[CANCER RESEARCH 36. 2482-2484, July 1976] Carcinoma, Carcinoma in Situ, and “EarlyLesions―ofthe Uterine Cervix and the Urinary Bladder: Introduction and Definitions1

Gilbert H. Friedell Departments of Pathology, St. Vincent Hospital and University of Massachusetts Medical School, Worcester, Massachusetts 01610

At the outset of this combined session on “earlylesions― evident before calling the lesion cancer. Others have ac of the uterine cervix and the urinary bladder, I should like to cepted the terminological paradox of a ‘‘noninvasive propose some definitions as a basis for the discussions to cancer' ‘andhave used ‘‘superficialcarcinoma―or “carci follow. First of all, however, I would remind you how the noma in situ―when the markedly abnormal epithelium does pathologist gives meaningful names to morphological en not appear to penetrate the basement membrane when tities. Basically, there are 3 phases to naming such an en seen with the light microscope. I prefer the term carcinoma tity. in situ, and use the following definition. First, the pathologist applies a descriptive term to the Carcinoma in situ is epithelium that has the histological lesion so that all who hear the term or see it in print will features characteristic of cancer, but is noninvasive. It is know what the entity looks like. It is best if the term carries related in space or in time to the presence of carcinoma, with it neither pathogenetic nor prognostic implications, and will, if untreated, progress to carcinoma of the same since only a purely descriptive designation is appropriate at histological type in a significantly high percentage of cases. this stage. In the cervix, the spatial relationship between invasive In the 2nd phase, the natural history of the lesion in ques and noninvasive carcinoma was recognized almost a cen tion is studied. Clinicians and pathologists alike provide in tury ago by SirJohn Williams (19), was noted and illustrated formation concerning the behavior and biology of the in 1900 by Cullen (4), and was described in greater detail a morphological entity. few years later by others (12, 13, 15, 16). They all noted the When the clinical significance is known, when the natural presence of noninvasive but histologically malignant epi history of the lesion has been elucidated, we then enter thelium adjacent to carcinoma. It was Broders in 1932 (2) Phase 3 of the nomenclature sequence. A name is selected who first termed this epithelium carcinoma in situ. which will not only convey information about the morphol Subsequent cases were reported in which the presence ogy of the entity, but will also have pathogenetic and of such noninvasive malignant epithelium preceded by prognostic significance. The word “cancer,―forexample, months or years the development of invasive cervical when applied by the pathologist to a biopsy specimen, has cancer (6, 17). Gradually, this concept of a sequential grave prognostic significance and very definite therapeutic temporal relationship between the presence of carcinoma implications. One would be loathe to designate a prolifera in situ and the development of cervical carcinoma was ac tive epithelial lesion as ‘‘carcinoma'‘withouthard data con cepted. Based on data concerning the peak age incidence cerning the natural history of the entity in question. The of both in situ and Stage I carcinoma, it has been esti term carcinoma could be appropriately applied in Phase 3 mated that the progression of in situ to invasive carcinoma of the nomenclature sequence, but not in Phase 1. of the cervix takes an average of 10 years (6, 18). We would restrict the designation of carcinoma to those That such progression is not inevitable, however, was epithelial lesions that meet the histological criteria for clearly pointed out by the work of Dr. Olaf Petersen (11). malignancy, that invade the subepithelial or supporting Indeed, through personal communication with him and connective tissue, and that metastasize and/or kill the pa with Professor Johannes Clemmesen since 1960, it is clear tient (unless prevented from doing so by the introduction that, in some of Petersen's cases, carcinoma in situ has of appropriate treatment). Use of the term carcinoma not persisted —without either progressing or regressing —for only indicates that the prognosis is poor unless the patient many years, and may possibly do so through the remaining is treated appropriately, but it also implies that the user of lifetime of these patients. Others have also found that pro the term knows what the outcome will be. gression is not inevitable in untreated cases of carcinoma If we accept this definition of carcinoma, however, we in situ, and at this time it is probably fair to say that then have a problem in giving a name to the superficial carcinoma in situ of the cervix, if not treated, will progress lesion which histologically resembles carcinoma but does to carcinoma in some 50 to 60% of cases over a period of 5 not invade the subepithelial tissue. Some have suggested to 20 years. This is not to say that the lesion regresses “precancer―asa designation, waiting until invasion is spontaneously in 40 to 50% of cases, but simply that it does not progress in these cases. “Spontaneousdisappearance ‘Presented at the Conference. “Early Lesions and the Development of of carcinoma in situ apparently does occur, but it is an ex Epithelial Cancer,―October 21 to 23, 1975, Bethesda, Md. Development of this manuscript supported by USPHS Grant 15490 from the National Cancer traordinarily rare event―(9). Institute through the National Bladder Cancer Project. Thus, as we define carcinoma in situ of a given organ, it

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becomes important to know just what constitutes a ‘‘sig without this stimulus, will not go on to carcinoma. Some nificantly high percentage of cases.―Ifwe take as a stand epithelial hyperplasias of the cervix and bladder would fall ard the 50 or 60% progression that we have just given for into this category of precursor or preneoplastic lesions. cervical carcinoma in situ, how many lesions now called Morphologically, the early and precursor lesions will be carcinoma in situ in other organs will meet this part of the similar, but the irreversibility of the 1st and reversibility definition? Suppose we find that in some organ a given of the 2nd would distinguish them biologically. A biochemi noninvasive lesion which histologically resembles carci cal, biological, or other marker would be most helpful in noma, if left untreated, will progress to carcinoma only in making this distinction. 15% of cases. Is this a sufficiently high figure to justify During this first conference session dealing with early the diagnosis of carcinoma in situ? If not, how should this lesions of the uterine cervix and the urinary bladder, there lesion be designated? As “precarcinomainsitu―?Another will be references made to experimental models. Such possibility, of course, is that we should have a sliding scale models may be defined as experimental systems, either for “significantlyhigh percentage of cases―so that we in vitro or in vivo, in which some aspect of the natural would diagnose carcinoma in situ in one organ if the figure history of a human cancer can be studied. Generally, the is 15 or 20%, while in another organ the diagnosis would model will be the growing tumor or the tumor interacting have a 70% figure attached to it. with the host, but it might also be the host itself, as in the The spatial and temporal relationship between nonin development of a model for screening carcinogenic com vasive and invasive carcinoma of the bladder is also clearly pounds. For example , a N-[4-(5-nitro-2-furyl)-2-thiazolyl]- evident. The study of giant tissue sections illustrates the formamide-induced bladder tumor in the Fischer rat might spatial relationship particularly well (1, 14). The temporal be a good model for the study of the pathogenesis of relationship has been shown by information from longitu human bladder cancer (3), but the Fischer rat itself might dinal studies of patients with bladder cancer (7, 8, 10). be a model for screening carcinogenic compounds. These studies indicate that an'in situ phase precedes the During this meeting we will be discussing models in development of invasive cancer in the bladder as it does in which tumor cell markers or the markers of host response the uterine cervix, but the in situ entity is less well defined to tumors (or early lesions) can be identified and followed. and the relationship between noninvasive flat and papillary A marker of an epithelial tumor, or of the epithelial cell com lesions remains to be worked out. Nevertheless, in many prising the early lesion is that structural or functional cellu ways the principles derived from the study of cervical carci lar characteristic which can be used to identify a tumor noma in situ would seem to be applicable, and the defini cell or the cellular components of an early lesion. The latter tions just given can probably be used as we discuss pro would be called early lesion markers and might include liferative lesions of the bladder (5). cytological, histological, or ultrastructural characteristics In studies of the cervix, attention has also been devoted of epithelial cells, or the identification of some product to characterizing the early lesion which precedes the de elaborated by the cells in question and detected locally or velopment of histologically recognizable carcinoma in situ. systemically. Terms applied to it include atypical hyperplasia, anaplasia, At the same time, we will be discussing host markers, dysplasia, and others. This early lesion might be defined i.e. , the structural or functional characteristics of host tis as an epithelial proliferation with characteristic, but non sues that appear in response to the presence of tumors or neoplastic, histological features which, if untreated, will be early lesions. These might be specific or nonspecific, or followed in a significantly high percentage of cases by car perhaps both, in response to a tumor or early lesion. cinoma in situ or carcinoma. It represents the induction by I would hope that during the course of this conference a simple or complex carcinogenic stimulus of an irreversi we will be provided with some qualitative evidence of the ble but not necessarily progressive lesion which must be presence of such tumor or host markers in various experi distinguished from reversible hyperplastic lesions. mental systems and in human patients with tumors or early However, if the definition of carcinoma in situ in various lesions. This would be the first step in the development of organs is somewhat clouded by our lack of knowledge con quantifiable means of assessing the biological potential of cerning the percentage of cases which would go on to in proliferative epithelial lesions of the cervix and bladder. vasive neoplasms, the same problem confronts us as we try to use our definition of the early lesion in discussing References the pathogenesis of cervical and bladder cancer. If the definition requires that the lesion, comprised of epithelial 1. Austen, G., Jr., and Friedell, G. H. Observations on Local Growth Pat cells with defineable, but nonneoplastic, cytological or terns of Bladder Cancer. J. Urol. , 93: 224-229, 1965, 2. Broders, A. C. Carcinoma in Situ Contrasted with Benign Penetrating histological characteristics will, if untreated, go on to carci Epithelium. J. Am, Med. Assoc,, 99: 1670-1674, 1932. noma in situ or carcinoma in a significantly high percentage 3. Cohen, S. M., Jacobs, J. B., Arai. M., Johansson, S., and Friedell, G. H. Early Lesions in Experimental Bladder Cancer: Experimental Design and of cases, what figure would constitute a significantly high Light Microscopic Findings. Cancer Res., 36: 2508-2511, 1976, percentage of cases? —5%?25%? 50%? 4. Cullen, T. 5. Cancer of the Uterus. New York: D. Appleton & Co., 1900. Finally, we should note what is not an early lesion in our 5. Farrow, G. M., Utz, D. C., and Rife, C. C. Morphological and Clinical Observations of Patients with Early Bladder Cancer Treated with Total terminology. This would be a reversible, proliferative epi Cystectomy. Cancer Res., 36: 2495-2501 , 1976. thelial change that can be characterized in histological or 6. Friedell, G. H,, Hertig, A. T., and Younge, P. A. Carcinomain Situ of the Uterine Cervix. Springfield, III.: Charles C Thomas, Publisher, 1960, cytological terms and that will provide a more-than-usually 7, Greene, L. F., Hannah, K, A., and Farrow, G. M. Benign Papilloma or susceptible substrate for a carcinogenic stimulus—but that, Papillary Carcinoma of the Bladder. J. Urol., 110: 205-207, 1973.

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8. Koss, L. G., Melamed, M. A.. and Kelly, R. E. Further Cytologic and 13. Rubin, I. C. The Pathological Diagnosis of Incipient Carcinoma of the Histologic Studies of Bladder Lesions in Workers Exposed to Para Uterus. Am. J. Obstet. Gynecol., 62: 668-676, 1910. aminodiphenyl: Progress Report. J. NatI. Cancer Inst., 43: 233-243, 14. Schade, R. 0. K. Some Observations on the Pathology and Natural 1969. History of Urothelial Neoplasms. Beitr, Pathol., 145: 325-335, 1972. 9 Koss, L. G., Stewart. F. W., Foote, F. W., Jordan, M. J., Bader, G. M., and 15, Schauenstein, W. Histologische Untersuchung Uber atypisches Platten Day E. Some Histological Aspects of Behavior of Epidermoid Carcinoma epithelials an der Portio und an der Innenflache der Cervix uteri. Arch, in Situ and Related Lesions of the Uterine Cervix. Cancer. 16: 1160-1211, Gynaekol.. 85: 576-616, 1908, 1963. 16. Schottlaender, J, , and Kermauner, F. Zur Kenntuis des Uteruskarzinoms. 1ciMelamed,M,R.,Voutsa,N.G.,andGrabstald,H.NaturalHistoryand Berlin:S.KargerA.G.,1912. Clinical Behavior of an in Situ carcinoma of the Human Urinary Bladder. 17, Smith, G. V., and Pemberton, F, A. The Picture of Very Early Carcinoma Cancer. 17: 1533-1545. 1964. oftheUterineCervix.Surg.Gynecol.,Obstet,,59:1-8,1934. 11. Petersen. 0. Precancerous Changes of the Cervical Epithelium in Rela 18.Wheeler,J,D.,and Hertig,A.T.The PathologicAnatomyofCarcinoma tion to Manifest Cervical Carcinoma. Acta Radiol. Suppl., 127: 1-168, oftheUterus.I.SquamousCarcinomaoftheCervix.Am.J.Clin.Pathol., 1955. 25: 345-375, 1955. 12. Pronai, K. Zur Lehre von der Histogenese under dem Wachsthum des 19. Williams, J. Cancer of the Uterus; Harveian Lectures for 1886. London: Uterus carcinoms. Arch. Gynaekol,. 89: 596-607. 1909. H. K. Lewis. 1888.

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Gilbert H. Friedell

Cancer Res 1976;36:2482-2484.

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