Primitive Neuroectodermal Tumors of the Uterus: A Report of Four Cases

DEAN DAYA, MD, FRCP(C), H. LUKKA, MD, FRCP(C), AND PHILIP B. CLEMENT, MD Four cases of primitive ine corpus

neuroectodermal

are reported,

bringing

tumor (PNET)

the total number

PNETs

in this site to seven. The four women

decade

of life and presented

in two cases, an enlarged subtotal abdominal

postoperative

Gross examination dometrial

were in their seventh vaginal

uterus. The patients

hysterectomy

tomy and, in one patient, received

with abnormal

and bilateral

revealed

therapy,

Histologic,

immunohistochemical, revealed

masses filling

Two

with other

admixed

grade I endometrial endometrial related

stromal

adenocarcinoma sarcoma.

The

to their stage: two patients

with no evidence

the en-

the myometrium.

that exhibited

and medulloepithelial

were

patients or both.

variable degrees differentiation.

neoplasms:

and in the other a low-grade prognosis

of the tumors

with stage I tumor were

of disease at 5 and 6 years, whereas

it has been suggested

from displaced vided

that uterine

germ cells or implanted

by this study, including

and an admixture

PNETs

origin

alive Al-

may be derived pro-

ages of the patients

with neoplasms of unquestioned

suggests a miillerian

was

two patients

fetal tissues, evidence

the advanced

miillerian

origin,

for these tumors in at least some cases.

HUM PATHOL 23:I 120-I 129. Copyright

MATERIALS

AND METHODS

in one case a

with stage III or IV tumor died of tumor at 6 and 12 months. though

tract.‘..’ In the latter site PNETs are most common in the ovary where they are considered to be of germ cell origin.“.” Only three PNETs have been described previously in the uterus, the last in 1987.7,x In this report we describe four additional examples of I’NET of the uterus, most of which created initial problems in differential diagnosis. A number of features of our cases provide insight into the possible histogenesis of these tumors.

and, in two cases, ultrastructural

typical PNETs

of neural, glial, ependymal, PNETs

Three

chemotherapy,

fleshy polypoid

and,

total or

salpingo-oophorec-

cavity and, in two cases, deeply invading

examination

bleeding

underwent

pelvic lymphadenectomy.

radiation

of the uterof reported

8 1992 by W.B. Saunders

Company

neuroectodermal tumor” The term “primitive (PNET) was first coined in 1973 by Hart and Earle’ to denote a group of tumors thought to be derived from fetal neuroectodermal cells and that had morphologic features of small round cell tumors with variable de&Tees of neural, glial, and ependymal differentiation. Despite the controversy that exists concerning the use of this term,’ the designation PNET has gained general acceptance and is included in the most recent World Health Organization Classification of Tumors of the Central Nervous System.” Primitive neuroectodermal tumors have been encountered in a variety of sites outside the central nervous system, including the female genital

The cases wel-e encoun~r~d in the XII-gi,rlc-al pathology files of the Henderson General Division of the H:nnilron Civic Hospitals (cases no. I to 3) and Vancouver General Hospital (case no. 4). Twenty 10 -IL’ slides (average, 32) of specimens from the tunlnrs s&etl with herllatoxylin-rc,sin were avail;tblr for rrview. Immunohistoch~t~i~~~~l slains using tbc p~~~oxid;~se-arltiperoxidase method were perli)rmed on rhe four c;tscs rtsirtgantisrl-a against the following antigens: c~ytokeratin AE,/AE,, (DAKO, Copenhagen, Denmark; diluted I :X), carcinoenhryonic anrigen (DAKO; diluretl 1:25), S-l 00 protrin (DAKO; diluted 1 :%I), vimentilt (I’rogen, Heidelberg. (krntany; tiilured I :30), neuron-specific enolase (NSF,) (DAKO; diluted 1 :-10(J). $ial fibrillary acidic protein (GFAP) (DAKO; diluted l:.‘(J), chrotnogrmin (k&o Diagnostics. New York, NY; diluted I : 1,OOO),and protein gene product 9.5 (PC;P 9.5) (L!lrraclotte l.td, Isle of Wight, LIF;; diluted 1:400).!‘-” Alq)ropriatc positive mcl negative cor~trols were ~1set1in rach cam. Tttr Iumors were staged according to tlw revised International FcdcrarioIl or (;vnecolo~~ and Obstetrics (FI(:O) staging system L’oI-C;IIIc‘el-s;jf the urerine c.c)rptts. Atlditiotial follow-up w;is obt;~inrtl on one of‘ the c’ases prc’viomsly repor~etl in cftr litetxtutx~.x

CASE REPORTS Case No. 1 A (i7-year-old w01na11 pt-esetttetl with ]~ost~li~t~~~l);~~‘“;‘I bleding and an enlaq@ ulc~-us ant1 uldcrwcnc a frac3ional curettage. Following ;i diagnosis of “poorly differ-etttiatecl C;II‘cinotmt,” lapxoltml~ rcw;tlad an I %weeks’-size ~ltt‘~-us willt 1uInot on its sctx~s;d srtrf:tce. l’rlvic and lxttx;tot.tic lyntph;~l~nopathy was ttctretl. hut t1wt.c was no other cvit1enc.e of extl’;tuterine tumor. A subtotal hystercctotny alid I~ilatcral salpingooophoI-ectotny were performed. Pos~o~~er;ltively. llic patient was given a palliarivc c~ourkc 01 pelvic r;dic~tb~r;ipy ;III~ conbination cbetnotberq~~~ (c,isplatin and tlosorubicin). l)ue to ;L

lack of response. she was given intraperitc~tteal cisplatin fotlowed hy carhoplatin and 5-flucmwxil. She died from tumor 6 n~otirhs aftrt- rhe initial tliagnosis.

1120

PRIMITIVE NEUROECTODERMAL

TUMORS

c’~;iiiiin;ilioi~ the uterus was enlai-ged (16 X there were ~iodules up to 1 .L’cm in uiaximuni dimlcter ou its posm‘ior serosal surface. The endornetrial a\it\ wit\ ti.i\torted II? ;I large, pale, edematous, fleshy, pohpaid WISS arising from the furldus and extending to the lower showed titcI.iii(. wg~ii~til. Srctions through the niyonietriutn tl~~l) iii\:i~ioii. ‘Ilie o\~arirs gild Lillopian lubes were unrc(hi

OF THE UTERUS (Daya et al)

ipbs

I r) 3 IL’ cnil

md

I1l.I1klIk

Case No. 2 with lieav\ pos1nieno.\ tiS-yc.~i~-c~l~f w011i;iii prrsrnted fxi~iwl l)lcrtliilg ;und pain in tlie rqicm of Oic%upper Icft tibia. uterus. Following ;I I’c,l\,ic ex;u~lin;~tion rt~vral~d ;II~ enlarged ;111cl cxtrcrtagr on which a diagnosis of “poorly diffkt-riitiatccl cai.< iiioiiia” was ninde, 3 coinputcd totnographic v .iii of’ the ;\t,tlonirii and pelvis revealed a large ukrine ni;lb5 c\lrrrding IO the, r-ight pelvic. sitle wall. A hone scaii revcalctl the whole of tlic lcfr tibia. Pelvic itrc~r~asctl ii~~l;ih~~ in~olbiiig I ;idialic)n \v.L\ ~oiii~nm~~d. t)ut brcause of poor r~~spon5e aiicl a (otal abdominal hyster.ec.toni! iii< rcasingl~ IIC~\\ tkeding. ;ititl t)il;itcr;il sall)irr~:c,-ooplioi.ec.tomy and a right p&c Iymph;~~Ici~~~~ioii~~ wvrc~ performrd. At operation thr ur?i.tis was et)IW~CYI.tntl’a IL’-~1 r-i@ adnexal mass adhrr-rnr to thr pos\V;IS 11oted. There was IIO othrr I(‘~IOI .I\,w, I of ttw ute~~us ~\itl~iic c of illt~-,~l)rl\ic or iritra-;lt)doiliiiral tumor. l’ostoper;iI I\C r;ldialil>ll lo Ilrcz lefi upper lit)ia was give11 for 5yiiiptoniatic i-vlic.1. J‘l~rt:(, ilioulhs aftrrthe ol)er;~tion supi-;I( IaviCulaiI\ tnpti;i~I~n~ q);ilh! appeai-etl. Despite cisplatin thyi-al)>-, the palic,iit tlictl 111 l~i~iioi proqc3zion 1 2 months after lhr initial

tlila~;itio~l

RESULTS Microscopic. exaninatiotl of’ eac.h c‘;~w revealed ;I atttl lijc~lly ;tdtnixed PNET that was pure in two ases with another neoplastn in tticb other lt\o cases (we below). k:ach I’NVET was charac~teri/.cd 1)~) :I pr-otninent I)ritiiitivc ~~otitpoiit7il of densely cellular sheets 0C sniall, iieui.oec.toc-lei.m;~l cells with acatity c.\~toplasiii and h!,~~r~-~~ht~otiiati~~, I-ouiici to owl Iluc~lbi arid oc.casioiial protninc7it nu&2oli; tnilotic figures were t~~tttiero~ts (> 10 tnitotic figures per 10 high-power fields) (Figs I and 2). Iti these

cellular

features axes)

(Fig

4).

forttted

;treas

coluiiitt;tr

trw

rosette-i

(Fig 2), Hotner-LITright and Inedulloepitheli~~l c;lSe

cOllf~Uellce

h.itli

sirnilat-

tit~cle;tt-

cctttral luincti (all pseudot-osetlc’s (tlvo casts) tulntlcs (IWO cases) (Fig

3).

111 OW

cdls bitti

Of‘

thCW

a

~UbUkS

KSUlted

iii

resrnihled 3 iiiedulloepithelioiii~~ (Fig 3,). I tI the same use there WI-~ other ;IIWS in which cells with fihi-illar\ cytoplasniic processt3 were arranged arortntl t)Iood vessels. forming perkascular rost~ttrs of epeittlvinal type (Pig 6). Similar peri\2sc,ikii rocetlrs wc’rc less protiiiii~tir in lwo other c~lses.

atom

that

cli.lg~~o\is. On

gr( 15, c.k,unina(ion

1li~

,G..Yc 111);iiicl q q

um5b

llm1

1, ‘i\ i..’

Illctriuln.

cm

f’:tllopial~

\\‘;I:,

X.5

lSSl\

were

ii1 yt~;ll~.st

c‘iii

l)t”u1~111

tril)e

mateGal.

were

matted

( I5 X 4 X

enlarg:etl

filled

with

3 polypoitl

dimension.

‘fhe

mass

deeply

arid

invaded the myonoted. The right ovar-)

also

together

dinitmsion

The

was was

in Illi1xillllllll

wall

S(~cr;~l Iriomvonlas

xrti

uterus c.avity

II-on1 1hc I)ostrr.iol.

.II OM

“If n

thr

~t~clotneliial

and

let‘1 ovary

to form

contained and

a mass

that

yellow-brown

fallopiail

tube

wew

rlrll-l~l~l;lr~~;lt~l~~.

Case No. 3 pwsrnted with ~~ostiii~iiop~i~ls;il .\ (i!b-\c-,II--I )I(1 boiii;iit t,lcrtliiig. I;c4vic r~x;ur~inalic~ti was unret~iark~ihle. Following ii on ;i dilatation and curettage tli,r::_llo& oi “slit mr;il ~r~m~;~” \pcc

llic

inrvn, ;iiid

lc~nr~

I~CXII jiilv,

\\.,s

p;iliell(

21 ttl

tinderwent

a total

;it)doniiii;il

hysterec

-

pelvic I~nipliadcprl\,ic I adi;lriori. ‘Ike (i-vear- postoperative period

t)il;~lcr;ll

~;~lpiiigc,-oophorectoiii),

ul1(‘\.(‘nlful. ( )II gr, 15, ckiniiii;uion

thv

exteriially

ccbn(;kiricd ;I polvpoid rndoitieti-ial cIII ill ili;aitllum tli~ile~lsion. I‘hcre ilrvii.iliiii

in!abioii.

.\

sniall

urit.eriiai-l\~il,le

fundit

mass

~vas no

iiitr~miur;~l

uterus

1lia1

evident

was

C’ of

I~ioin~on~;~

2.0 myo-

was

al50

l” C%‘IIl.

Case No. 4

( ;I-O\S

rt~\c~;ilctl

\crfl,

t~~amin;~lio~l

of llic

;I tlilf’ilsc4~ thickcried

\\.hi(C

IJot\p\

tt1;rt

‘Iv(‘1.c

~sl~rnally

~iiir-~iil~it.l\;it)l~

eirdon~etriuiii tt5r

than

2.0

uteru\

well ;IS iiiul~iplr (‘iii ill rlxisiniuiii

;I$

FIGURE 1. Primitive neuroectodermal tumor of the uterus. The tumor is polypoid, but focally invades the myornetrium (arrows) (Hematoxylin-eosin stain, magnification ~,:3 )

1121

HUMAN PATHOLOGY

Volume 23, No. 10 (October

1992)

appearance of a complex atypical hyperptasia, whereas in the other case (no. -t) the appearance of the endometrium varied from a complex atypical hyperplasia IO a grade I endometrial ~ldenocarcinoma of usual type. The tatter was focally admixed with the PNET (Fig 1 1). In case no. 3 part of the potypoict tumor noted grossly resembled a low-grade endometriat stromal sarcoma (ESS), being composed of densely cellular sheets of endometrial stromal-type cells with mild nuclear atypicality; the mitotic rate was similar to that of the I’NET cxmponent. A network of small blood vessels was prominent within the ESS. The PNET and ESS, although mostly distinct from each other, were focally admixed. Focal areas of rlecrosis were present in three tumors and in one case there was a prominent inttammatory component that included foamy histiocvtes. In cases no. 1 and 2 the tumor permeated the myc;metrium (Figs 1 and 9) and myometrial lymphatics. reaching the serosa in both cases. In case no. 3 the tumor extended for only several millimeters into the myometrium; in case no. 4 the myonretrium was not involved. In case no. 2 the tumor invaded the cervix and some of the pelvic lymph nodes contained metastatic tumor. The inlnlunohistoc~~emical findings are summarized in Table 1. In~~nunohisto~t~e~~~i~~ll stains showecl posi-

FIGURE 2. Primitive neuroectodermal tumor invading the myometrium. Note the two rosettes with a central lumen (between arrows). (Hematoxylin-eosin stain; magnification x100.)

In each case the densely cellular areas merged with foci exhibiting glial differentiation, with glial-type cells dispersed through a loose fibrillary background (Figs 3. 7, and 8). The gliat cells typically had scanty cytoplasm, but some had moderate amounts of eosinophilic cytoplasm and were reminiscent of gemistocytes. The latter were numerous in one case and were focally arranged in a sheet-like pattern (Fig 9, top) in which numerous intracellular and extracellular eosinophilic hyatine bodies were present. In case no. I! extensive areas of the tumor resembled a fibriltary astrocytoma (Figs 7 and 8), including focally prominent endothelial proliferation. In another case small areas of Lumor consisted of large bizarre cells with pleomorphic, hyper-chrorn~itic: nuclei, some of which were multiple or mulrilohed; the appearance of these foci resembled that of glioblastoma muttiforme (Fig IO). In three cases occasional ganglion or ganglion-like cells were present (Fig 8). Occasional endometrial glands that were inactive (two cases) (Fig 9, top) or atypical (two cases) were SLWrounded and entrapped by the PNET. In the cases with the inactive glands the endometrium elsewhere in the uterus was also inactive in one case, but was not sampled in the other. In one of the cases with entrapped atypical glands the endometrium uninvolved by tumor had the 1122

FIGURE 3. Two Homer-Wright rosettes within a background of glial fibrils. (Hematoxylin-eosin stain; magnification r’400.)

PRIMITIVE NEUROECTODERMAL

TUMORS OF THE UTERUS (Daya et al)

hyperplasia and hyperthecosis ries in one case.

wrrc: pwwnf

in the ova-

DISCUSSION

In this report we have descrihetl firer cases of I’NPT of the uterus. bringing the total nuinkr of reported in this site to seven. The clinicopathPNETs described in Tahlc ologic features of these cases arc surnnlariozd 2. Five of the patient\ were l~ostmenol~;~~~“al while two were aclolescent, rvith an age range of 1L’ to 69 years (mediall. 67 years). All the patients presmted with abin thaw case4 an entarged iiormal vaginal bleeding; uterus or a pelvic miss was palpable on ~saniination. One patient also had bone pain seco~At-y to a tibia1 metastasis. At the tinie of presciitatioii the tumor was confined to the uterine corpus in two GISCS (FICXJ stagt I) and invot\ed the cervix in a third (‘aw (stage IIK). Two cases were stage IIIith~li~rm that. in contrast 10 I’NF,Ts, was ;ISSOciated with ~LI~~OLIS and nlucinous q~ithclium, cartiGM inlplallts wc‘rc found lage, Imne. and a tooth bud. on the peritoneal surfaces of both ovaric~s. The patkrit wxs giLen postoprrative irradiatior~ xnd \as free of dise:ise L’ years later. Hendrickson and &nqxon briefly tc~a~onla with glial refer IO another case of imnlature arose in thr uterus. ” tissue chat apparently Two esmiples of pure uterine glioinas have heeli k’oung et al described such a case in a I Sreporttd. year-old girl bho underwei~t hvstrrcctc)niy for intrat table vaginal Meeding.‘” ‘4 po&xGcl tunlt)r tilled the endometrial cavity and invaded the nl~tmetrium. Microscopic- examination revealed a lowgrade fibrillary astrocvtonm The marked cellularitv. mitotic activity, and the diverse diffrrentiation that c.harat.trrizr PNETr were ahsent The patient was free of disraw during ;I 6-vex-

FIGURE 8. Higher power view of the tumor illustrated in Fig 7. Note the ganglion-like cells (arrows). (Hematoxylin-eosin stain; magnitication ) 250 )

bone, and adipt )se tissur c~lrnitwts., such 3s cartilage, (or. ill one case, refractile fimzign iiiatwial); and ils typical assoc.iatiorr \t ith 3 previtws instr_unKwtal abortioli ;iitl in [II,: distiuctioll of‘ the &ion from a PNET arid >upport tlic. irl~t.rpretation that the glial rissue I-epresenls irnplailte~ t L.et;tl 1‘e11i11;ii11s.“1.‘4.‘xIndeed, it has been suggcsttld lhat at least SOIIIC uTerine Iesions cx)ntaining hetcrotopic tissue (including. in ;I \~arirry of ~M~LIW sonic cast’s, glial tissue) pre\:iously reported as “teratofrtal tissur.“’ (;lial tissue 111;15 “2”m1’x also lihelv represent i? likely capal)le of pcrsisrin, 0 iii the uIcrLis f’tjr years. In 0w 01 A?1 tr.rgrcn’s casts lhe interval twtween the last al~or~ioii and 111~finding 01‘ glial tissw was L’Z vears.“’ In such C’;ISCS. Ilowevcr, it is difficult to esc~lutle t’he posGhilitv of‘ fetal iinplanta~ior~ from a mow rc‘ctwt linrt’c‘tqiiixtl s~~oiitaiiwus abortioii. ” II1c’rinc n~c~plasms other than PNI7Ts that contain

FIGURE 9, Sheets of polygonal cells with moderate amounts of pale (eosinophilic) cytoplasm (top) that was immunoreactive for GFAP (bottom). Note the entrapped endometrial gland. (Top: hematoxylin-eosin stain; magr~ificatiori - 400 Bottom, GFAP stain; magnification q400 )

1125

HUMAN PATHOLOGY

Volume 23, No. IO (October

1992)

literature.“” With respect to glial differentiation in MMMTs, it is noteworthy that Liao and Choi have found a high frequency of GFAP expression in typical uterine MMMTs.“” In their study both carcinomatous and sarcomatous cells were immunoreactive for GFAP in nine of 13 cases. A final tumor in this group is the exceedingly rare “retinal anlage” tumor of the uterus, one example of which has been reported. Schulz described the case of a 69-year-old woman who underwent curettage after 2 years of postmenopausal bleeding.“” The patient was treated with pelvic irradiation, but died of tumor progression 2 months later. At autopsy the endometrial cavity was filled with a pedunculated mass measuring up to 3 cm. Its sectioned surface was predominantly black and similar tumor involved the myometrium and cervix. There was extensive metastatic tumor within the abdomen as well as the pleura. The predominant microscopic pattern was that of irregular acini, glonieruluslike structures and nests and strands formed by large, cuboidal, melanin-laden cells. Other areas of the tumor had the appearance of a typical endometrial adenocarcinema with squamous differentiation, and several small foci of hyaline cartilage also were found.

FIGURE 10. Primitive neuroectodermal tumor with an area resembling glioblastoma. Note the pleomorphic giant cells. (Hematoxylin-eosin stain; magnification X250.)

follow-up interval. In contrast to foci of mature glial tissue, the size of the lesion in this case, its invasion of the myometrium, and a reliably negative coital history indicated that it was a true neoplasm and was unlikely to be of fetal derivation. Although not described in detail, a second case of endometrial glioma encountered by Lao and Choi was associated with metastatic nodules on the uterine serosa.“’ Another group of uterine tumors that may contain neuroectodermal tissues of central nervous system type are malignant miillerian mixed tumors (MMMTs). Gersell et al recently have described the case of an otherwise typical MMMT in a 66-year-old woman that contained a large component of neuroectodernral tissue. including glial and neuronal elements, that was intimately admixed with carcinosarcomatous foci.“’ Cornpared with the curettage specimen, the neuroectodermal component was more prominent in the uterus that was resected after radiation therapy. The patient died of tumor progression 2 years after the initial diagnosis. In addition to this case, Young et al briefly refer to a 61-year-old patient with a uterine MMMT that exhibited glial differentiation and cite another possible example of such a tumor in a 5%year-old woman reported 70 years ago in the German 1126

FIGURE 11. Primitive neuroectodermal tumor (between arrows) admixed with grade I endometrial adenocarcinoma. (Hematoxylin-eosin stain; magnification r250.)

PRIMITIVE NEUROECTODERMAL

TABLE

1.

lmmunohistochemical

TUMORS

OF THE UTERUS (Daya et a0

Results of Primitive Neuroectodermal

Tumors of the Uterus

:\~llilwll\

( .Lh,’ cc,.

(‘\ l~k~!~;111*1 .\F,,.,Ak..,

__. ___~

__

:Iltlio~rgh

.~_

USE:

S-100

thq~ would tiot be ;i serious

\~i,,,c,,tin

clifferential

~tc’r~ous ,iVstenl) h;rw also heen These rtlrrine corpses or cwvix.

cww_tntered in the include examples of I)““;tS;tt’gliorn;1 of typical and melanotic types.“‘.“” “pigtnentcd myomalous nettrocristoma,““” gatiglioneuand malignant sCh~,anli(~tlta.4’-~‘~ 1‘0111a.“I and benign The ~difkren~ ial diagnosis of PNE:Ts includes other lltrrittc tttmors characterized by a population of small inaligt~anl cells. Rare endotnctrial carcinonias resernhle iindif‘erctitiated small cell carcinoma of thr’ lung, in-

for chromogranin and NSE on ultrastructural exaniina1iota. “-“’ ‘l‘h~ Itttnors may hc adtnixecl with squamous or an MMMT,“’ hut the neu( ell or atieiioc~~trcii~ottia’J I otwodcr-ma1 differenriation of PNETs is absent. Lllerine sarc‘onias c~otnposcd Of small cells (such as ES!%) and arid

ilrtttllrtnc,re;t~ti~,it~

deti~-core

granules

TABLE 2. .JKY ( :J\(. NC,

(\1l

Clinicopathologic

1’1~3rl~rir~g I~t~;i,urtY

FI(;O Stage

Features of Primitive Neuroectodermal Initial

l’(:I’

!I.!!

(:I,, ~m,og,~;,,,i,,

malignant lytnphotna and leukemia irtw~l~ing the uterus also entrr rhe differential diagnosis, hut their histologic and intntttnohistoc.hc-tnical featut-c4 ditttir sufficientI\ from those of PNETs to twtder diagnc ISIic ( onfusion with the Iat tct- rtnlikelv. ‘l‘he hislogenesis bf uterine I’NlXs and ol her utt’rine lumors containing tissues of. cmtral iict’votts system tvpe is speculative. Sortie ma) represent iicoplasms arising from glial and other neut.oec(oderttt;tl tissues of fetal origin. Other 1utttors, such as the itirniat tire teratomas rioted ahose, are likely of gem cell origin. ~~xtragonadal trratomas h;tve twen descril)ecl in ntan)- cliffevent sites, so it is 1101 unrcasonal~le lo postttlatc tlW sU( h tutnot occasiotiall~ at-isc in the uterus. Siniilatlv, stsveral esatnples of volk sac tlltnor, attother 1utnor of qmi c,ell origin, also have twm encoitnterecl iti thtx iltm~s.‘i Get-nl cell tumors in extt-agonadal sites arc I)elicvvtl to origitta(t front germ ~~11s that have been tnisplact~tl 01 al-twted in their mit~ryotiic~ tnigratic~n.

tliagttostic c.ottsidrration in cases of uterine I’NETs, it 4~)11ld IX rctnenltwred that ;I variety of tumors generaIl) consiclerttl to ark from the neural crest (or peripheral

t luding

CiP:21’

(;,-I ,\\ :\l>l”‘;l,xw

Iklgnosi~

Tumors of the Uterus --_--.-._ ~-__ I‘w:\lnwlt

Follw-111,

l’dvpoid twdomrt rial ,,,.,ss with ,,~;ms,,,u, ;,I invadon Katlit~,hrr;,~~v, RSO

l‘;\H.

Yk.1). I) ??FIl.

1127

\‘l’

.5 \,

HUMAN PATHOLOGY

Volume 23, No. 10 (October

There is also cogent evidence that at least SOIW uterine tumors with neuroectodermal differentiation are of miillerian (mesodermal) origin, thereby representing, as suggested by Young et al, a form of “neometaplaof five of the sevm uterine sia. “X The occurrence PNETs in postmenopausal women, four of whom were in their seventh decade of life, suggests that a fetal or germ cell origin for these tunlors is unlikely. A miillerian origin is also suggested by the admixture of PNETs in two cases with tumors of knows miillerian origin (an endometrial adenocarcinoma and an EM), as well as by the occurrence of neuroectodermal cliffercntiation in occasional cases of MMMTs. The high frequency of GFAP immunoreactivity in otherwise typical MMMTs, as noted above, is also consistent with this interpretation. Immunohistochemically, PNETs stain positively for NSE, S-l 00, GFAP, vimentin, and neurofilaments.“~” Although the intensity and amount of tissue reaction vary from case to case, positivity of the above antigens is present in virtually every case. Positive staining foI GFAP can be “very uncommon “‘I’ to almost 80%‘” and is a function of differentiation of the glial elements. In two of our cases there was very focal positivity. whereas more diffusely positive staining was noted in the other two cases. Recently, Harris et al have demonstrated that PGP 9.5 is a reliable marker for PNET.!’ Sixteen of their 21 cases were immunoreactive for this antigen, strongly so in 12. Protein gene product 9.5 is a soluble protein originally detected in human brain extracts, the number 9.5 relating to the position of the polypeptide in gel electrophoresis.“’ The antigen is expressed by the neurons of the central nervous system as well as by peripheral neurons and neuroendocrine cells. The distribution of PGP 9.5 is very similar to that of NSE. The usefulness of the latter antibody in the assessment of neuroendocrine tumors has been described by Rode et al.” Because NSE and S-l 00 have been criticized often as being nonspecific, PGP 9.5 appears to be a useful addition to the panel of antibodies used in studying tumors of neuronal differentiation. It is important to note that PGP 9.5 was strongly positive in all our cases, and the degree and extent of immunoreactivity exceeded those of NSE and s-100. The ultrastructural features of PNET and related tumors are well documented.“‘-“” Briefly, these tumors exhibit distinctive broad cytoplasmic processes with groups of electron-dense granules, and in the interstices there are basal lamina-like deposits and Luse bodies. Intercellular junctions often are poorly formed and infrequent. Neuronal development usually is manifested by cytoplasmic accumulation of organelles, particularly stacks of rough endoplasmic reticulum. Microtubules and synaptic vesicles also may be seen. Astroglial differentiation is evidenced by striking cytoplasmic accumulations of bundles of 80- to 1 OO-mn microfilaments. Clearly, the ultrastructural features in any given tumor are often a function of tumor differentiation and sampling procedures. Our case no. 1 showed some of the features mentioned above. The material in case no. 2 was not optimally fixed, but some glial filaments were noted. 1128

1992)

It is difficult to make any treatment recommendations based on the small number of cases of uterine PNET. Obviousl?, the best chance of curative therapy depends on surgical extirpation of the tumor. Thr typically aggressive behavior of these tumors suggests that appropriate staging procedures be performed at the time of hysterectomy. inc,lucling peritoneal washings, omentectomy, and evaluation of retroperitoneal lymph nodes. Radiation therapy and chemotherapy were tried unsuccessfully in four of the five cases with high-stage disease. Chemotherap\i may play a role, however, as suggested b\, the patient described bv Rose et al who had metastaiic tumor in 10 of 13 pel;ic lymph nodes.” Postoperatively. this patient was treated with a c.ombination of vincristine, cisplatin, daunorubicin, dactinomycin, cyclophosl~hamide, and VP-l 6. and was alive with no evidence of tumor 5.5 years postoperativelv. In summary, PNETs ‘occur rarely in the uterus, where they appear to have a predilection for the corpus. Although most such tumors are pure PNETs. an admixture with neoplasms of unquestionable miillerian origin in occasional cases, as well as other ohservations noted above, suggests a miillerian (mesodermal) derivation for at least some of these tumors. Awareness of the occurrence of PNETs in the uterus and their typical histologic features should facilitate their distinction from other uterine tumors that may differ in their behavior and treatment. AckrtowlmIpr/d. The authors thar~k Dr Amyn R(!jiarti, Division of Neltropatliolo~~, Vancouver General Hospital, Vancouver. Cam&, for his helpful c‘onmwnts mtl review of histologic slides from the foul- cases in this study and Dr Robert V. O’Toole, The Ohio State I_Tniversity Hospital, Colun~bus, OH, for supplying additiorlal follow-up on a previously IXported case of uterine PNET.’ Dr Robert H. Young pl-c,\&ti helpful conments on the manuscript. The authors xc also grateful to~joan Haltlen for her excellent sec.retarial help.

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PRIMITIVE

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(Daya et al)