Condylomata of the uterine cervix andkoilocytosis ...origin, whereas condyloma acuminatum has a...

J Clin Pathol 1981 ;34:532-541

Condylomata of the uterine cervix and koilocytosisof cervical intraepithelial neoplasiaSILVANA PILOTTI,* FRANCO RILKE,* GIUSEPPE DE PALO,tGABRIELLA DELLA TORRE, LOREDANA ALASIO*

From the *Division of Anatomical Pathology and Cytology, tDivision of Clinical Oncology A,and $Division of Experimental Oncology A, Istituto Nazionale per lo Studio e la Cura dei Tumori,Via Venezian 1, 20133 Milan, Italy

SUMMARY In 202 women with koilocytotic atypia in cervical smears, 136 had predominantly smallcondylomata of the uterine cervix, and 66 had cervical intraepithelial neoplasia (CIN) of varyingdegree either with koilocytosis of the neoplasia or associated with condylomata. Koilocytosiscorrelated well with the histological diagnosis of condylomata, but occasionally it obscured thecytological evidence of CIN. Human papilloma virus particles were found in the cells of condylo-mata in 10 cases and in those of CIN II with koilocytosis in two cases of 21 examined ultrastruc-turally. There was evidence that the condyloma of the uterine cervix is a well-defined morphologicalentity and also that cytopathic changes similar to those seen in condylomata are present in some

cases of CIN.

Condylomata acuminata are papillomatous lesionsthat arise mainly in the genital and anal regions ofboth sexes. The lesion is caused by a DNA tumourvirus, the human papilloma virus (HPV), whichforms the group of the papovaviruses with thepolyoma viruses and the simian virus 40. The virusdetected in condylomata acuminatal 2 has beendefined as HPV 6 in a recent classification3 anddiffers biochemically4 and immunologically5 fromthat of the common wart. Studies on viral onco-genesis have shown that a wart has a unicellularorigin, whereas condyloma acuminatum has amulticellular one.6 The multicellular derivationstresses the importance of environmental factors inthe formative process of condyloma acuminatum,which is considered a transmittable venerealdisease7 8 with a high incidence in populations whoshow sexual promiscuity.9 Condylomata acuminataoccasionally undergo malignant transformation.10

In the uterine cervix condylomata acuminata arerare whereas less papillomatous and even flat lesionsare more common. The latter have been consideredpossible early precursors of the exophytic lesions."Their unsuspected frequency in asymptomaticwomen has been particularly stressed.'2 The cyto-logical appearances in smears of early and floridcondylomatous proliferations are similar. One oftheir most striking features is the cytoplasmic

Accepted for publication 17 December 1980

clearing with nuclear atypia (koilocytotic atypial3),which is now known to be a viral cytopathic effect.Ultrastructural investigations have shown thepresence of papilloma virus particles in flat cervicalcondylomata,14 noncondylomatous wartylesions,'5-17 koilocytotic cells,'8 and exfoliatedkoilocytotic and dyskeratotic cells of flat condylo-mata of the uterine cervix.19 The similarity ofcondylomatous lesions to mild and moderatedysplasia of the uterine cervix and their possibleassociation in some patients have been recog-nised."1 20-22 However, the problem of the possiblesignificance of these viral lesions in the genesis ofcervical carcinoma is still unsolved.On the premise that koilocytotic cytopathic

effects can be seen histologically not only in condy-lomata but also in some cases of cervical intra-epithelial neoplasias (CIN),23 24 our study evaluatesby histology and, in part, by electron microscopy thereliability of the cytological finding of koilocytoticatypia in both benign and CIN-derived cells incervical smears and evaluates the possible signifi-cance of the association of condylomata and CINand of the condyloma-like features occasionallydisplayed by CIN.

Material and methods

We examined 202 women aged between 17 and 66years (mean 32-5 years, median 32) whose cervical,

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Condylomata of the uterine cervix and koilocytosis of cervical intraepithelial neoplasia

vaginal, endocervical smears (CVE) taken at theoutpatient clinic of this institution containedkoilocytotic cells or cells deriving from CIN withkoilocytotic changes or both and whose biopsymaterial taken from the uterine cervix showedcondylomata or CIN with koilocytosis, or both.Only four patients were postmenopausal. Allpatients underwent colposcopic examination andhad directed biopsy specimens taken from theircervix within a month of the cytological diagnosis.Fifty-five patients with condylomata only had atleast one repeat smear six months after biopsy.The smears were stained with Papanicolaou's

method. The biopsy material for light microscopywas fixed in Bouin's fluid, embedded in paraffin,and the 5 ,um-thick sections were stained withhaematoxylin-eosin and PAS-haematoxylin withand without diastase pretreatment. The search forviral particles by electron microscopy was made inone vaginal and 21 cervical biopsy specimens. Of theformer and of 15 cervical specimens, one-half wereprocessed for electron microscopy. They were fixedfor 2 hours at 40C in 0-1 M phosphate-buffered 2-5%glutaraldehyde and after fragmentation, postfixedfor 2 hours at 4°C in 0-1 M Millonig buffer contain-ing 1% OS04, dehydrated through graded alcohols,and embedded in Epon. Suitable samples wereselected under the light microscope from 1 ,um-thicksections stained with 1 % methylene blue and 1%azure II. The tissue areas of interest selected onhistological sections were removed from paraffinblocks of the remaining six cervical specimens,deparaffinised in xylene, and processed for electronmicroscopy after aldehyde fixation. Ultrathinsections of all biopsy specimens were collected on150 mesh naked grids, double stained with uranylacetate and lead citrate, and then examined with aPhilips EM 300 electron microscope at 60 kV.Colposcopic examination was performed with aZeiss colposcope before and after treatment withacetic acid and Lugol's solution.

In one case concomitant vulvar and in anothervaginal condylomata acuminata were present, andbiopsy specimens were taken. We examined themale partners of two patients at the same time andfound penile condylomata acuminata which werebiopsied.

Results

HISTOLOGYIn 136* cases (67 3 %), biopsy material taken fromthe uterine cervix showed the presence of condy-lomata (group 1); in 39 (19-3 %) there were condy-* In one case with cervical condyloma a nonadjacent invasivesquamous cell carcinoma (stage IB) was found.

lomata and adjacent CIN (group 2), and in 27 cases(13.4%) CIN with koilocytosis of varying degree inthe absence of condylomata was found (group 3).Mean and median ages of the first group wererespectively 32-2 and 31 years; mean and medianages of the second and third groups combined wererespectively 33-7 and 32 years. The vast majority ofthe condylomata were small and flat or only moder-ately papillomatous. Fully developed condylomataacuminata were seen in only six cases. Occasionally,there was an association of the various types.

Group IIn 104 out of the 136 (76-5 %) cases with cervicalcondylomata, the histological picture was charac-terised by a honeycomb pattern of the epitheliumwith few cells in the superficial and intermediatelayers. Cell size had increased, and a clear peri-nuclear halo not containing glycogen was present.The basal layer was well preserved. The nuclei of thecells with the halo were often eccentric and some ofthem were hypochromatic showing a "dusty"appearance while others were hyperchromatic andpyknotic. The nuclei were occasionally multiple.The mitotic index was low and no abnormal mitoticfigures were found. The degree of acanthosis andhyperkeratosis of the epithelium and the amount ofsmall cell infiltration of the underlying stroma werevariable but usually mild to moderate. This appear-ance is defined as condyloma type 1 (Fig. la).

In the other 32 cases (23-5 %) the changes weremore severe. The majority of the cells had a verylarge cytoplasm, which was almost completelyreplaced by the koilocytic halo. The honeycombpattern covered the whole thickness of the epithelium,with disorder of the stratification. The nuclei werehyperchromatic and often bizarre; multinucleationwas common, as was karyorrhexis. In the inter-mediate layer there was occasional single cellkeratinisation. Within the epithelium inflammatorycells were present. The mitotic index was also low inthis lesion, and no abnormal mitotic figures werefound. The more severe lesion described is definedas condyloma type 2 (Fig. 2a). An attempt to dif-ferentiate type 2 condylomata from CIN I or milddysplasia with koilocytosis was unsuccessful.

Group 2In 39 (19-3 %) cases, single or multiple condylomatatype 1 and 2 as described above were found adjacentto foci of CIN. In addition, a variable number ofcells of the neoplastic lesions showed koilocytosis(Figs 3a and b). CIN II was associated with condy-loma type 1 in 12 cases and with condyloma type 2in six cases, and CIN III, respectively, in 15 and sixcases.

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Pilotti, Rilke, De Palo, Della Torre, Alasio

la lbFig. la Flat condyloma of the uterine cervix type 1. Haematoxylin and eosin x 100Fig. lb Cytology offlat condyloma type 1. Papanicolaou x 400t~~~~~~~~~~~~~~~~~~~

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2a 2bFig. 2a Flat condyloma of the uterine cervix type 2. Haematoxylin and eosin x 100Fig. 2b The cytology offlat condyloma type 2. Papanicolaou x 250

Group 3Of the 27 cases (13A4%) with CIN with koilocytosisand no condyloma, 12 were rated as CIN II (Fig. 4a)and 15 as CIN III (Figs 5a and b). The cytopathicchanges such as perinuclear clear halos, abnormalpyknotic nuclei, multinucleation, and single cellkeratinisation were variable in frequency and pre-dominantly evident in the most superficial layers of

the neoplastic epithelium (surface koilocytosis). Insome cases hyperkeratosis was present.The total number of cases of CIN irrespective of

the association with condylomata was therefore 66:30 of CIN II and 36 of CIN III. The data are sum-marised in Table 1. The histology of the vaginal,vulvar, and penile condylomata acuminata was con-sistent with the clinical diagnosis.

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3a 3b

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3cFig. 3a Flat condyloma type 1 (right end of the epithelium) and transition to initial CIN with koilocytosis(left end). Haematoxylin and eosin x 100Fig. 3b Enlarged area ofA: maturation arrest and abnormalities of the nuclei in the deep layers of theepithelium. Haematoxylin and eosin x 250Fig. 3c Cytological appearance of CIN II with koilocytosis: perinuclear halos are present.Papanicolaou x 400

S1iriny the lower and the Int a l , w a c

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4a 4bFig. 4a CIN II with koilocytosis. The maturation arrest with nuclear abnormalitiesirtvolves predominantly the lower and the intermediate layers, whereas cytopathicchanges are recognisable in the superficial layers of the epithelium. Haematoxylin andeosin x 250Fig. 4b Cytological appearance ofCIN II: the cytoplasms in part are fairly large andpleomorphic and contain small halos. The nuclei are atypical, bizarrely shaped and oftenmultiple. Papanicolaou x 400

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Sa 5b 5cFig. 5a CIN III with marked koilocytosis and a high mitotic index. Haematoxylin and eosin x 250Fig. 5b CIN III with moderate koilocytosis and hyperkeratosis. Haematoxylin and eosin x 250Fig. 5c Cytological appearance of CIN III. The cells show marked nuclear atypia. Perinuclear halos arevery rare and small. Papanicolaou x 250

Table 1 Cervical condylomata types 1 and 2 and theirassociation with CIN in relationship to the presence ofkoilocytosis in cervical smears from 202 patients

Condyloma* CIN II CIN III Total

Condyloma type 1 104 12t 1St 131Condyloma type 2 32 6t 6t 44Absence ofcondylomatat - 12 15 27

Koilocytosis incytology 136 30 36 202

*Group 1 cases with cervical condylomata only (n = 136).tGroup 2 cases of CIN associated with condylomata (n = 39).tGroup 3 cases of CIN with koilocytosis (n = 27).

CYTOLOGYThe cytological features of the CVE smears of the136 cases with histologically proven condyloma werecharacterised by the presence of sheets of cells withvarious degrees of dyskeratosis and sheets or co-hesive clusters of superficial and intermediate cellswith large cytoplasm and a perinuclear clear halo

(koilocytotic atypia) (Fig. Ib). The nuclei were ofteneccentric, occasionally enlarged, with pale dustychromatin, and resembled those described ascondylomatous intermediate cells20 but were moreoften hyperchromatic and pyknotic. The cytoplasmwas usually markedly polychromatic, whereas singlecell cytoplasmic keratinisation and phagocytosis ofgranulocytes were rare. Multinucleated cells werequite numerous in some cases, and their overlappingand hyperchromatic nuclei showed a blackberry-shaped pattern. In general, a large number of multi-nucleated cells, isolated keratinised cells, and phago-cytosis of granulocytes were related to the cases withcondyloma type 2 (Fig. 2b). The cytological follow-up of 55 cases with both cond94iata type 1 and 2showed no koilocytotic cells in smears,of 60% of thewomen after six months, while they persistedunchanged in 40 %.The cytological findings of the 66 cases in which

the histology showed either CIN with koilocytosisor the combined presence of condylomata and CIN

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were similar (Figs 3c, 4b, Sc). In general, neoplasticcells with the characteristic perinuclear halo wererare. They were more common in CIN II than inCIN III. In the smears from cases with CIN III withkoilocytosis, the atypical cells were predominantlysingle and roundish with little cytoplasm. However,some of them had a moderately large pleomorphiccytoplasm which was either acidophilic or almostunstained. The atypical nuclei were hyperchromatic,pyknotic, bizarrely shaped, often multiple, and oftenassociated with retrogressive changes. Perinuclearhalos were small and rare. A variable number ofneoplastic cells without koilocytosis and of non-malignant koilocytes was also found.

CYTOHISTOLOGICAL CORRELATION (Table 2)The cytological diagnosis in 125 of the 136 cases ofcervical condylomata (group 1) had been simplykoilocytosis, whereas in the remaining 11 cases thediagnosis of CIN II with koilocytosis was sub-sequently revised and downgraded. The histologicalpattern of five of these 11 cases was consistent withcondyloma type 2. The cytohistological correlationof the 66 cases of either CIN with koilocytosis orCIN with accompanying condylomata showed thatin 18 the cytological diagnoses had not reflected theactual degree of severity of the lesion. However, therevision reconfirmed the original underestimatedcytological diagnoses in five cases of CIN II and nineof CIN III, whereas in four cases of CIN III thesmears were reclassified as inadequate.

Table 2 Cytohistological correlation

Cytology Histology Total

Condyloma CIN IS + CIN III +K± C K± C

Koilocytosis 125 (92%) 5 4* 134CIN ll + K 11 25 (83%) 9 45CIN III + K - - 23 (64%) 23Total 136 30 36 202

K = koilocytosis; C = condyloma.*Superficial smears.

COLPOSCOPY AND COLPOSCOPIC-HISTOLOGICAL CORRELATIONThree main colposcopic patterns were seen in 81of 136 cases (59%) with histologically proven con-dylomata. In 38 cases we found leukoplakia-like con-dylomatosis made up of sharply defined areas ofdifferent shapes and sizes, whitish-ground glass incolour, and slightly raised above the mucosa of theportio with either straight or branching vessels. In37 cases we found white-patches condylomatosisshowing multiple, small, roundish, smooth, andwhitish formations which were slightly raised above

the ectocervical mucosa and surrounded by athickening at the periphery. In the remaining sixcases we found florid condylomatosis revealing amulticentric, whitish, elevated proliferation on theectocervix with a rough "cobblestone"-like surface,which was poorly vascularised and did not showatypical vessels. In no case of condyloma was therecolposcopic evidence of atypical transformation.

In the 18 cases of CIN II associated with condy-lomata, the latter were recognised colposcopically in17, of which 10 showed a leukoplakia-like patternand seven white patches. In the 21 cases with CIN IIIwith condylomata, colposcopy showed mixedpatterns in seven.

ELECTRON MICROSCOPIC FINDINGSSpherical viral particles, approximately 350 to 400 Ain diameter and morphologically identical to humanpapilloma virus (Figs 6, 7), were found in 12 (57%)of the 21 cervical lesions examined. Ten of the posi-tive lesions had been identified on semithin sectionsas condylomata. In two of these cases the histologyof the whole biopsy material had shown CIN IIIadjacent to the condyloma. In the other twocervical lesions with viral particles, semithinsections showed CIN II with koilocytosis. Of thenine cervical lesions that exhibited no viral particles,seven were condylomata and two CIN III withkoilocytosis.

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Fig. 6 Intranuclear viral particles grouped aroundchromatin clumps or independent in the nucleoplasm.x 61 000

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Fig. 7 A higher magnification of intranuclear viralparticles showing a dense core with a surrounding clhalo. Note their regular form and size. x 177 000

The viral particles were contained in the nuwsuperficial epithelial cells. Most particles wereand either freely scattered throughout the niplasm or closely associated with chromatin cliOthers were assembled in small or large clustthe nucleoplasm. Viral particles of the cytowere found in cells with a ruptured nuclear en(Fig. 8). In six cases of condylomata and in cCIN II with koilocytosis, a small number ofparticles was present in a few nuclei, whereas ii

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condylomata cases and in the other case of CIN IIwith koilocytosis there were many nuclei with viralparticles and most of them had a high concentrationof viral particles.

In the cells of both condylomata and CIN II withkoilocytosis, two types of nuclei with viral particleswere observed. Many were enlarged, had irregularprofiles and a clear aspect, contained large clumpsof chromatin mainly attached to the nuclear en-velope, and showed no separation between thenuclear envelope and clumped chromatin (Fig. 9aand b). Others with a round shape and a markedlydiminished size were striking because of the com-pact arrangement of their chromatin clumps. Themargins of the chromatin were prominent and thenuclear envelope unidentifiable (Fig. 10a and b).The nuclei were surrounded by a large clear areaalmost devoid of cytoplasmic organelles. In thisarea a few cytoplasmic remnants were recognisable,and they were scattered sparsely or sometimes con-densed and aligned on the outer margin of the nuclei.

'ear Occasionally glycogen-like material such as rareisolated granules was observed. The clear peri-nuclear area was delineated at the periphery by adense narrow band of cytoplasm containing irregu-

clei of larly arranged bundles of tonofilaments. Thesingle boundary between the perinuclear and outer area ofucleo- the cytoplasm was sharply defined.umps. Numerous papilloma virus particles were alsoters in observed in the vaginal condyloma acuminatumplasm examined. They were dispersed or arranged in avelope paracrystalline fashion in the enlarged nuclei of themne of superficial epithelial cells, which showed denser viral peripheral and clear perinuclear areas of cytoplasmn four as described above.

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Fig. 8 Part ofa nuckus showing the ruptured nuclear envelope (arrows). Single viral particles can be seenin the cytoplasm. x 28 000

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Fig. 9a Benign koilocytes with largenuclei: the morphology of the nuclei insemithin section. Methylene blue-azureII x 1000

Fig. 9b A large nucleus with irregularoutline showing a thin margination opfthe clumped chromatin. A cluster of viralparticles independent of chromatin can beseen in the nucleoplasm. x 14000

Fig. lOa Small nuclei in a semithin section: prominentmargination of the chromatin. Methylene blue-azureII x 1000

Fig.lbbA small, round nucleus with large compactclumps of chromatin. Note the nucleoplasm entirelyfilled with viral particles. x 161000

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Discussion

The results show that the cytological diagnosis ofkoilocytosis without marked nuclear abnormalitiesin CVE smears was, on the whole, reliable withreference to the presence of condylomata of thecervix. However, it is recognised that the reverse maynot be true.25 The occasional overestimation of thecytological diagnosis and its interpretation as CIN IIwas probably related to the traditional cytologicalapproach." However, since in about half of theoverestimated cases histology showed a condylomatype 2, which more closely resembles CIN than doestype 1, the low grading after revision was limited toless than 5% of the cases. We did not observemarked nuclear atypia indicative of a malignancysuch as that described for condylomata acuminata.25On the contrary, there was underestimation ofthe cytological diagnosis of CIN when koilo-cytosis was a prominent feature. The decreasedaccuracy of cytology in some of these cases may berelated to the peculiar histological structure of thelesions, with well-preserved neoplastic cells ofdiagnostic value located in the deeper layers andkoilocytotic cells not readily recognised as beingneoplastic being found superficially. The smearstaken from some of the cases of CIN with koilo-cytosis, and particularly from those with hyper-keratosis, showed the presence of parakeratotic cellsand abnormal, pleomorphic cells but which appearedmature with a large cytoplasm. The resulting patterncorresponded in part to those described as pleo-morphic parakeratosis and pleomorphic keratinisingdysplasia.26Although the follow-up was short and incomplete,

it seems that the cytological changes of condy-lomata disappear at least temporarily in a highpercentage of the cases.'2 15 20 27 In view of the factthat condylomata type 1 and particularly type 2 maybe interpreted histologically as mild or moderatedysplasia and koilocytosis in smears as mild dys-plasia, the reported high regression rate of theselesions finds a partial explanation. Because there isfrequent spontaneous regression and because theirnatural history is uncertain, small condylomata ofthe cervix should not be overtreated but kept underclinical and cytological control. The incidentalfinding of penile condylomata acuminata in thesexual partners of two patients stresses the indicationfor the systematic examination of the couple.28 29The colposcopic findings were consistent with thehistological report in about 60% of the cases withcondylomata and were essentially the same in thecases with condylomata and CIN. In most of thecases of CIN with or without condylomata, thecolposcopic picture was, however, dominated by the

areas of atypical transformation from which thebiopsies were taken. Therefore, the absence ofaccompanying condyloma in some cases of CIN withkoilocytosis may have been a sampling error.

In keeping with the rarity of papillomatous condy-lomata of the cervix, the colposcopic pattern of floridcondylomatosis was the least common. The leuko-plakia-like pattern had to be distinguished from thetrue mosaic on the basis of the appearance of thevessels, whereas the white-patches condylomatosishad to be differentiated from cornified glandularoutlets. The latter was the most difficult type torecognise at colposcopy, and for its identification thepreceding cytological diagnosis of koilocytosis wasvery helpful.The presence of intranuclear viral particles in 12

of 21 cases examined expands our own results onfour of the present casesl4 and confirms those pub-lished by others.'5-19 Frequently, as in condylomataacuminata, a few viral particles and only a smallnumber of koilocytes were present. The viralparticles detected could not be distinguished by theirnumber, ultrastructure and intranuclear distributionfrom those that have been identified in condylomataacuminata and considered to be their aetiologicalagent.2 The similarity with the findings in condy-lomata acuminata suggests that the cervical infectionby a papilloma virus is responsible for the cytopathicchanges of condylomata non-acuminata as well as ofCIN. In accordance with the histological findings,the clear perinuclear halos of the koilocytes did notcontain glycogen and they may be related to oedemaand vacuolisation of the cytoplasm.30

It is noteworthy that in published reports in theexamples given of the histological appearance of thevarious grades of CIN, often in the superficial andoccasionally in the deeper layers of the epithelium,there are cells with evident koilocytosis.31 32 Ourhistological findings clearly indicate that the smalland predominantly flat condyloma of the uterinecervix, also named noncondylomatous wart virusinfection,17 is a well-defined entity even though itmay show some variations in appearance. Thedegree of atypia shown by type 2 is compatible withcytopathic effects and is not necessarily neoplasticin origin. Cellular pleomorphism does not allow anyclear distinction from CIN. Also we cannot saywhether CIN II and III with koilocytosis are justCIN with superimposed viral infection or peculiarprecursors of cervical carcinoma. It should be notedthat all our cases of CIN III with koilocytosis wereof the large cell type and never of the small cell type.The ultrastructural findings of papilloma virus

particles in CIN II-derived cells as in the presentseries and in cells originating in areas surroundingcarcinoma in situ'7 and from a cervix with infiltrating

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carcinomal4 do not support any causal relationshipbetween papilloma virus infection and cervicalneoplasia. The same applies to the coexistence ofcondylomata and CIN and to the apparent tran-sition from the first to the latter. Undoubtedly, thecases of proven progression of "verrucous dysplasia"to CIN33 and those of development of mild dysplasticlesions with koilocytic atypia after cone biopsy forCIN III27 point to an interaction of papilloma virusinfection of the human uterine cervix with the pre-malignant and malignant transformation of thecells. Should this be confirmed, then the hypothesis,proposing the existence of several pathways, bothinfectious34 and noninfectious,35 leading to cervicalcarcinoma, would gain ground.

We thank Ms B Johnston for her assistance inpreparation of the manuscript. This study waspartially supported by grant no 78 02860 96 from theConsiglio Nazionale delle Ricerche, Rome.

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Requests for reprints to: Dr F Rilke, Department ofPathology and Cytology, Istituto Nazionale per loStudio e la Cura dei Tumori, Via Venezian 1, 20133Milan, Italy.

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