, Piiiktis and Could, in 19:5!) (10), dc-scriloccl the association of a liasaloid libr(K'])itlu'liallesion with cxtiamammary Pagct's disease of theperianal region. Their patient (their Case ;5), a 57-year-old black man, had a pcriiical lesion assorialrdwith inguinal lymphadcnopathy of 1 year knownduration. Ihis man died soon allcr ihc rha<;iiosiswas established, and a rcclal carcinoma was lound.In the low-power photograph stip])lic(l in the article,there was coexistence ol the Pagct |5hcnomcnon anda reticular basaloid lesion described hy llu- atithorsas "a marked atypical proliferation of the epidermalridges, which formed a comphcalcd ni-iwork" simi-lar to the cases Pinkus later dcsci'ibcd as "picnialig-nant (ibroc|Dithc'lial tnmors of skin"(l).

Warner ct al, in I9H2, were ihc lirsl authors torecognize the (ihrocpithclionia-c.xiranianiniary Pa-

gel's disease association as stich (27). 'fheir jxiticntwas a :59-ycar-()ld man who (lc\clopcd a red,cracked, llaking perineal lesion. Alter a ncgatixcsystemic cx-alnalion, lie was snccessftilly (rcated by aMohs' surgical tcchni(|ui- and was clinically diseaselice lor 4 years. .Additional lbllow-ti|) revealed thatihc ])alicnt died of niclastatic anal carrinonia in1982 (Dr. Thomas F. C.S. Warner, jjcrsonal coni-numication, No\cnihci' 7, 1990).

Our cases arc morjjliolooicalh' similar to the litcr-aluic cases, cx(C|n that both ofonr paticnls had anunderlying mticinous carcinoma itiiassociatcd witli avisceral malignancy, based on (lu- ronlexl of onrknowicdgc at the time of this report. Additional!),the s]5ccial stains for mucins in otn- Clasc 1 arcsimilar to sweat gland nuicins. Based on these data,we conclude that the orioin of ihc Pa^cl |3henoni-enon in our cases was most likely from the res])ectiveanogcnilal nmcinotis carcinomas.

139

Hurt et al.

'1 he common histologic features of our cases andthose from the literature are tlie fibroepithelioma-tous changes and the Paget phenomenon. Of these,the lesion with the poorest statistical prognosis is thePaget phenomenon, as it is often associated withcutaneous or visceral adenocarcincjmas. I hus, as adias^no.siic or clinicoj^athological concept, all tlieknown information, both histological and clinical,must be considered, especially in application of theconcept to an individual case. It is for this reasonthat we, like Pinkus and Gould (10), diflerentiatebetween the hiUological concept of adenocarcinomacells existing individually and in clusters within theepidermis (the Paget phenomenon) and the diai^-no.slic concept of Paget's disease of either type, whichincludes the Paget phenomenon plus any other cuta-neous or visceral adenocarcinoma that may give rise(o, or result from it. Because it is well establishedthat the Paget phenomenon can be an attribute ofextramammary Paget's disease or can occur withoutother disease, a systemic search should be undertak-en to rule out any other cutaneous or visceral malig-nant timior if such knowledge is not already knownat the time of diagnosis.

Regarding the association ol the fibroepithelioma-like changes wilh the Paget phenomenon, there aretwo possiljle mechanisms. First, it could represent acollision tumor. Allhotigh this is possible, both cjfthese tumor types are uncommon and tlieir chanceassociation would seem unlikely, cs])ecially whenthe clinical and pathcjlogical extent of the lesions inour cases is considered.

The scccjiid possibility is that one lesion couldsomehow inlluencc or induce the formation of theother. The nicjst likely possibility would be that thePaget phenomenon would be the inducer of thefibroepithelioma, similar to follicular proliferationsthat have been associated with lesions such as sn-perficial angiomyxomas (trichogenic) (28,29) ordermatofibromas (30,31). In some of the reportedlesions, the basaloid ])roHleratioiis displayed a coin-plex reticular architecture and even produced papil-lary mesenchymal bodies, similar to both c)( ourcases. A i^roposed mechanism in our cases is thatthe basaloid proliferations formed from the mechan-ical barrier of dermal mucin, in contrast with der-matofibromas or the muein ol the triehogenic niyxo-ma.s in the cases from the literature.

From a diflbrent viewpoint, it would seem un-likely that a follicular tumor or even a Ijasal cellcarcinoma could somehow cause an adenocarci-noma tcj form, especially ilOne considers the rarityof extramammary Paget's disease (or, for that mat-ler, any sweat gland carcinoma) compared to theabundance ol basal cell carcinomas or basaloid ha-martomas. The only rca.sonable mechanism in sucha context wottld be that o( niueinous syringcjme-

taplasia in the fibroepithelioma-like areas. Such ob-servations have been reported as isolated lesioiLs(!32), but, to our knowledge, have nevei' been ob-served in fibroe]Mtheliomas.

In conclusion, we projiose that the [v\\n fibroepi-Ikeliomalous Pagel pkertomenoii be used as a concept todenote future cases in whieh there are histologicalfeatures in common with our cases and those previ-ously reported. These features are: individual, c lus-tered, or both patterns of intraepidermal cells olphenotypic adenocarcincjma associated with basal-oid fibroepithelioma-like changes. Based on c tn rentevidence regarding the nature of (nnieo) etitaneousPaget's disease cjf any ty])e, it wotild seem reason-able that these lesions would most likely occur in thejjerineum, but we suspect that it could be ]3ossil)lefor a similar relationship to occur elsewhere, stic h asthe axilla or brea.st. Additionally, we spc-eulate thatit will ultimately be shown that this assot iaiion willhave a natural history .sjjectrtim similar to typicalcases of (muco) etitaneotis Paget's disease of anytype.

Acknowledgements

The authors thank Dr. Thomas Chuprevic, GreenBay, Wisc;onsin, and Dr. TlKjmas F. C. S. Warner,Madison, Wisconsin, for supplying follow-up infoi-mation on their case (27). Phred Petersen, Photo-graphy Supervisor, Photographic Services, Univer-sity of Texas Health Scienc Center, San AntcMiio,assisted with the gross and microscopic photo-graphs. Donna Clarkson, H T (ASCP) assisted withelectron microscopy.

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140

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e e r 1 9 7 9 : 4 4 : 1 7 5 7 . 2 7 .

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r ( - p o i i ol l i m r e-a.se-.s ui w l i i e l i n - r l a n i l ( -a lut(-s of lnstoi ;(-ne-sis

wvvv e 'xlnl) i l (-d. C a n e - r r 1 9 5 2 : 5 : I 1 6 1 . 2fi.

15 . Bo<-ian I J , I n s c h k a ( ) . Pa^c - l ' s d i sease - of t in- a n n s . A m |

S n r g 1 9 5 7 : 9 3 : 1 10. 2 9 .

16 . G r i m e s Ol. K x t r a n i a m n i a r y P a n e l ' s disi-ase-. .Snrge-|-y 1 9 5 9 :

4 5 : 5 6 9 .

17 . G r o d . s k y L . I ' - N l i a n i a n n n a e l r y I ' ane- l ' s elise-ase-of llu- p e r i a n a l 3 0 .

re-g ion . D i s C 'o lon R e - c t u m 1 9 6 0 : 3 : 5 0 2 .

18. I l u t c l u - s o n | B . ( J r o e i o n J B , I ' l iepia W ' N . " l ' , x t r a n i a m m a r y 'M.

Pa.i^e-l s elise-asi-" ol i h c anore-e-Ial j nne -Uon . /Vreh Palhe>l I 9 6 0 :

6 9 : 7 2 8 . 3 2 .

19 . Ye)ell J H . P r u ' ( - \ \ C j . Pai;e- | s elis(-ase-ol l l u - p e - r n u - a l .skui w u h

a.ssoe-iatcd aelene>e'ai-e-uu)ina. .Are-h D e - r n i a l o l I9()0: 8 2 : 98()

2 0 . VVooel W ' S . C n l l i n n C.V:\. Pe- i ia i ia l Pa<;(-l elis(-as(-. A r e h

Pai lu>l 1 9 7 5 : 9 9 : I 12.

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Bibe-rslein H. t ' ibronu- mil at\pise-lu-r cpit lu-Kvuelu-rung.

Arch liir De rm Syph (Berl in) 1931: 164: 69.

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Madise)n J K , C^oeifjcr PI I, Btn geloif W'l IC. Mne-inons sy-

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141