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Oral carcinoma in situ
oral pathology Editor:
CHARLES
A. WALDRON,
D.D.S.,
M.S.D.
American Academy of Oral Pathology School of Dentistry, Emory University 1462 Clifton Road, N.E. Atlanta, Georgia 30322
Oral carcinoma in situ DEPARTMENT OF
OF
ORAL
PATHOLOGY,
IiXDIANA
UNIVERSITY
SCHOOL
DENTISTRY
Oral carcinoma in situ (CIS) as a histopnthologic entity was studied in seventy-seven patients to determine the clinical and histologic parameters of the disease. There were forty-nine male and twenty-eight female patients, with 45.1 per cent of the lesions being described clinically as white, 15.9 per cent as red, and 8.5 per cent as a combination of the two. The high-risk sites for CIS were floor of the month (23.2 per cent of all lesions), tongue (22.0 per cent), and lips (in males only, 19.5 per cent). Histologically, there was a considerable range of variation in surface keratinization, thickness of epithelium, and certain cytologic alterations. The most consistent of all cytologic changes was loss of orientation of cells. There is no information available concerning possible regression of oral CIS, as is known for CIS df uterine cervix. Furthermore, there is no information concerning the frequency of or the period of transition from oral CIS to invasive carcinoma or whether all oral carcinoma is preceded by CIS. Further studies on this disease are essential.
C
arcinoma in situ of the oral cavity is a well-recognized lesion commonly thought of as a premalignant disease, although there have been few definitive studies dealing with the condition in this location. It is more appropriately considered a histopathologic entit.y rather than a clinical entity, since a number of clinical diseases with a wide variation in their gross appearance may show the variable microscopic characteristics of carcinoma in situ. These clinical diseases include leukoplakia, erythroplakia, combinations of these two, some ulcerations alone or in combination with the preceding, and, finally, Bowen’s disease. There have been numerous articles, such as those of Shafer and Waldroni and of Pind-
Grant
This investigation was supported in part by United States Public Health No. 5.TE-CAY006 from the National Cancer Institute. ‘Distinguished Professor and Chairman, Department of Oral Pathology.
Service
Training
227
228
Oml Fcbrunry,
Rhnfel
Rurg. 1975
borg and his associates,” dealing with the microscopic characteristics of oral leukoplakia, which include carcinoma in situ in a certain limited percentage of cases, as well as several articles, such as those of Shear!’ and of Shafer and Waldron,s dealing with oral crythroplakia and its microscopic findings of carcinoma in situ in a much higher pcrccntagc of cases. 111 addition, Gorlin” has discussed the uncommon Bowcn’s tliscasc of the oral cavity, another form of carcinoma in situ. Howcvcr, there has been only one significant contributory study of the ~linicopathologic features of a series OFcasts of oral carcinoma in situ as a histopathologic entity. In that study, reportetl by Shedtl and his associates,7” ten cases of the discasc were examined ant1 it was found that in three casts the lesions appeared as an crythroplakia, in t.hree casesthey appeared as a leukoplakia, ant1 in three cases they were a misturc of the two. In one case, negligible gross changes were visible. Kramer% has provided an exccllcnt academic and practical discussion of’ carcinoma in situ of the oral mucosa and drawn attention to the known similarities and dissimilarities between it and carcinoma in situ of the uterine cervix, on which far more information is available. De has also discussedcarcinoma in situ as a “premalignant” disease, the concepts of this terminology, and its relationship to invasive carcinoma, stating that “the risk of progression to invasive carcinoma, and the rate of such progression, may bc substantially greater than carcinoma in situ of the cervix” The pnrposc of the present study is to begin to provide some base-line data on carcinoma in situ as a histopathologic diseaseentity as a prelude to furthering our knowledge of the natural history of the disease, as has been already largely accomplished for carcinoma in situ of the uterine cervix. There is a fairly substantial amount of data available concerning the microscopic nature of certain of the clinical entities, such as leukoplakia and erythroplakia, which sometimes represent carcinoma in situ. However, there is very little information extant Conccrning the diseaseas a microscopic entity regardless of its clinical nature. MATERIALS
AND
METHODS
The files of the tissue diagnosis scrvicc of Indiana University School of Dentistry, Department of Oral Pathology, served as the source of material in this study-. All casescoded as carcinoma in situ (CIS) between Oct. 1, 1950, and June 30, 1974, were retrieved and the histologic sections were reviewed. No caseswere accepted for inclusion in the study if there had been a previous diagnosis of carcinoma at the same site as the CIS. Therefore, all lesions were “virgin” lesions and did not represent any form of recurrence or residual tumor. As each case history was examined, note was made of the patient’s age and sex, location of the lesion, description of the clinical appearance of the lesion, whether the lesion was suspected by the clinician as being a dysplastic or neoplastic one, the known duration of the lesion as stated by the patient, and whether the lesion was symptomatic. The histologic criteria used for the diagnosis of CIS were those generally stated by most authoritative sources. These included (1) increased and abnormal mitoses, (2) individual cell keratinization, (3) epithelial pearl formation, (4)
\‘olume ITumber
39 2 MALE (49) FEMALE ( 77 /45,702
( 28) = 0.17% )
17
5
3rd
4th
5th
6th DECADE
Pig.
1. Distribution
of occurrence
of oral
7th
8th
in situ
by decade
9th
OF LIFE
carcinoma
of life
according
to
sex.
alteration in the nuclear/cytoplasmic ratio, (5) loss of cell polarity, (6) disorientation of cells, (7) hyperchromatic nuclei, (8) large and prominent nucleoli, (9) nuclear atypism with giant nuclei, (10) poikilocarynosis, and (11) basilar hyperplasia, with the individual lesion showing no invasion of connective tissue and being confined by the “basement membrane.” Obviously, in any given case not all of these alterations need necessarily be present for a diagnosis of carcinoma in situ to be made. The number or degree of such alterations necessary to establish such a diagnosis is simply a matter of experience on the part of the pathologist. It has been well established (for example, by Qovan and his associate@ and from unpublished data from the meeting of investigators on Histopathological Nomenclature and Classification of Oral Precancerous Conditions of the World Health Organization in 1973) that not only is there seldom uniform agreement among a group of even experienced pathologists on a series of cases of “probable carcinoma in situ” but there is even variation from one day or one week to the next by the same pathologist as to his diagnosis of degree of epithelial dysplasia or carcinoma in situ. However, typical examples of what I have considered as carcinoma in situ and included in the present study are illustrated subsequently. Each case was reviewed histologically, and at that time specific note was made concerning certain microscopic characteristics of the lesion. These included (1) presence or absence or orthokeratin or parakeratin over the surface of the lesion, (2) presence or absence of individual cell keratinization or epithelial pearl formation in the lesion, (3) whether the lesional epithelium appeared of normal thickness, atrophic, or thicker than normal for the site involved, (4) presence of an increased nuclear/cytoplasmic ratio of lesional cells, (5) presence of prominent cellular pleomorphism, (6) presence of prominent nuclear hyperchromatism, (7) loss of orientation of cells, (8) presence of basilar hyperplasia, and (9) involvement of underlying accessory salivary gland ducts, if present.
Oral Surg.
230
Shafer
Table
1. Carcinoma in situ, site of OCCUB~~~CC by sex Site
February,
i
Xale
I
Fern&
I
1
Total
h-0.
Per total
1975
cent of lesions
T,ip
Upper
Lower Maxillary gingiva, ridge and fold Mandibular gingiva, ridge and fold Palate, soft lhxxl mucosa Tongue Floor of mouth Retromolar Tonsillnr pillal Total numijer of lrsions
2 14
2.4 17.1
3
4.9
1 5 4 7 11 3 1
6.1 6.1 11.0 22.0 23.2 4.9 2.4
1
RESULTS
A total of seventy-seven patients with oral carcinoma in situ were found among the 45,702 cases accessioned during this approximately 26year period. In five instances, two biopsy specimens were taken at the same time because of simultaneous involvement of two different sites, so that the total number of lesions was eighty-two. In reviewing the histories, it was found that five of these seventy-seven patients had or previously had had an invasive carcinoma at some other intraoral site. In addition, four patients hat1 or previously had had an unrelated malignant tumor at someother site in the body. Of these seventy-seven patients, forty-nine were males and twenty-eight mere females. The age distribution by sex is shown in Fig. 1. Interestingly, the peak incidence of occurrence in the fifth, sixth, and seventh decades of life coincides almost exactly with the age at occurrence of invasive oral epidermoid carcinoma in a series of 490 casesstudied several years previously in this laboratory. In this same previous study, the male/female ratio was 2.2 :1, while in the present CIS study the ratio is I..8 :l. Clinical
findings
The site of occurrence of the eighty-two lesions, separated according to sex, is shown in Table I. As may be noted, there were no casesof CIS occurring on the lips or palate in female patients. This was to be expected on the lips, but it was not expected on the palate. However, this latter finding may be fortuitous because of the limited number of casesavailable. It is significant that all casesof CIS on the palate in males involved the soft palate. No caseswcrc found on the hard palate. This is in consonance with the generally recognized finding that invasive epidermoid carcinoma of the hard palate is quite rare. No other rcmarkable differences were found between the sexes in the distribution of the lesions. It is apparent that the floor of the mouth (23.2 per cent of lesions), tongue (22.0 per cent of lesions), and lips (in males, 19.5 per cent of lesions) are the high-risk sites for CIS of the oral cavity, followed by the buccal mucosa (11.0 per cent of
Volume Number Table
Oral carcinoma
39 2 II.
Carcinoma
in
1
Site
site of occurrence
situ, R
1
W
) R-W
:
-
Lip Upper Lower Mynyaro;dgingiva,
ridge
1
2 Mandihular gingiva, ridge and fold Palate, soft Buccal mueosa Tongue Floor of mouth Retromolar Tonsillar pillar Total number of lesions Per cent of total lesions
2 2
-
2” 2 2
13 15.9
-
2
-
2 9 9 1
7
37-T 45.1
2 4 8.5
by clinical 1
) R-U
1 6
-
-
-
-
-
1 1 1 ii--i--z-T 13.4
231
appearance
lJ
1
in situ
(
W-U
I
Uris. -
) Total
2
2 14
-
1
4
-
-
1
5 5 9 18 19
1
1
1
1 3 -
-
1 3
i sz
1.2
4.9
11.0
R-Red lesion. W-White lesion. R-W-Mixed red and white lesion. U-Ulcerated lesion. R-U-Red and ulcerated lesion. W-U-White and ulcerated lesion. Uris.-Appearance unstated.
lesions). This distribution is roughly comparable to that found in a series of 158 lesions of asymptomatic early oral squamous-cell carcinoma reported by Mashberg and his associates.5 The clinical appearance of the lesions as described by the clinicians was found to be of six basic types: (1) red lesions, (2) white lesions, (3) mixed red and white lesions, (4) ulcerated lesions, (5) red ulcerated lesions, and (6) white ulcerated lesions. In a few cases, the appearance of the lesion was not described. These data are shown in Table II. Thus, thirty-seven of the eighty-two lesions, or 45.1 per cent, were described as white lesions (“leukoplakia,” “keratotic lesions, ” etc.), with four additional lesions (4.9 per cent), being described as white lesions with an area of ulceration. In thirteen instances, or 15.9 per cent of the total number of lesions, the CIS was described as a red lesion, while in one additional case it was noted to be a red ulcerated one. In seven cases (8.5 per cent of lesions), the description was that of a mixed red and white lesion. Interestingly, the majority of lesions described as ulcers occurred on the lips, with only four cases appearing at other intraoral sites. Thus, forty-eight of the eightytwo lesions (58.5 per cent) had some degree of white appearance, while only twenty-one lesions (25.6 per cent) had some degree of red appearance. This is in distinct contrast to the study by Mashberg and his associates, who found that 90.5 per cent of the early oral carcinomas had an erythroplastic component and that only four lesions were solely white. There were no apparent differences between males and females in the clinical appearance of t,he lesions, with one exception: In males, there were ten lesions described as ulcers while there was only one such instance in a female. Carcinoma in situ was not suspected by the clinician in the vast majority of cases, In only eleven instances in males and seven in females (a total of 23.4 per
232
Rhrrft?,
Table
III. Carcinoma
Table
IV.
Oral Fdxuary,
Carcinoma
in situ, clinical appearance
in situ, rlinical I
Male P‘ernalr Total
Table
numller
V.
of
cases
Carcinoma
Yes
suspicion
1975
by sex
of dysplasia X0
or neoplasia Xot
stated
11 7
19 14
19 7
Ix
33
-z
in situ, duration
Slug.
of lesion hy sex
cent of cases) (lid the clinician state that hc thought that hc might he dealing with a dysplastic or neoplastic lesion (Table IV). In nineteen cases in males and fourteen C~SCS in females, he either stated spwifically that he did not consider this a serious lesion or gaw a provisional diagnosis of some other less serious condition. In ninctccn cases in males ant1 seven cases in females, the clinician did not state whether hc consitleretl the lesion to be serious, so presumably he did not. The lesion was found to bc synptomatk in fourteen cases in males and ten cases in females, but it was specifkally asynptomatic in thirtg-four males and eighteen females. 111one case involving a male patient,, it, was not statctl whether the lesion was symptomatic. The duration of the Icsion n-as givcw in only twenty-one cases in males ant1 thirteen wscs in females. As shown in Table V, the Icsion in swrntcen of the twenty-one male cases (81 per cent) had a duration of 6 months or less, while only six of the thirteen female caases (46 per cent) were of similar duration. Surprisingly, there were only two males who stated that their lesions had been present for more than 7 y~lr (36 mont,hs in one wsc ant1 “years” in t,hc other). However, there w’cre five womw~ who statetl that their lesions hat1 been prcscnt for more than 1 year ( 18 months, 2 years, ‘Ll/! years, 3 years, and 8 years). Thus, the mean duration of the lesions in males (tlisrcgartlin g the one prcscnt for “years”) was approsimatclr 5.2 months, while for females it, was 1X.1 months (or 11.6 months if the X-year lesion is (lisrcgardetl). \Vhcthcr this longer duration of lesions prior to diagnosis in females is significant or fortuitous tluc to the small sample size remains to be determiiictl.
Volume Kumber Table
Oral carcinoma
39 2 Vi.
(
VII.
233
Carcinoma in situ, presence of surface keratin
Males Females Total number
Table
ilz situ
Parakeratin
1
25 19 44
of cases
Combination
Orthokeratin
1
None
2 0 :
11 1 75
11 8 19
Carcinoma in situ, thickness of lesional epithelium I
Males F’cmales Total number
of cases
Hyperplastic 17 13 30
(
Atrophic 19 4 24
No
change 13 11 23
In this connection, it might be suggested that the cause of the apparent rarity of oral CIS (seventy-seven casesin 45,702 accessions,or 0.17 per cent) could be a relatively short transition period from CIS to invasive carcinoma, SO that it would be almost pure chance if the lesion were to be diagnosed during this time. This could be in contrast to CIS of the uterine cervix, where the transition period is often measured in years. Histologic
findings
A rather remarkable range of variation existed in the histologic appearance of this series of casesof CIS (Fig. 2). In the five casesin which biopsy specimens of multiple sites were taken, t,he findings in each case were combined, since the changes in each instance were identical. The presence or absence of a keratinized surface over the lesion was ascertained in each case, and the findings are shown in Table VI. The lesional surface was covered by parakeratin in forty-four cases,by orthokeratin in twelve eases, and by a combination of the two in two cases,while there was no keratin over the surface in nineteen cases.In the majority of unkeratinized cases,the lesions were red or erythroplakic. However, this was not invariably the case, since a few lesions described as erythroplakia did show a keratotic surface while a few lesions described as leukoplakia showed no surface keratin. There were no apparent sex differences in the occurrence of a keratotic surface except for the formation of orthokeratin where it was found to be present in eleven males but in only one female. Individual cell keratinization and epithelial or keratin pearl formation were exceedingly rare. In fact, the study of these casesof CIS and of casesof superficially invasive epidcrmoid carcinoma strongly suggest that the presence of individual cell keratinization and/or pearl formation is often a hallmark of transformation of CIS into superficially invasive carcinoma and that either of these two findings in an apparent case of CIS should mandate a further search for evidence of carcinomatous invasion. In the present series, only three instances of individual cell keratinization and four instances of pearl formation were found. In these cases,the cellular keratinization was limited to just a few cells or to usually a single pearl.
234
Shnfer
Oral February,
Surg. 1975
Fig. 8. Different examples of oral carcinoma in situ to illustrate the variation in pattern of the epithelium. All photomicrographs were taken, printed, and reproduced at the same magnification for comparative purposes. A, A hyperplastic type of CIS showing a sharp line of demarcation l)cltween normal and altered epithelium. H, An atrophic type of CTS showing a similar sharp Iine of demarcation ?)etw+en normal and altered epitheliuni. C, Rasilar hyperplnsia with top-to-bottom change and no significant pleomorphism. D, An atrophic type of CTS \vith moderate pleomorphism and hyl’erettronlntislll. B, A keratinizing CIS shaming a stratification of the lower two thirds of the epithelium exhibiting basilar hyperplasia but the upper third being essentially normal. P, a CIS with a rather pleomorphic top-to-bottom basilar hyperplasia. C, An atrophic CIS with a very thick surface layer of orthokerntin in one area but no keratin over the adjacent area. The nature of the lesional epithelium was also studied to ascertain hyperplasia, atrophy, or absence of significant change, and the findings are shown in Table VII. The epithelium was thicker than usual in thirty cases (seventeen males and thirteen females) and thinner than usual in twenty-three cases (nineteen males but only four females), while no significant change in over-all thickness was found in twenty-four casts (thirteen males and eleven females), Whether the low incidence of epithelial atrophy in females is significant remains to be determined. However, it was quite unexpcctetl in view of its being a common finding in females in such disorders as the Plummer-Vinson syndrome. Certain individual cytologic alterations were studied to determine the frequency with which they occurred in CIS. Specifically, these were (1) a prominent increased nuclcar/cytoplasmic ratio, (2) a prominent cellular plco-
Volume Number
Oml cm-oi~~om~ i?l situ,
39 2
Fig.
8. E-G.
For
legend,
see opposite
235
page.
morphism, and (3) a prominent nuclear hyperchromatism. A prominent increased nuclear/cytoplasmic ratio was not a particularly common finding. It was present in forty-two cases (twenty-eight males and fourteen females) but absent in thirty-five cases (twenty-one males and fourteen females). Similarly, a prominent nuclear hyperchromatism was not particularly common. It was present in forty-four cases (twenty-nine males and fifteen females) but absent in thirtythree cases (twenty males and thirteen females). However, one of the surprising findings was the relative infrequency of cellular pleomorphism, being present in thirty-one cases (eighteen males and thirteen females) but absent in forty-six cases (thirty-one males and fifteen females). Furthermore, this absence of cellular pleomorphism could not be correlated with a high frequency of basilar hyperplasia, where there would obviously be a general lack of pleomorphism, since only seventeen cases (ten males and seven females) showed significant basilar hyperplasia while sixty cases (thirty-nine males and twenty-one females) did not. The one most conspicuous and almost uniformly consistent cytologic alteration was the loss of orientation of cells. This loss of orderly arrangement of cells, individually and with respect to their neighbors and their loss of normal polarity, was found in all forty-nine cases of CIS in males and in twenty-six of the twentyeight cases in females. Both of the latter two lesions in females where this was not present occurred in leukoplakie lesions covered with parakeratin. Finally, accessory salivary ducts were present in the biopsy specimens in only
twelve of the seventy-six cases. In only one instance did the CIS changes appeal to involve any of these underlying ducts. No particular attempt was made to evaluate degree of mitotic activity in these cases, since the number of mitotic figures in thr cases rcvicwrtl generally was estremcly limited. In a given lesion, three or four mitotic figures might bc found in one low-power field, but none in closely adjacent fields. This inconsistency and lack of widt range of variability made such an evaluation, in our ol)inion, of little significance. Several additional observations arc also of some interest. In certain lesions, a very sharp line of division existed between the CIS and the adjacent microscopically normal epithclium. This was so pronounced on some occasions that it appeared as though a full layer of normal epithelial cells were abutting directly against a full layer of dysplastic or neoplastie cells. In this connection also, in a few instances multiple areas of carcinoma in situ were found distributed throughout cssentiallp normal epithelium, producing the picture of multifocal carcinoma in situ analogous to multifocal basal-cell carcinoma of the skin. DISCUSSION
Present-day knowledge of oral carcinoma in situ is exceedingly limited in scope, partly because of a lack of any significant number of reported cases.Fairly good data have been accumulated indicating that a certain small percentage of cases of leukoplakia are, in fact., histologically carcinoma in situ. There is considerablc evidence also that a very cdonsiderablcpercentage of cases of crythroplakia are histologically carcinoma in situ. 111addition, as found in the present study and as emphasized by others, these lesions of carcinoma in situ may appear mixed red and white, slightly ulcerated, or even show no appreciable gross change. I:nfortunately, there is a total lack of information on the clinical behavior of oral c.arcinoma in situ in general or on whether each of the clinically diRerent forms of carcinoma in situ will ha\-e a clinically similar or different behavior. In contrast, there is a voluminous amount of information available concerning the nature of carcinoma in situ of the uterine cervix and considerable knowledge as to the clinical behavior of the lesion in that location. While it is tempting to extrapolate data on carcinoma in situ of the cervix to carcinoma in situ of the oral mucous membranes, the epithelia in these two locations arc similar in some respects but totally different in others. For this reason, it will be necessary to go through the same slow, prolonged painstaking process of accumulating data on oral carcinoma in situ as was necessary in the past for cervix. It will be essential to determine whether the various stages of epithelial dysplasia of the oral mucosa (mild, moderate, and severe) will regress, persist, or progress to carcinoma in situ, as has been done for similar lesions of the cervix. It will be necessary to determine the frequency of transition of oral carcinoma in situ to invasive cancer, as has been done for similar lesions of the cervix, as well as to determine the frequency of spontaneous disappearance, if, indeed, such a thing does happen with oral carcinoma in situ. It will be necessary to determine the preinvasivc period of the various clinical forms of oral carcinoma in situ, as has
already been done with respect to the cervical lesions. It will be essential also to determine the frequency of occurrence of multiple oral lesions for better management of patients. Some efforts hare already been made in this direction (for example, by Slaughter and his co-workers11 and by Wynder and his associate+‘). Unfortunately, the present report does not answer any of the above questions. It is only the modest beginning of an attempt to collect some clinicopathologic information on a series of patients with this disease. The nature of this patient population totally precludes obtaining significant follow-up information. The vast majority of these patients were those of private general dental practitioners in Indiana and surrounding states. Following receipt of a biopsy report of carcinoma in situ, one of several events would occur. The practitioner, in a very few instances, would rc-excise the lesion. More frequently, the patient would be referred to an oral surgeon, who would either rc-excise the lesion and send the tissue to this laboratory or to a hospital or private pathology laboratory or refer the patient to a general surgeon. In still other cases, the patient would be rcferrcd to the family physician, who elected to treat the lesion himself, refer the patient to a general surgeon for treatment, or refer him to this or some other medical center. In still other instances, the pa,tient was referred directly to a medical center by one of the dentists involved. Because of the many possibilities of patient disposal, we have practically no information on the eventual outcome of the cases in this series. Yevcrthcless, we can be almost certain that each patient was treated further, by some means, properly or improperly, so that no information would bc possible from this group regarding data comparable to existing data from cervical lesions (for example, outcome of untreated lesions, prcinvasire period of untreated lesions, ctc) . Little attention has also been paid to the question of exactly what immediately precedes the development of invasive oral epidermoid carcinoma. Does it cllways develop in a prc-existing carcinoma in situ, or does this occur only occasionally? Ackerman and RIcGarranl ha\-e stated their belief that at least many invasive cancers originate as in situ lesions and that the speed of evolution of this lesion from intraepithclial to invasive cancer is cxtremcly variable. In thei thoughtful discussion of “field canccrization” of oral stratifietl squamous epithelium, Slaughter and his associates I1 found that abnormal and hypcrplastic, often atypical, epithelium was found to surround all oral cancers for varying distances in their series of 783 pat,icnts. This might imply that carcinoma develops only in altered cpithelium, but whether this is ncccssarily altered to the point of carcinoma in situ is certainly not clear. Finally, Shedd and his associate+” have concluded that carcinoma in situ is a stage in the evolution of cancer. It is hoped t,hat the present study, by re-cmphasizin g many unanswered questions concerning carcinoma in situ of the oral cavity, will serve to stimulate further investigation of this disease. REFERENCES
1. Ackerman, L. V., and McGavran, M. H.: Proliferating Eenign and Malignant Lesions the Oral Cavity, J. Oral Surg. 16: 400-413, 1958. 2. Gorlin, R. J.: Bowen’s Disease of the Mucous Membrane of the Mouth, ORAL SUI:G. 35-51, 1950.
of 3:
238
Shafat
Oral slug. February,
1975
3. Govan, A. 1). T., Haines, R. M., Langley, 1”. A., Taylor, C. W., and Woodcock, A. S.: Chances in the Euithelium of the Cervix Uteri: a Studv 1)~ the Panel of Pntholoeists Engaged in a Sur;ey of Carcinoma-in-Situ Carried Out b; the Royal College1 of Obstitricians and Gynaecologists, J. Obstet. Gynaecol. Br. Commonw. 73: 883-896, 1966. 4. Kramer, 1. R. H.: Carcinoma-in-Situ of the Oral Mucosa, lnt. Dent. J. 23: 94.99, 1973. 5. Mashberg, A:, Morrissey, J. B., and Garfinkel, L.: A Study of the Appearance of Early Asymptomatic Oral Squamous Cell Carcinoma, Cancer 32: 1436.1445, 1973. 6. Pindborg, J. J., Renstrup, G., Poulsen, H. E., and Silverman, S., Jr.: Studies in Oral Leukoplakias. V. Clinical and Histologic Signs of Malignancy, Acta Odontol. Scantl. 21: 407-414, 1963. 7. Shafer, W. G., and Waldron, C. A.: A Clinical and Histopathologic Study of Oral Leukoplakia, Surg. Gynecol. Obstet. 112: 41 l-420, 1961. 8. Shafer, W. G., and Waldron, C. A.: Erythroplakia of the Oral Cavity, Cancer (In press.) 9. Shear, M. : Erythroplakia of the Mouth, Int. Dent. J. 22: 460.473, 1972. 10. Shedd, D. P., Hukill, P. B., Kligerman, M. M., and Gowen, G. F.: A Clinicopathologic Study of Oral (:arcinoma-in-Situ, am. .I. Surg. 106: 791.796, 1963. 11. Slaughter, D. P., Southwick, H. W., and Smejkal, W.: “Field Cancerizat,ion” in Oral Stratified Squamous Epithebum; Clinical Implications of Multicentric Origin, Cancer 6: 963-968, 1953. 12. Wynder, E. L., Brass, 1. J., and Feldman, K. M.: A Study of the Etiologic Factors in Cancer of the Mouth, (:ancer 10: 1300-1323, 1957. requests to: Dr. William G. Shafer Department of Oral Pathology Indiana University School of Dentistry Indianapolis, Ind. 46202 Reprint
CHARLES
A. WALDRON,
D.D.S.,
M.S.D.
American Academy of Oral Pathology School of Dentistry, Emory University 1462 Clifton Road, N.E. Atlanta, Georgia 30322
Oral carcinoma in situ DEPARTMENT OF
OF
ORAL
PATHOLOGY,
IiXDIANA
UNIVERSITY
SCHOOL
DENTISTRY
Oral carcinoma in situ (CIS) as a histopnthologic entity was studied in seventy-seven patients to determine the clinical and histologic parameters of the disease. There were forty-nine male and twenty-eight female patients, with 45.1 per cent of the lesions being described clinically as white, 15.9 per cent as red, and 8.5 per cent as a combination of the two. The high-risk sites for CIS were floor of the month (23.2 per cent of all lesions), tongue (22.0 per cent), and lips (in males only, 19.5 per cent). Histologically, there was a considerable range of variation in surface keratinization, thickness of epithelium, and certain cytologic alterations. The most consistent of all cytologic changes was loss of orientation of cells. There is no information available concerning possible regression of oral CIS, as is known for CIS df uterine cervix. Furthermore, there is no information concerning the frequency of or the period of transition from oral CIS to invasive carcinoma or whether all oral carcinoma is preceded by CIS. Further studies on this disease are essential.
C
arcinoma in situ of the oral cavity is a well-recognized lesion commonly thought of as a premalignant disease, although there have been few definitive studies dealing with the condition in this location. It is more appropriately considered a histopathologic entit.y rather than a clinical entity, since a number of clinical diseases with a wide variation in their gross appearance may show the variable microscopic characteristics of carcinoma in situ. These clinical diseases include leukoplakia, erythroplakia, combinations of these two, some ulcerations alone or in combination with the preceding, and, finally, Bowen’s disease. There have been numerous articles, such as those of Shafer and Waldroni and of Pind-
Grant
This investigation was supported in part by United States Public Health No. 5.TE-CAY006 from the National Cancer Institute. ‘Distinguished Professor and Chairman, Department of Oral Pathology.
Service
Training
227
228
Oml Fcbrunry,
Rhnfel
Rurg. 1975
borg and his associates,” dealing with the microscopic characteristics of oral leukoplakia, which include carcinoma in situ in a certain limited percentage of cases, as well as several articles, such as those of Shear!’ and of Shafer and Waldron,s dealing with oral crythroplakia and its microscopic findings of carcinoma in situ in a much higher pcrccntagc of cases. 111 addition, Gorlin” has discussed the uncommon Bowcn’s tliscasc of the oral cavity, another form of carcinoma in situ. Howcvcr, there has been only one significant contributory study of the ~linicopathologic features of a series OFcasts of oral carcinoma in situ as a histopathologic entity. In that study, reportetl by Shedtl and his associates,7” ten cases of the discasc were examined ant1 it was found that in three casts the lesions appeared as an crythroplakia, in t.hree casesthey appeared as a leukoplakia, ant1 in three cases they were a misturc of the two. In one case, negligible gross changes were visible. Kramer% has provided an exccllcnt academic and practical discussion of’ carcinoma in situ of the oral mucosa and drawn attention to the known similarities and dissimilarities between it and carcinoma in situ of the uterine cervix, on which far more information is available. De has also discussedcarcinoma in situ as a “premalignant” disease, the concepts of this terminology, and its relationship to invasive carcinoma, stating that “the risk of progression to invasive carcinoma, and the rate of such progression, may bc substantially greater than carcinoma in situ of the cervix” The pnrposc of the present study is to begin to provide some base-line data on carcinoma in situ as a histopathologic diseaseentity as a prelude to furthering our knowledge of the natural history of the disease, as has been already largely accomplished for carcinoma in situ of the uterine cervix. There is a fairly substantial amount of data available concerning the microscopic nature of certain of the clinical entities, such as leukoplakia and erythroplakia, which sometimes represent carcinoma in situ. However, there is very little information extant Conccrning the diseaseas a microscopic entity regardless of its clinical nature. MATERIALS
AND
METHODS
The files of the tissue diagnosis scrvicc of Indiana University School of Dentistry, Department of Oral Pathology, served as the source of material in this study-. All casescoded as carcinoma in situ (CIS) between Oct. 1, 1950, and June 30, 1974, were retrieved and the histologic sections were reviewed. No caseswere accepted for inclusion in the study if there had been a previous diagnosis of carcinoma at the same site as the CIS. Therefore, all lesions were “virgin” lesions and did not represent any form of recurrence or residual tumor. As each case history was examined, note was made of the patient’s age and sex, location of the lesion, description of the clinical appearance of the lesion, whether the lesion was suspected by the clinician as being a dysplastic or neoplastic one, the known duration of the lesion as stated by the patient, and whether the lesion was symptomatic. The histologic criteria used for the diagnosis of CIS were those generally stated by most authoritative sources. These included (1) increased and abnormal mitoses, (2) individual cell keratinization, (3) epithelial pearl formation, (4)
\‘olume ITumber
39 2 MALE (49) FEMALE ( 77 /45,702
( 28) = 0.17% )
17
5
3rd
4th
5th
6th DECADE
Pig.
1. Distribution
of occurrence
of oral
7th
8th
in situ
by decade
9th
OF LIFE
carcinoma
of life
according
to
sex.
alteration in the nuclear/cytoplasmic ratio, (5) loss of cell polarity, (6) disorientation of cells, (7) hyperchromatic nuclei, (8) large and prominent nucleoli, (9) nuclear atypism with giant nuclei, (10) poikilocarynosis, and (11) basilar hyperplasia, with the individual lesion showing no invasion of connective tissue and being confined by the “basement membrane.” Obviously, in any given case not all of these alterations need necessarily be present for a diagnosis of carcinoma in situ to be made. The number or degree of such alterations necessary to establish such a diagnosis is simply a matter of experience on the part of the pathologist. It has been well established (for example, by Qovan and his associate@ and from unpublished data from the meeting of investigators on Histopathological Nomenclature and Classification of Oral Precancerous Conditions of the World Health Organization in 1973) that not only is there seldom uniform agreement among a group of even experienced pathologists on a series of cases of “probable carcinoma in situ” but there is even variation from one day or one week to the next by the same pathologist as to his diagnosis of degree of epithelial dysplasia or carcinoma in situ. However, typical examples of what I have considered as carcinoma in situ and included in the present study are illustrated subsequently. Each case was reviewed histologically, and at that time specific note was made concerning certain microscopic characteristics of the lesion. These included (1) presence or absence or orthokeratin or parakeratin over the surface of the lesion, (2) presence or absence of individual cell keratinization or epithelial pearl formation in the lesion, (3) whether the lesional epithelium appeared of normal thickness, atrophic, or thicker than normal for the site involved, (4) presence of an increased nuclear/cytoplasmic ratio of lesional cells, (5) presence of prominent cellular pleomorphism, (6) presence of prominent nuclear hyperchromatism, (7) loss of orientation of cells, (8) presence of basilar hyperplasia, and (9) involvement of underlying accessory salivary gland ducts, if present.
Oral Surg.
230
Shafer
Table
1. Carcinoma in situ, site of OCCUB~~~CC by sex Site
February,
i
Xale
I
Fern&
I
1
Total
h-0.
Per total
1975
cent of lesions
T,ip
Upper
Lower Maxillary gingiva, ridge and fold Mandibular gingiva, ridge and fold Palate, soft lhxxl mucosa Tongue Floor of mouth Retromolar Tonsillnr pillal Total numijer of lrsions
2 14
2.4 17.1
3
4.9
1 5 4 7 11 3 1
6.1 6.1 11.0 22.0 23.2 4.9 2.4
1
RESULTS
A total of seventy-seven patients with oral carcinoma in situ were found among the 45,702 cases accessioned during this approximately 26year period. In five instances, two biopsy specimens were taken at the same time because of simultaneous involvement of two different sites, so that the total number of lesions was eighty-two. In reviewing the histories, it was found that five of these seventy-seven patients had or previously had had an invasive carcinoma at some other intraoral site. In addition, four patients hat1 or previously had had an unrelated malignant tumor at someother site in the body. Of these seventy-seven patients, forty-nine were males and twenty-eight mere females. The age distribution by sex is shown in Fig. 1. Interestingly, the peak incidence of occurrence in the fifth, sixth, and seventh decades of life coincides almost exactly with the age at occurrence of invasive oral epidermoid carcinoma in a series of 490 casesstudied several years previously in this laboratory. In this same previous study, the male/female ratio was 2.2 :1, while in the present CIS study the ratio is I..8 :l. Clinical
findings
The site of occurrence of the eighty-two lesions, separated according to sex, is shown in Table I. As may be noted, there were no casesof CIS occurring on the lips or palate in female patients. This was to be expected on the lips, but it was not expected on the palate. However, this latter finding may be fortuitous because of the limited number of casesavailable. It is significant that all casesof CIS on the palate in males involved the soft palate. No caseswcrc found on the hard palate. This is in consonance with the generally recognized finding that invasive epidermoid carcinoma of the hard palate is quite rare. No other rcmarkable differences were found between the sexes in the distribution of the lesions. It is apparent that the floor of the mouth (23.2 per cent of lesions), tongue (22.0 per cent of lesions), and lips (in males, 19.5 per cent of lesions) are the high-risk sites for CIS of the oral cavity, followed by the buccal mucosa (11.0 per cent of
Volume Number Table
Oral carcinoma
39 2 II.
Carcinoma
in
1
Site
site of occurrence
situ, R
1
W
) R-W
:
-
Lip Upper Lower Mynyaro;dgingiva,
ridge
1
2 Mandihular gingiva, ridge and fold Palate, soft Buccal mueosa Tongue Floor of mouth Retromolar Tonsillar pillar Total number of lesions Per cent of total lesions
2 2
-
2” 2 2
13 15.9
-
2
-
2 9 9 1
7
37-T 45.1
2 4 8.5
by clinical 1
) R-U
1 6
-
-
-
-
-
1 1 1 ii--i--z-T 13.4
231
appearance
lJ
1
in situ
(
W-U
I
Uris. -
) Total
2
2 14
-
1
4
-
-
1
5 5 9 18 19
1
1
1
1 3 -
-
1 3
i sz
1.2
4.9
11.0
R-Red lesion. W-White lesion. R-W-Mixed red and white lesion. U-Ulcerated lesion. R-U-Red and ulcerated lesion. W-U-White and ulcerated lesion. Uris.-Appearance unstated.
lesions). This distribution is roughly comparable to that found in a series of 158 lesions of asymptomatic early oral squamous-cell carcinoma reported by Mashberg and his associates.5 The clinical appearance of the lesions as described by the clinicians was found to be of six basic types: (1) red lesions, (2) white lesions, (3) mixed red and white lesions, (4) ulcerated lesions, (5) red ulcerated lesions, and (6) white ulcerated lesions. In a few cases, the appearance of the lesion was not described. These data are shown in Table II. Thus, thirty-seven of the eighty-two lesions, or 45.1 per cent, were described as white lesions (“leukoplakia,” “keratotic lesions, ” etc.), with four additional lesions (4.9 per cent), being described as white lesions with an area of ulceration. In thirteen instances, or 15.9 per cent of the total number of lesions, the CIS was described as a red lesion, while in one additional case it was noted to be a red ulcerated one. In seven cases (8.5 per cent of lesions), the description was that of a mixed red and white lesion. Interestingly, the majority of lesions described as ulcers occurred on the lips, with only four cases appearing at other intraoral sites. Thus, forty-eight of the eightytwo lesions (58.5 per cent) had some degree of white appearance, while only twenty-one lesions (25.6 per cent) had some degree of red appearance. This is in distinct contrast to the study by Mashberg and his associates, who found that 90.5 per cent of the early oral carcinomas had an erythroplastic component and that only four lesions were solely white. There were no apparent differences between males and females in the clinical appearance of t,he lesions, with one exception: In males, there were ten lesions described as ulcers while there was only one such instance in a female. Carcinoma in situ was not suspected by the clinician in the vast majority of cases, In only eleven instances in males and seven in females (a total of 23.4 per
232
Rhrrft?,
Table
III. Carcinoma
Table
IV.
Oral Fdxuary,
Carcinoma
in situ, clinical appearance
in situ, rlinical I
Male P‘ernalr Total
Table
numller
V.
of
cases
Carcinoma
Yes
suspicion
1975
by sex
of dysplasia X0
or neoplasia Xot
stated
11 7
19 14
19 7
Ix
33
-z
in situ, duration
Slug.
of lesion hy sex
cent of cases) (lid the clinician state that hc thought that hc might he dealing with a dysplastic or neoplastic lesion (Table IV). In nineteen cases in males and fourteen C~SCS in females, he either stated spwifically that he did not consider this a serious lesion or gaw a provisional diagnosis of some other less serious condition. In ninctccn cases in males ant1 seven cases in females, the clinician did not state whether hc consitleretl the lesion to be serious, so presumably he did not. The lesion was found to bc synptomatk in fourteen cases in males and ten cases in females, but it was specifkally asynptomatic in thirtg-four males and eighteen females. 111one case involving a male patient,, it, was not statctl whether the lesion was symptomatic. The duration of the Icsion n-as givcw in only twenty-one cases in males ant1 thirteen wscs in females. As shown in Table V, the Icsion in swrntcen of the twenty-one male cases (81 per cent) had a duration of 6 months or less, while only six of the thirteen female caases (46 per cent) were of similar duration. Surprisingly, there were only two males who stated that their lesions had been present for more than 7 y~lr (36 mont,hs in one wsc ant1 “years” in t,hc other). However, there w’cre five womw~ who statetl that their lesions hat1 been prcscnt for more than 1 year ( 18 months, 2 years, ‘Ll/! years, 3 years, and 8 years). Thus, the mean duration of the lesions in males (tlisrcgartlin g the one prcscnt for “years”) was approsimatclr 5.2 months, while for females it, was 1X.1 months (or 11.6 months if the X-year lesion is (lisrcgardetl). \Vhcthcr this longer duration of lesions prior to diagnosis in females is significant or fortuitous tluc to the small sample size remains to be determiiictl.
Volume Kumber Table
Oral carcinoma
39 2 Vi.
(
VII.
233
Carcinoma in situ, presence of surface keratin
Males Females Total number
Table
ilz situ
Parakeratin
1
25 19 44
of cases
Combination
Orthokeratin
1
None
2 0 :
11 1 75
11 8 19
Carcinoma in situ, thickness of lesional epithelium I
Males F’cmales Total number
of cases
Hyperplastic 17 13 30
(
Atrophic 19 4 24
No
change 13 11 23
In this connection, it might be suggested that the cause of the apparent rarity of oral CIS (seventy-seven casesin 45,702 accessions,or 0.17 per cent) could be a relatively short transition period from CIS to invasive carcinoma, SO that it would be almost pure chance if the lesion were to be diagnosed during this time. This could be in contrast to CIS of the uterine cervix, where the transition period is often measured in years. Histologic
findings
A rather remarkable range of variation existed in the histologic appearance of this series of casesof CIS (Fig. 2). In the five casesin which biopsy specimens of multiple sites were taken, t,he findings in each case were combined, since the changes in each instance were identical. The presence or absence of a keratinized surface over the lesion was ascertained in each case, and the findings are shown in Table VI. The lesional surface was covered by parakeratin in forty-four cases,by orthokeratin in twelve eases, and by a combination of the two in two cases,while there was no keratin over the surface in nineteen cases.In the majority of unkeratinized cases,the lesions were red or erythroplakic. However, this was not invariably the case, since a few lesions described as erythroplakia did show a keratotic surface while a few lesions described as leukoplakia showed no surface keratin. There were no apparent sex differences in the occurrence of a keratotic surface except for the formation of orthokeratin where it was found to be present in eleven males but in only one female. Individual cell keratinization and epithelial or keratin pearl formation were exceedingly rare. In fact, the study of these casesof CIS and of casesof superficially invasive epidcrmoid carcinoma strongly suggest that the presence of individual cell keratinization and/or pearl formation is often a hallmark of transformation of CIS into superficially invasive carcinoma and that either of these two findings in an apparent case of CIS should mandate a further search for evidence of carcinomatous invasion. In the present series, only three instances of individual cell keratinization and four instances of pearl formation were found. In these cases,the cellular keratinization was limited to just a few cells or to usually a single pearl.
234
Shnfer
Oral February,
Surg. 1975
Fig. 8. Different examples of oral carcinoma in situ to illustrate the variation in pattern of the epithelium. All photomicrographs were taken, printed, and reproduced at the same magnification for comparative purposes. A, A hyperplastic type of CIS showing a sharp line of demarcation l)cltween normal and altered epithelium. H, An atrophic type of CTS showing a similar sharp Iine of demarcation ?)etw+en normal and altered epitheliuni. C, Rasilar hyperplnsia with top-to-bottom change and no significant pleomorphism. D, An atrophic type of CTS \vith moderate pleomorphism and hyl’erettronlntislll. B, A keratinizing CIS shaming a stratification of the lower two thirds of the epithelium exhibiting basilar hyperplasia but the upper third being essentially normal. P, a CIS with a rather pleomorphic top-to-bottom basilar hyperplasia. C, An atrophic CIS with a very thick surface layer of orthokerntin in one area but no keratin over the adjacent area. The nature of the lesional epithelium was also studied to ascertain hyperplasia, atrophy, or absence of significant change, and the findings are shown in Table VII. The epithelium was thicker than usual in thirty cases (seventeen males and thirteen females) and thinner than usual in twenty-three cases (nineteen males but only four females), while no significant change in over-all thickness was found in twenty-four casts (thirteen males and eleven females), Whether the low incidence of epithelial atrophy in females is significant remains to be determined. However, it was quite unexpcctetl in view of its being a common finding in females in such disorders as the Plummer-Vinson syndrome. Certain individual cytologic alterations were studied to determine the frequency with which they occurred in CIS. Specifically, these were (1) a prominent increased nuclcar/cytoplasmic ratio, (2) a prominent cellular plco-
Volume Number
Oml cm-oi~~om~ i?l situ,
39 2
Fig.
8. E-G.
For
legend,
see opposite
235
page.
morphism, and (3) a prominent nuclear hyperchromatism. A prominent increased nuclear/cytoplasmic ratio was not a particularly common finding. It was present in forty-two cases (twenty-eight males and fourteen females) but absent in thirty-five cases (twenty-one males and fourteen females). Similarly, a prominent nuclear hyperchromatism was not particularly common. It was present in forty-four cases (twenty-nine males and fifteen females) but absent in thirtythree cases (twenty males and thirteen females). However, one of the surprising findings was the relative infrequency of cellular pleomorphism, being present in thirty-one cases (eighteen males and thirteen females) but absent in forty-six cases (thirty-one males and fifteen females). Furthermore, this absence of cellular pleomorphism could not be correlated with a high frequency of basilar hyperplasia, where there would obviously be a general lack of pleomorphism, since only seventeen cases (ten males and seven females) showed significant basilar hyperplasia while sixty cases (thirty-nine males and twenty-one females) did not. The one most conspicuous and almost uniformly consistent cytologic alteration was the loss of orientation of cells. This loss of orderly arrangement of cells, individually and with respect to their neighbors and their loss of normal polarity, was found in all forty-nine cases of CIS in males and in twenty-six of the twentyeight cases in females. Both of the latter two lesions in females where this was not present occurred in leukoplakie lesions covered with parakeratin. Finally, accessory salivary ducts were present in the biopsy specimens in only
twelve of the seventy-six cases. In only one instance did the CIS changes appeal to involve any of these underlying ducts. No particular attempt was made to evaluate degree of mitotic activity in these cases, since the number of mitotic figures in thr cases rcvicwrtl generally was estremcly limited. In a given lesion, three or four mitotic figures might bc found in one low-power field, but none in closely adjacent fields. This inconsistency and lack of widt range of variability made such an evaluation, in our ol)inion, of little significance. Several additional observations arc also of some interest. In certain lesions, a very sharp line of division existed between the CIS and the adjacent microscopically normal epithclium. This was so pronounced on some occasions that it appeared as though a full layer of normal epithelial cells were abutting directly against a full layer of dysplastic or neoplastie cells. In this connection also, in a few instances multiple areas of carcinoma in situ were found distributed throughout cssentiallp normal epithelium, producing the picture of multifocal carcinoma in situ analogous to multifocal basal-cell carcinoma of the skin. DISCUSSION
Present-day knowledge of oral carcinoma in situ is exceedingly limited in scope, partly because of a lack of any significant number of reported cases.Fairly good data have been accumulated indicating that a certain small percentage of cases of leukoplakia are, in fact., histologically carcinoma in situ. There is considerablc evidence also that a very cdonsiderablcpercentage of cases of crythroplakia are histologically carcinoma in situ. 111addition, as found in the present study and as emphasized by others, these lesions of carcinoma in situ may appear mixed red and white, slightly ulcerated, or even show no appreciable gross change. I:nfortunately, there is a total lack of information on the clinical behavior of oral c.arcinoma in situ in general or on whether each of the clinically diRerent forms of carcinoma in situ will ha\-e a clinically similar or different behavior. In contrast, there is a voluminous amount of information available concerning the nature of carcinoma in situ of the uterine cervix and considerable knowledge as to the clinical behavior of the lesion in that location. While it is tempting to extrapolate data on carcinoma in situ of the cervix to carcinoma in situ of the oral mucous membranes, the epithelia in these two locations arc similar in some respects but totally different in others. For this reason, it will be necessary to go through the same slow, prolonged painstaking process of accumulating data on oral carcinoma in situ as was necessary in the past for cervix. It will be essential to determine whether the various stages of epithelial dysplasia of the oral mucosa (mild, moderate, and severe) will regress, persist, or progress to carcinoma in situ, as has been done for similar lesions of the cervix. It will be necessary to determine the frequency of transition of oral carcinoma in situ to invasive cancer, as has been done for similar lesions of the cervix, as well as to determine the frequency of spontaneous disappearance, if, indeed, such a thing does happen with oral carcinoma in situ. It will be necessary to determine the preinvasivc period of the various clinical forms of oral carcinoma in situ, as has
already been done with respect to the cervical lesions. It will be essential also to determine the frequency of occurrence of multiple oral lesions for better management of patients. Some efforts hare already been made in this direction (for example, by Slaughter and his co-workers11 and by Wynder and his associate+‘). Unfortunately, the present report does not answer any of the above questions. It is only the modest beginning of an attempt to collect some clinicopathologic information on a series of patients with this disease. The nature of this patient population totally precludes obtaining significant follow-up information. The vast majority of these patients were those of private general dental practitioners in Indiana and surrounding states. Following receipt of a biopsy report of carcinoma in situ, one of several events would occur. The practitioner, in a very few instances, would rc-excise the lesion. More frequently, the patient would be referred to an oral surgeon, who would either rc-excise the lesion and send the tissue to this laboratory or to a hospital or private pathology laboratory or refer the patient to a general surgeon. In still other cases, the patient would be rcferrcd to the family physician, who elected to treat the lesion himself, refer the patient to a general surgeon for treatment, or refer him to this or some other medical center. In still other instances, the pa,tient was referred directly to a medical center by one of the dentists involved. Because of the many possibilities of patient disposal, we have practically no information on the eventual outcome of the cases in this series. Yevcrthcless, we can be almost certain that each patient was treated further, by some means, properly or improperly, so that no information would bc possible from this group regarding data comparable to existing data from cervical lesions (for example, outcome of untreated lesions, prcinvasire period of untreated lesions, ctc) . Little attention has also been paid to the question of exactly what immediately precedes the development of invasive oral epidermoid carcinoma. Does it cllways develop in a prc-existing carcinoma in situ, or does this occur only occasionally? Ackerman and RIcGarranl ha\-e stated their belief that at least many invasive cancers originate as in situ lesions and that the speed of evolution of this lesion from intraepithclial to invasive cancer is cxtremcly variable. In thei thoughtful discussion of “field canccrization” of oral stratifietl squamous epithelium, Slaughter and his associates I1 found that abnormal and hypcrplastic, often atypical, epithelium was found to surround all oral cancers for varying distances in their series of 783 pat,icnts. This might imply that carcinoma develops only in altered cpithelium, but whether this is ncccssarily altered to the point of carcinoma in situ is certainly not clear. Finally, Shedd and his associate+” have concluded that carcinoma in situ is a stage in the evolution of cancer. It is hoped t,hat the present study, by re-cmphasizin g many unanswered questions concerning carcinoma in situ of the oral cavity, will serve to stimulate further investigation of this disease. REFERENCES
1. Ackerman, L. V., and McGavran, M. H.: Proliferating Eenign and Malignant Lesions the Oral Cavity, J. Oral Surg. 16: 400-413, 1958. 2. Gorlin, R. J.: Bowen’s Disease of the Mucous Membrane of the Mouth, ORAL SUI:G. 35-51, 1950.
of 3:
238
Shafat
Oral slug. February,
1975
3. Govan, A. 1). T., Haines, R. M., Langley, 1”. A., Taylor, C. W., and Woodcock, A. S.: Chances in the Euithelium of the Cervix Uteri: a Studv 1)~ the Panel of Pntholoeists Engaged in a Sur;ey of Carcinoma-in-Situ Carried Out b; the Royal College1 of Obstitricians and Gynaecologists, J. Obstet. Gynaecol. Br. Commonw. 73: 883-896, 1966. 4. Kramer, 1. R. H.: Carcinoma-in-Situ of the Oral Mucosa, lnt. Dent. J. 23: 94.99, 1973. 5. Mashberg, A:, Morrissey, J. B., and Garfinkel, L.: A Study of the Appearance of Early Asymptomatic Oral Squamous Cell Carcinoma, Cancer 32: 1436.1445, 1973. 6. Pindborg, J. J., Renstrup, G., Poulsen, H. E., and Silverman, S., Jr.: Studies in Oral Leukoplakias. V. Clinical and Histologic Signs of Malignancy, Acta Odontol. Scantl. 21: 407-414, 1963. 7. Shafer, W. G., and Waldron, C. A.: A Clinical and Histopathologic Study of Oral Leukoplakia, Surg. Gynecol. Obstet. 112: 41 l-420, 1961. 8. Shafer, W. G., and Waldron, C. A.: Erythroplakia of the Oral Cavity, Cancer (In press.) 9. Shear, M. : Erythroplakia of the Mouth, Int. Dent. J. 22: 460.473, 1972. 10. Shedd, D. P., Hukill, P. B., Kligerman, M. M., and Gowen, G. F.: A Clinicopathologic Study of Oral (:arcinoma-in-Situ, am. .I. Surg. 106: 791.796, 1963. 11. Slaughter, D. P., Southwick, H. W., and Smejkal, W.: “Field Cancerizat,ion” in Oral Stratified Squamous Epithebum; Clinical Implications of Multicentric Origin, Cancer 6: 963-968, 1953. 12. Wynder, E. L., Brass, 1. J., and Feldman, K. M.: A Study of the Etiologic Factors in Cancer of the Mouth, (:ancer 10: 1300-1323, 1957. requests to: Dr. William G. Shafer Department of Oral Pathology Indiana University School of Dentistry Indianapolis, Ind. 46202 Reprint