DYSPLASIA, C A R C I N O M A IN SITU, A N D MICROINVASIVE CARCINOMA OF T H E U T E R I N E CERVIX* William M. Christopherson, M.D. t Abstract Carcinonm in situ is defined as tim earl)' stage of cancer and must therefore be initiated by an as yet unknown carcinogen(s). Progression of the lesion to invasive carcinoma is reported to occur in a high proportion of nontreated cases. Reserve cell proliferations are frequently associated with both dysplasia and carcinoma in situ, and it is suggested that these are the cells from wlfich both lesions arise. Dysplasia may result from both carcinogenic and noncarcinogenic stimuli. Since dysplasia usually either regresses or remains stabilized over a prolonged period, it is suggested that it is more frequently associated with noncarcinogenic stimuli. Microinvasive carcinoma is limited to lesions with no more than 5 ram. o f stromal invasion as measured from tile surface. Confluence of growth and lymphatic-like space invasion should not interdict the diagnosis. *Iicroinvasive carcinoma thus defined rarely gives rise to lymph node xnetastasis or eventuates in death. The diagnosis cannot be made from punch biopsy specimens. Only if pathologists adhere to a standard nomenclature can followup studies be used successfully to identify the natural behavior of each type of lesion in this spectrum.

The significance of carcinoma in situ and associated epithelial abnormalities in the pathogenesis of cervical cancer has been intensively studied in the lmman and a variety of animals. T h e criteria for the cytologic and histologic diagnosis of the various lesions, however, still require -sharpening. The following is a consideration of the histopathologic features of various intraepithelial and early invasive lesions and their inter-relationships in the pathogenesis of cervical carcinoma. RESERVE CELL HYPERPLASIA, METAPLASIA, AND DYSPLASIA Basic to an understanding of atypical proliferations of tile cervical epithelium

is a consideration of tile subcolumnar reserve cells, pluripotential cells from which metaplastic cells develop. Difficult to see in their nonproliferating state, in hyperplasia they often form several layers beneath the columnar cells (Fig. 1). In their earliest stages of proliferation they appear to be primitive cells with poorly defined cell borders, very little cytoplasm, and rotmd to oval, sharply defined nuclei. As they mature toward squamous cells, they acquire more cytoplasm, develop distinct cell borders, and gradually displace tile overlying columnar cells (Fig. 2). Ahhough maturation of reserve cells usually proceeds in an orderly fashion toward metaplastic squamous cells, their development is occasionally disorderly, resuhing in dysplastic metaplasia (Fig. 3).

*This study was supported b)" NCI contract 1-CN-45059.

tProfessor of Pathology, University of Louisville School of Medicine, 1.ouisville, Kentucky.

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Figure I. Reservecell hyperplasia in endocervix. Some cellular maturation is evident. (Hematoxylin and eosin stain, x130.)

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Figure 2. Another area with more advanced immature metaplasia. (llematoxylin and eosin stain. x3-t0.)

When reserve cells proliferate and tile cytoplasm fails to develop, the epitheliuna shows m a r k e d nuclear crowding with varying degrees o f atypia. This abnormalit), has been called "atypical reserve cell hyperplasia," or "reserve cell dysplasia." Its characteristic features include nuclear e n l a r g e m e n t and hyperchromasia, and failure o f the cytoplasm to mature. T h e cytoplasm is scant)' and basophilic, and the cytoplasmic margins are indistinct or absent, g-iving a very cellular a p p e a r a n c e (Figs.-4, 5). T h e failure o f cytoplasmic maturation and keratinization distinguishes reserve cell dysplasia f r o m the usual type o f dysplasia, which arises in a m o r e m a t u r e metaplastic epithelium or in the native epithelium. T h e stimuli for the proliferation o f reserve cells and thus for metaplasia are t h o u g h t to be h o r m o n a l or local environmental factors. Since metaplasia is ubiquitous, the usual stimulus is evidently not a carcinogen. On the o t h e r hand, diso r d e r l y reserve cell proliferations nfight be initiated by either different or possibly

Figure 3. Atypical (d)'splastic) metaplasia with disturbed polarity in basal half of epithelit, m, as well as nuclear abnormalities. (Hematoxylin and eosin stain. •

DISORDERS OF T H E UTERINE CERVIX--Ctmm'roP~IERSOX

Figure 4. Atypical reserve cell hyperplasia (dysplasia) simulating carcinoma in situ. (Hematoxylin and eosin stain, x340.)

additional agents, o n e o f which could be a carcinogen. T h e r e is a basis for this postulation, since reserve cell dysplasia not only simulates carcinoma in situ morphologically but is known to p r e c e d e and accompany it. 1-a T i l e a b n o r m a l reserve cell proliferation tlmt fails to m a t u r e is o f the greatest concern. S u p p o r t i n g the relation o f reserve cell proliferation to carcinoma is the fact that the latter characteristically arises in the transformation zone o f the cervix r a t h e r than f r o m the native epithelium o f the ectocervix. W h e n carcinoma in situ or dysplasia is e n c o u n t e r e d in the portio or in the vaginal epithelium, a significant p r o p o r t i o n o f the cases occur after the t r e a t m e n t o f dysplasia, carcinoma fn situ, or invasive carcinoma. W h e n not p r e c e d e d by these lesions, they are o f t e n f o u n d in association with an epithelial abnormality r e s u h i n g in the extension or displacement o f the transformation zone, as in the case o f vaginal adenosis. Wentz 5 postulated that keratinizing carcinoma originates in the squamous epi-

thelium o f the portio or transformation zone, large cell nonkeratinizing carcinoma f r o m p r e f o r m e d metaplastic epithelittm, and small cell carcinoma f r o m reserve cells. This t h e o r y certainly is appealing, but p r o o f is lacking. In a 14 )'ear prospective study, J o h n son 2 was able to follow to the carcinoma stage only a single case o f dysplasia in mature, cornified, and keratinized epithelium o f the transitional zone and adj a c e n t portio. She stated that in all the o t h e r patients in whom in situ or invasive carcinoma d e v e l o p e d , the lesion originated in reserve cells, e i t h e r directly f r o m reserve cell dysplasia or indirectly via dysplastic metaplasia. O t h e r studies indicate reserve cell hyperplasia to be associated with dysplasia and carcinoma in situ in 72 per cent o f the patients? O u r own experience in a dysplasia clinic supports J o h n s o n ' s observations? O n e h u n d r e d eleven patients with dysplasia were foll o w e d for f r o m five to 14 years without treatment. All the lesions were detected cytologically and c o n f i r m e d by biopsy. T h e patients were followed by careful clinical

Figure 5. Reserve cell hyperplasia in a 20 year old pregnant woman. (llematoxylin and eosin stain. •

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HUMAN P A T H O L O G Y - V O L U M E 8, NUMBER 5 September1977 examination and regular cytologic studies. T o qualify for inclusion in the study, cytologic abiaormalities had to persist after p u n c h biopsy. In 17 per cent o f the cases the lesions progressed at least to carcinoma in situ. T h e initial biopsy specimen in 12 o f the 19 cases showed reserve cell dysplasia. Carcinoma in situ eventually de)'eloped in 10 o f these, carcin o m a is situ with possible stromal invasion in one, and microinvasive carcinoma in one. In the r e m a i n i n g seven cases that progressed t h e r e was a m o r e m a t u r e type o f dysplasia; f o u r were severe, two m o d e r a t e , and one mild.

Dysplasia T h e most c o m m o n o f the significant cervical epithelial proliferations detected cytologically in the asymptomatic patient is dysplasia. In o u r laboratory it is enc o u n t e r e d with a f r e q u e n c y at least t h r e e times that o f carcinoma in situ, and if we include minimal degrees it is man}' times m o r e common. T h e literal m e a n i n g o f the term is d i s o r d e r e d development. 6 Dysplastic epithelium is f r e q u e n t l y f o u n d in conjunction with carcinoma in situ and invasive cancer and is known to p r e c e d e these lesions by a significant n u m b e r o f years.3, 4, G It is thus t h o u g h t to be part o f a spectrum o f changes in the d e v e l o p m e n t o f squamous carcinoma. Animal experiments s u p p o r t this concept. Cytologic and histologic studies, as well as objective physicochemical m e a s u r e m e n t s such as a n h y d r o u s nuclear mass, nuclear water content, and DNA content, all indicate that dysplasia precedes experimentally induced cervical cancer, r-H It is o f interest that some investigators have f o u n d chemically induced dysplastic lesions to p r e c e d e cervical carcinoma, whereas typical carcinoma in situ was less fi-equently encountered.l-~ Others lmve r e p o r t e d a stage o f carcinoma in situ m o r e frequently.~4 Tiffs could well be due to variations in the pathologic interpretation o f intraepithelial lesions, which could also explain the wide range o f rep o r t e d incidence and progression rates in humans. Althougll the cytolog-ic and m o r p h o logic features o f dysplasia were clearly

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described m o r e than 20 years ago, the v o h n n e o f conllicting literature on tile subject has p r o d u c e d m n n e r o u s heated discussions. More recently tile term "cervical intraepithelial neoplasia" has been suggested. It would encompass dysplasia in its various forms as well as carcinoma in situ. ~r Although this simplification might have appeal to eolposcopists, it has not been widely accepted by pathologists. In an a t t e m p t to standardize the nomenclature o f neoplastic disease, the World Health Organization t h r o u g h international committees has published two volumes: o n e o n the cytologic and the o t h e r on the histologic classification o f uterine tumors. ~s'~9 Although no system o f n o m e n c l a t u r e is likely to please everyone, universal usage o f a single terminology would lead to clarification o f the behavior o f the various epithelial abnormalities u n d e r discussion. Basic to o u r c u r r e n t concept o f cervical dysplasia is the evidence that it may occur as a response to noncarcinogens as well as to carcinogens. -"~ T h e d e g r e e o f the reaction can vary f r o m mild to severe and the extent f r o m minimal to complete involvement o f tbe cervix. Because o f the time period involved in the evolution, the possibility tlmt a m o r e meaningful lesion was not included in the biopsy specimen c o m p o u n d s the problem and is partly responsible f o r the fact tlmt the biologic potential o f dysplasia has not as yet been full), defined. T h a t some lesions progress to carcinoma in situ or invasive cancer is indisputable. F u r t h e r m o r e , the risk o f cancer d e v e l o p i n g in a cervix with dysplasia is greatly increased. "6 It is equally evident that in most cases dysplasia reverts to normal o r remains u n c h a n g e d over a p r o l o n g e d period. 4'2r This is quite unlike the e x p e r i e n c e with carcinoma in situ, in which u p to 73 per cent are said to have progressed to invasive carcinoma. 28 Reagan and Patten 6 have studied the distribution o f dysplasia and carcinoma in situ within the cervix and d e t e r m i n e d that dysplasia tends to develop distal to the areas where carcinoma in sitti is most frequent, although both lesions occur in relation to the transformation zone. F u r t h e r more, these investigators have noted that dysplastic reactions that .are t h o u g h t to

DISORDERS OF THE UTERINE CERVIX--CHRlS-rOPnERsox arise from metaplastic epitllelium tend to be more proximal than those considered to arise from the native squamous epithelinm. In onr material, dysplastic changes in metaplastic epithelium are much more common than those originating in native epithelium. Some involve the crypts or glands, although at times t h e reaction is confined to the snrface. The degree of thickening of the epithelial layer varies. Like carcinoma in situ, there is a tendency for the epithelium to strip easily from the stroma, necessitating great care in obtaining the biopsy specimen and handling it in the laboratory. Rete pegs are less evident in metaplastic dysplasia and the}' tend to be broad and blunt. The surface is usually regular but at times may be papillomatous. A degree of cellnlar maturation is always present. There is at times a covering of parakeratotic or keratotic cells. Other histologic features include irregular polarity and a tendency for cytoplasmic maturation to increase as the surface is approached. The nuclei are enlarged and hyperchromatic with very dis-

Figure 7. Moderate dysplasia. (Hematoxyli,i and eosiu stain. • 130.)

Figure 6. Mild dysplasia with disordered cell growth and mitoses. At the extreme left one notes involvement of a crypt. (Hematoxylin and eosin stain. •

tinct, regular margins. Mitotic activity is variable, being confined to the lower half of the epithelium in mild dysplasia and extending into the more superficial layers as the severity increases. Nucleoli, when present, are nsually small and regnlar. When the underlying glands are invoh'ed, their epitllelium often shows considerably less maturation than does tile surface elfithelium, but tile diagnosis should be based on the clmnges in the covering epithelium. Since minimal dysplasia is very common and tends to blend imperceptibly with metaplasia, we do not recommend histologic confirmation of tiffs cytologically detected change. Experience Ires shown that it rarely progresses, and if perchance it should, little is lost in detecting a more severe reaction at the next cytologic examination. This policy is of considerable economic importance, since it eliminates the not inconsequential expense resulting fi'om colposcopy, biopsy, or even conization. A close surveillance of patients with minimal dysplasia on cytologic examination over a 20 year period ires convinced us of the safety of such practice.

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Figure 8. Severe dysplasia. Although there is disordered cell growth with a tendency toward vertical polarity, there is fairly good matt,ration as the surface is approached. (ttematoxylitl and eosin stain. x340.)

Figure 9. Carcinoma in situ (?) arisiqg in a field of atypical reserve cell hyperplasia in a 23 )'ear old primipara. The change persisted after delivery and was successfldly treated by conization. (Hematoxylin and eosin stain, x130.)

Ill addition to tile dysplastic reactions illustrated for reserve cell proliferations (Figs. 3 to 5), e x a m p l e s o f varying degrees o f dysplasia are shown in Figures 6 to 8. J u s t as the lower t h r e s h o l d f o r d i a g n o s i n g mild dysplasia c a n n o t be defined precisely, a s h a r p distinction b e t w e e n severe dysplasia a n d c a r c i n o m a in situ is lacking, with considerable variation a m o n g pathologists in the designation o f these lesions. T h e r a r e reaction that occurs m o r e distally on tile portio or even the vaginal wall a n d that arises fi'om native s q u a m o u s epithelium is quite unlike that related to tile t r a n s f o r m a t i o n zone. It is m o r e akin to what o n e sees in tile skin a n d m u c o u s m e m b r a n e s o f the vulva, oral cavity, and e s o p h a g u s , with a m u c h g r e a t e r t e n d e n c y toward cellular m a t u r a t i o n in both dysplasia a n d c a r c i n o m a in situ. It should he n o t e d as well that the invasive cancers in these sites are generally o f the keratinizing type.

SQUAMOUS CARCINOMA IN SITU C a r c i n o m a in situ can be defined as the earliest stage (stage 0) o f cancer in

Figure 10, Carcinoma in situ with bulky gland inw~Ivcment. (ttematoxylin and eosin stain, x35.)

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feature for distinguishing carcinoma in situ from dysplasia. It should be pointed out, however, that if the specimen is carefully obtained without prior scraping of the mucosa or vigorous prebiopsy preparation and manipulation of the cervix, there is frequently a superficial layer or two of. more mature cells with their nuclei oriented transversely. In cone or hysterectomy specimeus it is unusual to find carcinoma in situ that does not invoh'e the u n d e r l y i n g glands. At times there is bulky invoh'enlent with great distention o f the glands by t u m o r cells (Fig. 10). In imperfectly oriented specimens extensive deep gland invoh'ement can present the diagnostic problem of excluding early' invasion. T h e u n c o m m o n carcinoma in situ that arises from the native epitilelium of the portio vaginalis of the cervix or the vagina has a quite different morphology (Fig. 13). Irregular acanthosis is present, squamous maturation is evident, and there is frequently a conspicuous keratotic or Figure 11. Surface change in lesion shown in Figure 10. (Hematoxylin and eosin stain. X130.)

which tlle cells appear to be malignant but are confined to tile epithelium. Stewart ~ pointed out that all invasive carcinomas arise from carcinoma in situ, since there is no other way they can arise. It would seem obvious that if it were detected in the in situ stage, morbidity' and mortality, from cancer of the cervix could be controlled to the extent that cytologic screening was successful. 3~ 3~ Except for a rare case, carcinoma in situ arises in the transformation zone of the cervix. Its histologic features are illustrated in Figures 9 to 12. T h e thickened epitllelium is extremely crowded with cells containing scanty cytoplasm and lacking distinct cell borders. T h e cytoplasm is basophilic or amphophilic. T h e nuclei are usually sharply outlined, llyperch~'omatic, and devoid of nucleoli. Mitoses vary in n u m b e r and involve the entire thickness. Either nuclear polarity is totally" disturbed or the nuclr are oriented in a vertical or diagonal pattern. Unlike dysplasia, there is little if any' tendency toward squamous cell maturation. This uniformity o f cell type is the most dependable

Figure 12. Tangential cut of carcinoma ill situ, which may present a problem in excluding invasion. (Henaatoxylin and eosin stain, x55.)

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Figure 13. Carcinoma in situ of the portio vaginalis. Other pathologists might consider this dysplasla, and had the lesion been located in the transformation zone or endoccrvical canal, we would have made that diagnosis. (Hematoxylin and eosin stain. x55.)

parakeratotic covering. It is thus e x t r e m e l y i m p o r t a n t that the pathologist have information r e g a r d i n g the precise area subj e c t e d to biopsy. When specimens are obtained f r o m tim transformation zone and endocervical canal as well as f r o m tim distal portio vaginalis or vagina, each should be labeled and h a n d l e d separately. It is not surprising that carcinoma in situ is frequently f o u n d in cervices that have contiguous area o f dysplasia, since tim f o r m e r lesion by definition is caused by a carcinogen as are at least some areas o f dysplasia. Both lesions may be f o u n d in the presence o f invasive carcinoma as well. Carcinoma in situ is often muhifocal, suggesting a field cancerization process. We have seen a case that involved the entire transformation zone and e x t e n d e d proximally in continuity to involve both fallopian tubes. McKay et al. a2 have illustrated the intermingling o f various cervical abnormalities by detailed patholog-ic exanaination. A d e n o c a r c i n o m a in situ, alone or in combination with squamous carcinoma in situ, is less fl'equently e n c o u n t e r e d and will not be discussed further.

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Microinvasive carcinoma has been defined m a n y times. Tile difficult)' in arriving at a consensus is illustrated by the fact that the W H O international committee was unable to reach a g r e e m e n t r e g a r d i n g a definition, with the result that microinvasive carcinoma was not included in its schema, l'a Since microim'asive carcinoma is now accounting for an ever increasing p r o p o r t i o n o f cases o f invasive cervical cancer, a clear definition o f the lesion is obviously needed. As e x p e r i e n c e has accumulated, it now appears that squamous carcinoma with invasion no greater than 5 ram. f r o m the surface rarely results in lymph n o d e metastasis and rarely if ever produces death f r o m disease, aa-aa T w o recent studies, which included cases o f invasion u p to 5 mm. and did not exclude cases with lymphatic-like space invasion or those with a confluent pattern, f o u n d no lymph n o d e metastases, aa' a~ A n o t h e r study using the same criteria, with a minimal followu p period o f 10 years, f o u n d no deaths f r o m disease, aa Several prior investigations s u p p o r t the concept that microinvasive carcinoma with few exceptions behaves like carcinoma in situ. a6-41 T i m definition has i m p o r t a n t implications for tim evaluation o f t r e a t m e n t and tim end result reporting. T h e American J o i n t C o m m i t t e e for Cancer Staging and End Result Reporting, the Union International C o n t r a le Cancer, and the Cancer C o m m i t t e e o f tim International Federation o f Gynecology and Obstetrics (FIGO) have recently a g r e e d to a u n i f o r m staging system similar to the old F I G O system. 42 Microinvasive carcinoma in addition to any o t h e r carcinoma that was not diagnosed clinically is coded as stage Ia. F u r t h e r m o r e , tim system allows for the diagnosis to be based on biopsy alone. Occult carcinorna, which is also c o d e d as stage Ia, is often larger than 5 ram. and is known to have a different fl-equency o f lymph n o d e metastases as well as being associated with a different survival r a t e Y T h e Fifteenth A n n u a l F I G O R e p o r t apparently g r o u p e d all stage I carcinomas t o g e t h e r to d e t e r m i n e tlm a p p a r e n t survival rate~ a" T h e lowest and highest rates

DISORDERS OF T H E U T E R I N E CERVIX--CIIRISTOI'HERSON a m o n g t h o s e r e p o r t e d by institutions in the U n i t e d States w e r e 45.9 a n d 86.3 p e r cent, respectively. Since b o t h institutions are h i g h l y r e g a r d e d centers, the e x t r a o r d i n a r y d i f f e r e n c e in snrvival is m o r e apt to be d u e to the inchtsion o f a large n u m b e r o f m i c r o i n v a s i v e c a r c i n o m a s in t h e o n e r e p o r t i n g the b e t t e r results t h a n to its s u p e r i o r i t y in t r e a t i n g the disease. T h e inclusion o f microinvasive carc i n o m a with o t h e r stage I c a n c e r s m i g h t also s u g g e s t i m p r o v e m e n t in t r e a t m e n t o v e r a time p e r i o d w h e n in fact no improvement had occurred? ~ Like intraepithelial lesions o f the cervix, microinvasive c a r c i n o m a is usually a s y m p t o m a t i c , a n d a t t e n t i o n is called to it by cytologic e x a m i n a t i o n . T h e diagnosis c a n n o t be m a d e o n t h e basis o f less t h a n a c o n e o r t h e c o m p l e t e cervix, the e n t i r e c i r c u m f e r e n c e o f which m u s t be e m b e d d e d a n d sectioned. W e h a v e enc o u n t e r e d several instances in which biopsy s p e c i m e n s s h o w e d o n l y m i n i m a l invasion, at times less t h a n 1 m m . , alt h o u g l l invasion e x c e e d i n g 5 mtn. was f o u n d in t h e resected s p e c i m e n . Histologically t h e r e is usually e x t e n -

Figure 14. Microinvasive carcinoma with 1.2 ram. invasion. Note the surrounding lymphocyte and plasma cell infiltrate. (Henmtoxylin and eosin stain. x55.)

Figure 15. Microinvasive carcinoma with conflnent finger-like invasion to a depth of 1.7 nun. At the lower margin tumor can be seen invading lymphatic spaces. In both this case and the one shown in Figure 14 there was extensive carcinoma in situ overlying the lesion as well as elsewhere in the cervix. (Hematoxylin and eosin stain, x55.)

Figure 16. Microinvasive carcinoma with heavy surronnding lymphocyte infiltrate. Note the maturation of the squamous cells. (Hematoxylin and eosin stain, x130.)

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Figure 17. l.)ml)hatic space invasion; same case as Figure 15. (ttematoxylin and eosin stain, x340.)

sire carcinoma in situ associated with fingerlike o r tonguelike projections into the stroma (Figs. 14, 15). Invasive foci are usually isolated but at times may be confluent. In earlier studies confluent lesions o r lesions with lympltatic-like space invasion were often exclnded; T M however, the m o r e recent stndies o f Roche and Norris 3~ and o f Leman et ai.fl "~ as well as o u r own, have convinced us timt those findings do not warrant exclusion. A n i m p o r t a n t f e a t u r e o f microim'asire carcinoina is the c o m m o n t e n d e n c y for the invading cells to m a t u r e (Fig. 16). Such maturation conld explain why most

invasive sqtmtnous cancers are o f the large cell nonkeratinizing or keratinizing type. A heavy infihrate o f lytnl)hocytes, alone or in combination with plasma cells, often surrottnds the invasive foci. At times they a p p e a r to be destroying the tumor. Lyrnpltatic-like space invasion has been n o t e d in as m a n y as 57 per cent o f the patients when the lesions are extensively sectioned (Fig. 17). 34 Previotts biopsy may at times p r o d u c e epithelial inclusions in the stroma that simttlate microinvasion (Fig. 18)? 4 In general, however, the diagnosis o f microinvasive carcinoma is not difficult. W h e n carcinoma in situ with questionable invasion is present and serial or step-sections cannot resolve the problem, the lesion may be designated as carcinoma in situ with qnestionable stromal im'asion. At the o t h e r e x t r e m e , when invasion is greater than 5 ram., the lesion should not be included as microinvasive.

COMMENT T h e r e can be little d o u b t tlmt the pathogenesis o f squamous carcinoma o f the l m m a n cervix has been m o r e extensively studied titan that o f carcinoma o f any o t h e r site. Tiffs has resulted f r o m tim

I ' ~ r "L

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Figure 18. l'seudoim'asive epithelial implant in a hysterectomy specimen after a punch biopsy in a case of moderate dysplasia. (Hematoxylin and eosin

s ai.. •

Figure 19. Tile fresh cone specimen opened at 12:00 is pinned to a piece of cardboard and immersed in fixative before blocking.

DISORDERS OF THE UTERINE CERVIX--CnRxSTOpHERsoN

Figure 20. Tim entire fixedcone is cnt at 1 ram. intervalswith a razor blade. The surface to be embedded dowmvard is painted with Mercurochrometo insure that adjacent surfaces are not sectioned.

ever increasing acceptance of cytologic screening of asymptomatic women. The high lesion-specific accuracy of cytology, together with its low cost and patient and physician acceptibility, allows for a safe surveillance of patients. 4r Tim accurate assessment of a wide range of epithelial abnormalities allmvs tim pathologist to differentiate between changes that are life threatening and those that are not. This in turn requires the greatest cooperation among the cytologist, pathologist, and clinician. Ahlmugh more precise definitions will undoubtedly result from fnrther experience, uniform usage of definitions as they are currently constituted would facilitate progress in our knowledge of the disease. Loose definitions result in overtreatment and needless patient anxiety and stress. Tim quality of tlm specimen and its handling in the laboratory are of great importance. Colposcopically directed biopsies, altimugh tlmught to be highly accurate in sampling tim most abnormal area(s), often result in very small specimens. When used in conjunction with cytology, however, colposcopy has'proven to be a very helpful technique in those cases in which the area of invoh'ement can be visualized, as Tim specimen must be properly oriented on a piece of paper or cardboard by the colposcopist to insure the proper plane of sectioning. Furthermore, a sharp biopsy instrument must be used. Tim epithelium should not be de-

imded by manipulation before or during tile biopsy. Multiple sharp puncll biopsies after evaluation of tile mucosal surface by tile Schiller test Itave proved to be a successful ontpatient procedm'e in the bands of man), investigators, and when used in conjtmction with cytology have proved to be highly accurate. 49,~~ Here again the same precautions must be observed. We prefer to split the specimens with a razor blade and orient them in cooperation with the histotcchnologist responsible for embedding and sectioning. Muhiple sectioning of each piece is desirable. A suggested method for handling cone specimens is illustrated in Figures 19 and 20. I f a cone is submitted in several fragments or in a fixative, it is impossible to include the maximal critical area for patlmlogic examination. In order to determine margins of excision, the raw surfaces can be xnarked by India ink or silver nitrate. The estimate of margin involvement should not replace cytologic followup if tim cone is intended to be curative as well as diagnostic. Again multiple cuts of 1 ram. blocks should be obtained. For celhflar detail Bouin's solution has proved to be superior to buffered formalin. In the hysterectomy specimen tim cervix is amputated, opened at 12:00, held open by sticks, and placed in the fixative before blocking. This allows for tlm greatest exposure of the endocervix. Pie shaped sections are then made in a

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serial fashion and the upper endocervix is s e c t i o n e d t r a n s v e r s e l y . A l t h o u g h the recommended methods are somewhat tirrie c o n s u m i n g , the resultant product justifies the extra attention and care given the specimen by the clinician, histotechnologist, and pathologist.

13. 14.

15.

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