J Clin Pathol 1992;45:235-240

Fibroepithelial polyps of the vagina: Are they oldgranulation tissue polyps?

T B Halvorsen, E Johannesen

AbstractAims: To study the nature of fibroepi-thelial polyps of the vagina.Methods: Sixty five fibroepithelial polypsof the vagina and 64 granulation tissuepolyps diagnosed over 15 years were revi-ewed histologically.Results: Cytologically benign multinu-cleated stromal cells were present in largenumbers in 19 of the fibroepithelialpolyps of the vagina (FEPV). Only onepolyp contained atypical stromal cells, ahigh mitotic count, and abnormalmitoses and was indistinguishable from amalignant tumour. Immunostainingshowed the presence ofvimentin and des-min positive mono- and multinucleatedstromal cells in FEPV and occasionaloestrogen receptor positive nuclei. Des-min positive cells could not be shown ingranulation tissue polyps.Conclusions: FEPV are common lesionswith benign mono- and multinucleatedfibroblastic stromal cells in which myoiddifferentiation is often present. FEPVmay develop as a result of a granulationtissue reaction after some local injury ofthe vaginal mucosa. Hormonal factorsmay modulate the growth of FEPVs.Delayed differentiation of myofibroblas-tic cells may explain why granulationtissue sometimes does not contractproperly but turns into polyps.

Department ofPathology, TrondheimUniversity Hospital,N-7006 Trondheim,NorwayT B HalvorsenE JohannesenCorrespondence to:T B HalvorsenAccepted for publication5 September 1991

Fibroepithelial polyps of the vagina (FEPV)are mucosal polypoid lesions with a connectivetissue core covered by a benign squamousepithelium. They are thought to be rare.`3FEPV have attracted special interest during thepast decades because ofthe presence of atypicalcells and abnormal mitoses in some of them.2'Because of a striking histological similarity tosome highly malignant vaginal tumours, suchFEPV have been classified as "pseudosar-comas" and "pseudosarcoma botryoides".2The danger of misdiagnosing such lesions as

frankly malignant has been emphasised bymany authors, but ever since the first detaileddescription ofFEPV with atypical stromal cellsby Norris and Taylor in 19664 the benignnature ofthe lesions has repeatedly been confir-med.'2 Despite thorough light microscopicstudies with conventional staining techniquesand electron microscopic and immunohisto-chemical studies,'1'2 the pathogenesis ofFEPVand the true nature oftheir stromal cells remainuncertain. As it has been our impression that

FEPV are neither rare nor do they usuallyrepresent serious diagnostic problems withrespect to malignant lesions, we decided toreview all the vaginal polypoid tumours re-cently diagnosed in our department, payingspecial attention to FEPV and their relation togranulation tissue polyps.

MethodsHistological material from all polypoid primaryvaginal lesions diagnosed between 1976 and1990 was retrieved from the files at the Depart-ment of Pathology, Trondheim UniversityHospital, a general regional hospital with 1000beds. During the study period our departmentreceived from 15000 (in 1976) to 23000 (in1990) biopsy specimens, one third of whichcame from our hospital and the rest from otherhospitals and medical practitioners in the mid-Norway region.

Clinical data and macroscopic details wereobtained from the surgical pathology reports.Follow up data on a pregnant woman with anatypical polyp were obtained from her gyn-aecologist.

CONVENTIONAL LIGHT MICROSCOPYThe original sections were re-examined by oneof us (TBH). They had been cut at 5 gmthickness from formalin fixed and paraffin waxembedded biopsy specimens and were stainedwith haematoxylin and eosin and saffron(HES). The review yielded 149 lesions. Sixcondylomas, six leiomyomas, four epithelialcysts, three haemangiomas and one benignfibrous histiocytoma were excluded from thisstudy. The remaining 129 polyps were classi-fied on the basis of the predominant stromalcomponent. Polyps comprising mostly gran-ulation tissue were classified as granulationtissue polyps. The others were classified asFEPV and subdivided into four histologicaltypes: collagenous (fig 1); myxoid (fig 2); mixed(when substantial proportions ofmore than onestroma type were present); and atypical (whencontaining cytological features that were indis-tinguishable from those of malignant cells).The number of multinucleated cells, mast

cells, and mitoses were assessed semiquan-titatively: 0/ + = none or sparse, and + + =many. The overall cellularity was estimated asrelative to that of the normal vaginal mucosa:low/normal and high.

IMMUNOHISTOCHEMISTRYFive cases of collagenous, myxoid, and mixedFEPV, and five granulation tissue polyps were

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Figure 1 The stromal component in a collagiseen (left). Note multinucleated cells with ove(arrowheads) (HES).

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Figure 2 The stromal component in a myxoistromal cells in a loosely textured connective

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Figure 3 A myxoid area (lower half) in a g

enous FEPV.erlapping nuc

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randomly selected for immunohistochemicalexamination together with one atypical polyp.

*<ovt 8 ; Sections 5 gm thick were cut from storediZ°\;:}i w paraffin wax blocks. Dewaxed sections wereXj -fiN <immunostained using an indirect peroxidase-

*\';:! anti-peroxidase (PAP) method'3 with minor4,,¢* :@c modifications for detection of ca-1-antitrypsin

*.;;N< ..:S. '(AAT), myoglobin, muramidase (lysozyme)and oestrogen receptor; an avidin-biotin perox-

MM. idase complex (ABC) method" was applied for4ii, immunostaining with antibodies against

0- vimentin and desmin using the Vectastain kit

... ....(Vector Laboratories, Burlingame, California,

is;4:;5 USA). The following antibodies were used:monoclonal mouse anti-vimentin (batch 036,

A4+ b >$ dilution 1 in 100, Dakopatts Ltd, Denmark);monoclonal mouse anti-desmin (batch 076,dilution 1 in 100, Dakopatts Ltd, Denmark);monoclonal rat anti-oestrogen receptor (batch48374 M300, dilution 1 in 1 from a separate kit

° provided by Abott Laboratories, Northi. -* * Chicago, Illinois); polyclonal rabbit anti-AAT

Several blood vessels are (batch 0298, dilution 1 in 100, Dako Immun-lei and sparse cytoplasm oglobulin Ltd, Denmark); polyclonal rabbit

anti-myoglobin (batch 044-P, dilution 1 in 200,\3 ( * g Dako Corporation, Santa Barbara, California,

* '; . .. F ft,USA); and polyclonal rabbit anti-muramidase* f ' b q >(lysozyme) (batch 034, dilution 1 in 50, Dako

Immunoglobulin Ltd, Denmark). Positivef ; !controls were sectioned from archival blocks

with biopsy specimens of known histology..°. The immunohistochemical staining of the

stromal cells was scored as follows: 0 = no* ; sjj staining, + = positive staining.

A...

Pi^^ j, t h o_ . t ... Results'.IS;.: @ - FEPV and granulation tissue polyps were

equally common in this series: there were 30E9;1. 'i:Nw {f<> collagenous FEPV, 19 myxoid FEPV, 15

. t f'.;'mixedFEPV, one atypical FEPV, and 64granulation tissue polyps. Altogether, 12polyps contained small areas with a stromal

O.-0 m>i $ # component that differed from the predominat-ing one. Numerous young blood vessels and

*4.' occasional inflammatory infiltrates were com-mon findings in FEPV. Some granulation tis-

id FEPV, with spindle and stellate sue polyps contained myxoid areas mimicking*issue matrix (HES). the myxoid stroma of FEPV (fig 3).

The mean age of the patients was 46-5 (SEM1-6) years (range 4 to 85 years). Patients withgranulation tissue polyps and FEPV had

-N ;O .> similar mean ages and ranges.One hundred and seven (83%) of the polyps

were discovered incidentally during vaginalexamination; 16 polyps (10 granulation tissuepolyps and six FEPV) had caused a bloodydischarge, and six polyps (four granulation

A, tissue polyps and two FEPV) had been felt as aW, 4 * * > mass or had caused some local discomfort.

a> . Information on a recent gynaecological opera-tion involving the vaginal mucosa, or a recent

.,,S delivery was available in 48 of 64 (75%) gran-*,*t * 4 w ulation tissue polyps compared with 11 of 65

(17%) FEPV.-* & < < The vaginal vault was stated as the site of

origin in 31 granulation tissue polyps and threefo

1.0 mm * FEPV, whereas 14 granulation tissue polyps_____________, -- and 31 FEPV had been removed from the

anterior, posterior, or lateral wall of the vagina.In 19 granulation tissue polyps and 31 FEPV

granulation tissue polyp (HES). the site of origin was not stated.

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Vaginal polyps

Table 1 Histologicalfindings in stroma of 129 vaginal polyps

Histologicalfeatures

AtypicalMast cells Multinucleated cells Cellularity Mitoses cells present

Low!Polyp type 0/+* + +* 0/+ + + Medium High 0/+ + + YesINo

Granulation tissue polyps (n = 64) 61 3 55 9 7 57 64 0 NoFibroepithelial polyps: (n = 65)

Collageneous (n= 30) 25 5 20 10 29 1 30 0 NoMyxoid (n= 19) 7 12 14 5 19 0 19 0 NoMixed (n= 15) 5 10 12 3 14 1 15 0 NoAtypical (n = 1) 1 1 1 1 Yes

All 99 30 101 28 69 60 128 1

*0/ + none or sparse.+ + many.

The diameters of the polyps ranged from 0 2cm-3 5 cm (mean (SEM) 0 9 (0 06) cm). Themean (SEM) diameters of the various polyptypes were as follows: granulation tissue polyps0 7 (0 1) cm; collagenous FEPV 1-0 (01) cm;myxoid FEPV 1 4 (0 2) cm; mixed FEPVs 1 1(0 1) cm. One atypical polyp had a diameter of0-9 cm. Twenty four of 65 (37%) FEPV weregreater than 1 cm compared with 19 of 64(14%) granulation tissue polyps. The largestpolyp was a myxoid FEPV.

Multinucleated giant cells of foreign bodytype were observed in nine of 64 granulationtissue polyps (table 1). Giant cells with anappearance more akin to Langhans' cells werecommonly found in FEPV, and were observedin relatively large numbers in five of 19 myxoidFEPV (fig 4). In collagenous FEPV the giantcell nuclei overlapped conspicuously, and thecytoplasm was relatively sparse (fig 1). Thecells, although multinucleated, had the regularappearance of their nuclei, and were not con-sidered atypical. They were found with aboutequal frequency in the various age groups (datanot shown).

Mitoses were absent in most FEPV, but wereobserved in moderate numbers among fibro-blasts and endothelial cells in granulation tissuepolyps. Collagenous FEPV exhibited acellularity similar to that of normal vaginalmucosa; myxoid polyps were mostly lesscellular. A conspicuous number of mast cellswere found in 27 of 65 (43%) FEPV and inthree of 64 (5%) granulation tissue polyps

(table 1). They were most numerous in some ofthe myxoid FEPV. There was no "cambiumlayer" in the subepithelial zone in any of thepolyps, and no cytoplasmatic cross-striationwas observed in the stromal cells.One of the polyps contained clearly atypical

stromal cells with enlarged, bizarre, hyper-chromatic, and occasional multiple nuclei, anda large number of mitoses, some of which hadabnormal mitotic figures (figs 5A and B). Thecellularity was varied but generally increasedcompared with the rest of the FEPV. Thispolyp had been excised from a grape-like massin the vaginal fomix of a 20 year old primiparaat 28 weeks of an uncomplicated pregnancy.She had a normal delivery at term. A few dayslater a partly necrotic polyp presented in theentrance to the vagina. Outside necrotic areas,the histological picture was similar to that ofthe former polyp. Clinical checkups during thefollowing year showed no local recurrences andno metastases or any other signs of malignantdisease.Table 2 shows the immunohistochemical

findings in the randomly selected polyps. Des-min positive mono- and multinucleatedstromal cells were found exclusively in myxoidand mixed FEPV (fig 6). Vascular endotheliumwas stained with varying intensity for vimentinin all polyps. All granulation tissue polyps alsocontained scattered vimentin positive stromalcells, and most FEPV contained numerousstromal cells with intense cytoplasmic stainingfor vimentin. Positive nuclear staining for

Table 2 Immunohistochemicalfindings in 21 selected vaginal polyps

Staining reaction*

Desmin Vimentin Myoglobin AA Tt MAuramidase ERtstaining staining staining staining staining staining

Polyp type 0 + 0 + 0 + 0 + 0 + 0 +

Granulationpolyps (n = 5) 5 0 0 5 5 0 3 2 5 0 5 0Fibroepithelial polyps:

Collageneous (n= 5) 5 0 1 4 5 0 5 0 5 0 2 3Myxoid (n= 5) 0 5 0 5 5 0 3 2 3 2 0 5Mixed (n= 5) 2 3 2 3 5 0 2 3 3 2 3 2Atypical (n = 1) 1 - - 1 1 - 1 - 1 - I

*0

t =

I

= no staining.= positive staining.x-l-antitrypsin.oestrogen receptor.

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-+,> oestrogen receptor was observed in mono- andmultinucleated stromal cells in 10 of 15 FEPV.A few scattered cells in some of the polypsstained positively for oa-1-antitrypsin andmuramidase. Myoglobin positive cells were notobserved in any of the polyps.

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Figure 4 Characteristic multinucleated stromal cells of a myxoid FEPV. Note theabundant cytoplasm and the regular outline of the nuclei (HES).

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&~~~~~~~~~~~~~~~~~~~~Na-.'.tt~~~~; s;t v.*.:s,,.vJ ;. ^ * * t a .: 4 9v -8

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Figure 5 Histologicalfeatures of an atypical vaginal polyp with bizarre,hyperchromatic, and occasional multinucleated cells (A), and atypical mitoses (B)(HES).

DiscussionThis study has shown that FEPV are commonbenign lesions. They demonstrate a consider-

< able spectrum of histological appearances asalso emphasised by Mucitelli et al.'2 FEPV andgranulation tissue polyps occurred with aboutequal frequency in this series and shared somecytological, histological, and immunohisto-chemical features. The picture of FEPV hasbeen compared with that of nodular fasciitis,4self-limiting overgrowths of connective tissue,8and FEPV have been considered to be hyper-plasias of the subepithelial myxoid zone of thenormal vaginal mucosa.'5 Others have sugges-ted that FEVP with atypical stromal cellsshould be regarded as benign counterparts tosarcoma botryoides,7 hamartomas,l or

16 myofibroblastomas." Mucitelli et al providedevidence that stromal cells ofFEPV are collec-tions of functional fibroblasts that may becapable ofdifferentiating along two or more celllines.'2 Cells with an appearance consistentwith a fibroblastic and myofibroblastic originwere observed in most of the FEVP that were

' selected for immunohistochemical examination.*, in the present series. The presence of.t myofibroblasts and mast cells in FEPV may

reflect that FEPV originate from an exuberantgranulation tissue reaction following some localinjury to the vaginal mucosa, as has beensuggested by others.'2 A histiocytic origin for

sQ'4 the stromal cells could not be confirmed in this41 . ~~~7* series.

# u) Although myofibroblasts have long beenrecognised in human granulation tissue,'6 we

A:i were not able to show the presence of desminpositive cells in the granulation polyps selectedfor the immunohistochemical study. Myo-fibroblasts are considered important for thecontraction of granulation tissue.6 As theycould not be shown in granulation tissue polyps

t we suggest that granulation tissue polyps may5 develop when granulation tissue does not con-

tract properly due to delayed differentiation ofmyofibroblasts. An extensive search in theMedline Database covering 1972 to June 1991

^,Fs leads us to believe that this pathogeneticmechanism for granulation tissue polyps hasnot been reported. We also suggest that myxoidFEPV develop from granulation tissue polypsthrough proliferation in myxoid areas of cellswith delayed myofibroblastic differentiation.Collagenous FEPV may represent old polypswith dense stroma that have contracted. Therelatively sparse desmin negative cytoplasm inthe multinucleated stromal cells in collagenousFEPV may reflect that these cells are old

..4j myofibroblasts that have (temporarily?) lost* tk their contractile elements.

We were unable to show that granulationtissue polyps and FEPV had similar site dis-tributions in the present series. This would

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Figure 6 Micrographs from amyxoidfibroepithelial polyp showingmultinucleated stromal cells with positive cytoplasmic immunostainin;vimentin (B), and nuclear labelling of oestrogen receptors (C) (PA)

have strengthened our argument that one polypderives from the other. On the contrary, therewas a trend for granulation tissue polyps topredominate in the vaginal vault, whereasFEPV seemed to occur more commonly atother sites of the vaginal wall. Unfortunately,

A, however, in 50 ofthe 129 cases the site oforiginof the polyps was not stated on the histologyrequest form.Mast cells are common components of con-

nective tissues. They were frequently observedamong the stromal cells of the polyps in thepresent series. Similar findings have recentlybeen pointed out by others.'1 There is evidencethat mast cells interact with stromal cells,stimulate cellular and vascular proliferation,and promote matrix degradation.'720 They mayhave an important role among factors modulat-ing involution and organisation of granulationtissue, and growth of tumours.

1f The results of the present study have confir-med that stromal cells in FEPV may containoestrogen receptors.'0 Notably, many so-calledpseudo-sarcomatous polyps of the vagina haveoccurred during pregnancy.'2' The role ofhormonal stimulation in the pathogenesis ofFEPV is not known, however, and FEPV withatypical stromal cells have also been reported innon-pregnant women, in nulligravida, and inpostmenopausal women.'35891220 Oestrogenreceptor positive cells could not be observed inthe atypical polyp in our series. As only one ofthe polyps in the present 15 year materialcontained definite atypical cells (and abnormalmitoses) we believe that such lesions are rare.

w* * They may form a separate pathogenetic entity.The results of this study, however, allow nofirm conclusions to be drawn as to their truenature.A prominent finding in this series was the

abundance of cytologically benign multinu-im cleated giant cells in many FEPV. Rollason

efei...et al recently pointed to the difficulty indifferentiating between multinucleation andnuclear atypia in many cells." A micrograph intheir article nicely presents characteristic mul-tinucleated cells of similar appearance to thatobserved in our series. Pleomorphic multinu-cleated cells have been found in the vaginalmucosa of apparently healthy women,15 22 andhave been called "atypical stromal cells", al-though they may lack definite criteria ofmalignancy.23 During the past decades severalso-called pseudosarcomas, characterised bymultinucleated cells, and with a striking resem-blance to FEPV, have been reported at manydifferent sites.2s It should be recognised thatthe presence of multinucleated cells in theabsence of definite cytological atypia and

4*LJ abnormal mitoses most probably does notreflect a malignant process. Even the mostexperienced pathologist, however, would

-' * probably hesitate in diagnosing a neoplasticlesion as frankly benign when observingcytological and histological features like thoseof the atypical polyp in the present series, withhigh cellularity, atypical and bizarre nuclei, ahigh mitotic count and abnormal mitoses. We

mowno- and advise that patients with such ominous lesionsgfor desmin (A), should be controlled carefully for some timeP). following removal of the lesion.

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