Authors: Bouquot JE, Kurland LT, Weiland LH.
Jerry E. Bouquot, D.D.S., M.S.D., * Professor and Chairman, Department of Oral Pathology, West Virginia University School of Dentistry; Professor, Department of Pathology, WVU School of Medicine; Leonard T. Kurland, M.D., Dr.P.H., Professor and Chairman, Department of Medical Statistics and Epidemiology, Mayo Clinic and Mayo Medical School; and Louis H. Weiland, M.D., Professor, Department of Surgical Pathology, Mayo Clinic and Mayo Medical School
Note: This investigation was supported in part by Research Grant GM-14231, National Cancer Institute, National Institutes of Health, and was presented to the 1986 Biennial Congress of the International Association of Oral Pathologists (Edinburgh, Scotland). Dr. Bouquot was on sabbatical leave with the Department of Medical Statistics and Epidemiology, Mayo Clinic, during part of this investigation.
Epidemiologic analyses of carcinoma in situ (CIS) of the upper aerodigestive tract (UAT) are virtually nonexistent. The present investigation summarizes the total UAT CIS experience of a white, middle class community from 1935 through 1984. Average annual incidence rates varied between genders (3.1 per 100,000 person-years for males versus 0.6 per 100,000 person-years for females), and has increased from 1.5 to 3.1 lesions per 100,000 person-years between 1935-1964 and 1965-1984. Virgin CIS lesions represented 13% of all UAT carcinomas and the vermilion borders of the lips accounted for 42% of all UAT CIS cases. Age-specific incidence rates for males demonstrated a continuous increase to 40.5 per 100,000 males over 75 years of age. A detailed clinicopathologic analysis of these lesions is provided.
A dearth of epidemiologic data relating to the "preinvasive malignancy", carcinoma in situ (CIS) of the upper aerodigestive tract (UAT), has lead to the acceptance of clinicopathologic, hospital--based investigations for its characterization (1-21). The data from the latter, however, cannot be said to represent any population beyond that of the particular hospital from which the study originated (22-24). Hence, our understanding of CIS is necessarily skewed, probably to the more difficult or unusual referral cases.
The present investigation is the first to offer an epidemiologic and clinicopathologic (clinicoepidemiologic) characterization of CIS from a pool of patients known to represent virtually all cases of UAT CIS and invasive carcinoma in a delineated population, (Rochester, Minnesota, from 1935 through 1984).
Rochester, Minnesota is uniquely suitable for clinicoepid-emiologic studies. For many decades medical practice there has centered at the Mayo Clinic, and approximately 90% of the entire population registers in that institution for primary or specialty health care during a given three year period. Such registration requires the entry and indexing of all diagnoses made during each visit. A very large proportion of a delineated population, then, uses a single major medical center not only for secondary and tertiary care, but for primary care as well. Additionally, during the past half century 50-70% of resident deaths in any given decade have been autopsied.
For the local population, diagnoses from health care providers in Rochester and adjacent counties who are not affiliated with the Clinic, and from those hospitalized at the two large regional tertiary care facilities in Minneapolis (125 km. distant) are also entered into a centralized diagnosis and indexing system at the Mayo Clinic. This comprehensive records-linkage system is thought to ensure the identification of virtually all persons from Rochester in whom serious illness has been diagnosed (25). For a disease such as UAT cancer, case ascertainment is considered to have remained constant and extremely high throughout the fifty years encompassed by this study.
The validity of epidemiological data from such a small community (1984 population estimate=58,692) has been well established (26-29), and during the past two decades approximately eighty epidemiology papers relating to neoplasia in this and the surrounding Olmsted County population have been published. For this investigation, all medical, surgical, histopathologic, and autopsy records of Rochester residents given a diagnosis of neoplastic or precancerous disease of the mucous membranes and salivary glands of the UAT between January 1, 1935 and December 31, 1984 were reviewed after retrieval from the files of the Mayo Clinic and its affiliated hospitals, the Olmsted Medical and Surgical Group, the Olmsted Community Hospital, the Rochester State (mental) Hospital, all hospitals in counties adjacent to Olmsted County where Rochester residents may have gone for care, and the University of Minnesota and Veterans Administration Hospitals in Minneapolis, Minnesota.
All cases of sarcoma, neoplastic and inflammatory cervical lymph node disease, and facial skin cancer were also reviewed. In total, the medical records of more than 4,000 Rochester residents were reviewed, including those with such nonspecific diagnoses as "lesion", "mass", "ulcer", "irritation", etcetera of the UAT. Anatomic UAT subsites investigated, with Ninth Revision ICD codes (30), included: lip vermilion (ICD code=140.1-2); oral cavity (ICD=140.3-5, 141, 143-145); major salivary glands (ICD=142); pharynx (ICD=146-149); nasal and paranasal sinuses (ICD=160, excepting 160.1); and larynx (ICD=161). The present paper is concerned only with labial vermilion and internal UAT mucosal sites (excluding major salivary glands), which are herein referred to collectively as UAT or indexed sites.
Only histologically proven carcinomas of indexed sites were accepted; 99.4% of all UAT malignancies were histologically confirmed at diagnosis. Microscopic slides or tissue blocks were still available for 91.6% of the identified cases. The latter were re-examined by a single pathologist (JEB) who was unaware of the original microscopic diagnoses during his review. Diagnoses that differed substantially from the original were additionally reviewed by a second pathologist (LHW).
The term carcinoma in situ is herein used histologically to connote rather severe epithelial atypia from the basement membrane to the surface of the mucosa, or to the overlying parakeratin layer if such exists. The authors, in this regard, agree with Shafer (14), Batsakis (19), Waldron (31), and others (8,12,18,32) who contend that the classic CIS definition, which does not accept even an attenuated keratin layer, is far too narrow for practical considerations and has not been widely utilized. Lesions without "top-to-bottom" change were considered to be severe or lesser dysplasias and excluded from the study. Dermatopathologic tradition has allowed the use of the term CIS in certain skin masses, most noteably actinic keratoses (33). Several vermilion border CIS lesions in the present paper are of this type and most likely originated on the skin of the lip, but had extended onto the vermilion surface by the time of diagnosis.
Only those patients who had resided in Rochester for at least one year prior to diagnosis were considered bona fide residents. Death certificates were obtained, regardless of the location or cause of death, for all cases of carcinoma identified. Age-adjustment of incidence rates is to the 1970 U.S. white standard population and incidence data are based on the number of individual carcinomas, not the number of affected persons.
From 1935 through 1984, 35 "virgin" (without adjacent or inclusive invasive malignancy) and 13 "associated" (juxtaposed to or containing invasive carcinomas) CIS lesions were identified in 47 white residents of Rochester. Six of the associated lesions were predominantly CIS in nature, with only a small focus of invasion through the basement membrane noted microscopically. These are hereafter referred to as "microinvasive" CIS lesions and are assumed to be lesions which were fortuitously identified at the very earliest stage of transformation into invasive disease. The 48 CIS lesions diagnosed in Rochester residents represented 18.8% of all UAT carcinomas diagnosed from 1935 through 1984. When only virgin CIS lesions were included, this proportion was still a substantial 13.1%.
The most common indexed site of involvement was the vermilion border of the lips, accounting for 41.7% of all CIS lesions diagnosed. This anatomic subsite was also the most common site for invasive carcinomas of the UAT in this population and demonstrated the strongest male predilection for all UAT subsites, approximately 10 males:1 female for both CIS and invasive carcinoma. Sites of least CIS involvement, the nasal and paranasal sinuses, were likewise the sites of least frequency of invasive disease.
The average annual incidence rate for all forms of CIS in this predominantly white population was 2.4 per 100,000 person-years, with males being affected almost eight times more frequently than females (Table 1). When only virgin CIS lesions were considered, the average annual incidence rate decreased to 1.8 and the male predilection was 5.2 to 1. The average annual incidence rate for total CIS of the UAT doubled between 1935-1964 and 1965-1984, predominantly due to changes in rates for internal mucosal CIS (Table 2). The large increase in the mucosal CIS incidence rate, from 0.6 to 2.1 CIS lesions per 100,000 person-years (0.4 to 1.5 for virgin lesions), was not reflected by a similar rate increase for invasive carcinomas of these same UAT sites (Table 2). Invasive carcinomas of the lip vermilion, in fact, dramatically decreased during the half century of observation, from 12.9 in 1935-1944 to 1.7 in 1975-1984, while vermilion CIS incidence remained unchanged.
Additionally, the average age at CIS diagnosis, 64.9 years (range: 41-83 years), was lower for persons affected with mucosal lesions than for those with vermilion lesions (60.1 versus 69.8 years of age, respectively) (Table 3). Age-specific incidence rates for total UAT CIS demonstrated a continuously increasing incidence throughout life, with an increasing desparity between males and females as ages increased (Figure 1). The middle-aged male rate increased almost five-fold by the end of life (8.8 vs 40.5 lesions per 100,000 person-years for males 45-54 years of age and males 75 years and older, respectively). Figure 2, however, demonstrates that the continuing increase after age 65 is due entirely to vermilion CIS lesions and that, in reality, mucosal CIS incidence decreased after 65 years of age. Associated CIS lesions, furthermore, contributed more to overall CIS incidence in the older age brackets (Figure 3).
While the total number of CIS cases in the present investigation was somewhat small, the uniqueness of this cohort, resulting from its relative lack of referral biases, seemed to warrant an attempt to clinically characterize these patients and their lesions. Table 3 offers such a characterization and is summarized in the following paragraphs.
Almost all patients with UAT mucosal CIS lesions smoked tobacco in one form or another, and four of every five with vermilion lesions were smokers. A surprisingly high proportion of mucosal lesion patients were alcohol "abusers" (68%)--a condition seldom reported (7%) in the group of patients with vermilion CIS lesions. The typical CIS lesion in this cohort was 1.4 cm. in greatest diameter at diagnosis, and patients had been aware of a change in the affected area for an average of 2.7 years prior to diagnosis.
Mucosal CIS lesions had a much shorter average duration before diagnosis (2.1 years) than did vermilion lesions (3.4 years), even though lesion size was similar for both anatomic subsites. Approximately 82% of all lesions were at least partially white or leukoplakic and virtually all vermilion lesions were such. Furthermore, more than half of all vermilion CIS lesions were ulcerated at diagnosis, with another one quarter being found at the bases of actinic keratoses or cutaneous horns.
Internal mucosal CIS lesions were less likely to be leukoplakic than vermilion lesions, and much more likely to demonstrate areas of erythroplakia (clinical red plaques) (Table 3). Approximately 20% of mucosal erythroplakias were simple erythematous macules while the rest were interspersed with leukoplakia (erythroleukoplakia). Ulceration was a minor component of UAT mucosal CIS lesions.
All cases of UAT CIS in this cohort were treated immediately after diagnosis and patients were followed for an average of 10.5 years (range: 7 months to 29 years) (Table 3 and Figure 4). As expected in an investigation surveying half a century of disease experience, a large proportion (58%) of all identified patients died prior to the end of the observation period, usually of nonmalignant disease.
All vermilion CIS lesions were completely removed or destroyed via conservative surgery, usually stripping with or without diathermy, cryosurgery, or laser destruction. None recurred and none developed into invasive disease, not even those with initial microscopic foci of superficially invasive carcinoma. In contrast, 15% of virgin mucosal CIS lesions recurred, even though several were treated more aggressively than vermilion lesions (Table 3). Ten percent of virgin mucosal lesions became invasive after initial therapy. No microinvasive CIS recurred and the three virgin mucosal CIS recurrences occured at 12, 14, and 55 months after diagnosis. One of the latter lesions actually recurred four times within four years, with microinvasive squamous cell carcinoma being additionally diagnosed on the second and fourth recurrences. This lesion was found in the only Rochester resident to present with two CIS lesions of separate UAT subsites.
Only one patient in this cohort died of invasive squamous cell carcinoma apparently transforming from a virgin CIS lesion, but two patients were found to have invasive squamous cell carcinomas of other UAT subsites at the time of CIS diagnosis and two more were diagnosed with invasive disease of other indexed sites, one before (no radiotherapy given) and one after a CIS diagnosis. These invasive lesions were all several centimeters from the CIS lesions, with normal mucosa intervening.
Fifteen of the 47 CIS patients were diagnosed with non-UAT cancers during 1935-1984. All but two were carcinomas and eight arose from the lower digestive (n=7) or respiratory (n=1) tracts. Ten of these 15 patients died of their non-UAT malignancies.
The earliest epidemiological reports of CIS of the UAT provided little more than relative frequencies (34,35). A report of the National Cancer Institute's Surveillance, Epidemiology and End Result (SEER) survey (36) has, however, provided gender- and age-specific incidence data for these lesions in approximately 20,000,000 people. The SEER data are provided in a rather raw form and incorporated into tables pertaining predominantly to invasive cancers, perhaps explaining why the NCI data have not yet been cited in the literature (37).
Table 4 compares virgin CIS incidence rates for U.S. whites in the SEER survey with the present Rochester rates for similar lesions, demonstrating excellent correlation between the two studies for laryngeal CIS, but a considerably higher rate for oral/pharyngeal CIS in the Rochester population (1.4 per 100,000 person-years versus 0.2 in the SEER population). Much of the latter difference disappears, however, when vermilion CIS lesions are excluded from the Rochester data. The higher rate determined for vermilion CIS lesions in the Rochester population could, of course, be a real difference between the two populations. It is more likely, however, to be related to the different referral and reporting patterns of the two investigations. It would appear logical that the lip vermilion would be the one UAT subsite least likely to have a CIS lesion reported from it because such lesions are considered quite innocuous, are often treated in an office rather than a hospital setting, and are often treated by oral surgeons, a group of health professionals minimally involved in the SEER data collection (24,37).
Age-specific incidence rates varied considerably between the two investigations, with Rochester residents demonstrating a much higher incidence in late life than that noted for the larger SEER population (compare Figures 1 and 5). Excluding vermilion CIS cases from the Rochester data, however, domonstrates a similar incidence decrease in late life for males in the two populations, even though Rochester rates uniformly exceed the SEER rates in all age brackets (compare mucosal rates in Figure 2 with male rates in Figure 5). This would appear to further substantiate a low case ascertainment rate for vermilion CIS in the SEER investigation.
With only two exceptions (39,44), the frequency with which treated virgin UAT CIS cases in the present study recurred as invasive carcinoma (5%) was lower than transformation rates from the clinicopathologic literature (range=3.5-50.0%; mean=18.6%), and was considerably lower than the expected transformation rate had the lesions remained untreated (range=33.3-90.0%; mean=62.1%) (Table 5). This, as well as the low rate of recurrence without invasion (4%), is most likely secondary to the relatively small size of the Rochester lesions at diagnosis. Previous investigators have demonstrated a direct correlation between lateral clinical extension and the risk of invasion in these lesions (41). The very high transformation rates reported by Silverman et al (50) and Amagasa et al (18) for oral CIS lesions are, in this light, somewhat misleading, as both series included a high proportion of large lesions. Silverman et al, in fact, excluded small lesions by study design and further complicated the issue by grouping severe dysplasias with CIS, as did several other authors (Table 5). Hellquist et al (48,49) have demonstrated that when CIS and severe dysplasia are both included in follow-up studies, those lesions most akin to "pure" CIS (top-to-bottom dysplasia without keratin) are least likely to become invasive.
It is encouraging to note such a low transformation rate with minimal surgery in the Rochester cohort, and the fact that virgin CIS represented a much greater proportion (13%) of the total UAT carcinoma experience in the Rochester population than had heretofore been reported (13,17,32,41,46,54). The present study also offers insight into the extent of the case selection biases in clinicopathologic surveys of UAT CIS. The largest clinicopathological investigation of laryngeal and pharyngeal cancer patients, for example, found that only 2.8% of 1,912 affected patients had CIS of these anatomic sites, all others were diagnosed with invasive disease (16). The equivalent Rochester proportion was 14.3%.
It seems reasonable, then, that such relatively innocuous lesions are being treated locally, rather than being referred to the large teaching and research centers from which clinicopathologic data usually originate. Auerbach et al's (9) finding of laryngeal CIS in 16% of 644 consecutive autopsies of cigarette smokers further substantiates the present investigation's conclusion that CIS is a greater contributor to total UAT carcinoma than is usually thought.
In this light, furthermore, Mashberg et al's (10) report that 29% of 158 very small oral carcinomas were partially or completely CIS implies that early detection techniques will lead to an increase in the proportion of diagnosed CIS cases and a subsequent improved prognosis for affected patients. In fact, this has already been demonstrated in the Rochester population wherein only 6.3% of early (1935-1964) UAT mucosal carcinomas were CIS while 18.3% of more recent (1965-1984) UAT mucosal lesions were such.
A final significant difference between the present report and clinicopathologic reports in the literature was the surprizingly high proportion of unassociated (virgin) CIS lesions in the Rochester cohort. Only seven of 48 (15%) UAT CIS lesions were found adjacent to invasive carcinomas, while literature reports and textbooks have usually indicated that it was quite unusual to find CIS of indexed sites without juxtaposed invasive disease (7,11,13,19,21, 55). This might indicate that teaching centers are diagnosing CIS cases predominantly as incidental lesions in patients referred for invasive carcinoma. The excellent studies by Miller and Fisher (5,6,12,32,41) seem to be the most notable exceptions. Their series of laryngeal cases is the largest yet reported (n=203) and all appear to be virgin CIS lesions.
Much is yet to be learned about the clinicopathology and epidemiology of CIS of the UAT before we can claim a thorough understanding of this disease, especially as it is found in the mouth and pharynx. The fact that the present study, with only 41 virgin lesions, is the second largest collection of such cases reported (Table 5) certainly emphasizes this point, while at the same time reinforcing the importance of the Rochester data. As the first epidemiologic analysis, furthermore, the presently reported investigative results take on added significance. The authors present this information, however, not as a definitive characterization of CIS of the UAT, but as simply another step in the ongoing study of this most fascinating disease.
The rate per 100,000 person-years for carcinoma in situ (CIS) of the upper aerodigestive tract (UAT) in the population of Rochester, MN was 3.1 for males and 0.6 for females. Lip vermilion lesions were more common in males and intraoral mucosal lesions were more common in females, although female disease was uncommon enough (n=7) to make this association tenuous. The rates in Rochester are higher than those reported be SEER; this suggests underreporting in SEER rather than an excess in the Rochester population. The typical patient with an internal mucosal CIS lesion (excluding labial vermilion) was a 60.1 year old white male who used tobacco and alcohol in excess. The typical patient with a CIS of the vermilion border was a 69.6 year old white male who worked outdoors and used tobacco, but not alcohol, excessively.
The typical internal mucosal CIS lesion was 1.4 cm. in size, was associated with leukoplakia clinically, and had been present for 2.1 years prior to CIS diagnosis. The typical vermilion CIS lesion was 1.3 cm. in size, was also associated with leukoplakia, and had been noted for 3.4 years prior to CIS diagnosis. Almost half of all cases of internal mucosal CIS presented with erythroplakia, usually admixed with leukoplakia (erythroleukoplakia). After an average of 10 years of follow-up after treatment, one-third of virgin internal mucosal CIS lesions recurred and 10% transformed into invasive squamous cell carcinomas. No vermilion lesions recurred or transformed.
The average annual incidence rate for CIS of the UAT mucosa has tripled since 1935-1964, although vermilion lesions have remained essentially unchanged over the half century of observation. Age-specific incidence rates demonstrate that CIS frequency increases throughout life for males, to a peak of 40.5/100,000 person-years after 74 years of age, while the rates for females remained low for all but the oldest age bracket.
1. Howarth W. Precancerous epitheliomatosis (Bowen's disease) of the palate and fauces. J Laryng Otol 1935; 50:28-32.
2. Cipollaro AC, Foster PD. Bowen's precancerous dermatosis of the mucous membrane. NY State J Med 1940; 40:264-275.
3. Brighton GR, Altman F. Bowen's disease and superficial mucous epitheliomas of the upper respiratory and alimentary tracts. Arch Otolaryngol 1942; 36:354-371.
4. Gorlin RJ. Bowen's disease of mucous membrane of the mouth; review of literature and presentation of cases. Oral Surg 1950; 3:35-51.
5. Miller AH, Fisher HR. Carcinoma in situ of the larynx. Ann Otol Rhin Laryng 1953; 62:358-370.
6. Fisher HR, Miller AH. Carcinoma-in-situ of the larynx--a 10 year study of its histopathological classification, prognosis and treatment. Ann Otol Rhin Laryng 1958; 67:695-702.
7. Shedd DP, Hukill PB, Kligerman MM, et al. A clinicopathologic study of oral carcinoma in situ. Amer J Surg 1963; 106:791-796.
8. Miller AH. Carcinoma-in-situ of the larynx. A twenty year study of the results of its management. Amer J Surg 1070; 120:492-494.
9. Auerbach O, Hammond EC, Garfinkel L. Histologic changes in the larynx in relation to smoking habits. Cancer 1970; 25:92-104.
10. Mashberg A, Morrissey JB, Garfinkel L. A study of the appearance of early asymptomatic oral squamous cell carcinoma. Cancer 1973; 32:1436-1445.
11. Kramer IRH. Carcinoma-in-situ of the oral mucosa. Int Dent J 1973; 23:94-99.
12. Fisher HR. The delineation of carcinoma in situ of the larynx. Canad J Otolaryngol 1974; 3:522-532.
13. Bauer WC. Concomitant carcinoma in situ and invasive carcinoma of the larynx. Canad J Otolarygol 1974; 3:533-542.
14. Shafer WG. Oral carcinoma in situ. Oral Surg 1975; 39:227-238.
15. Shafer WG, Waldron CA. Erythroplakia of the oral cavity. Cancer 1975; 36:1021-1028.
16. Ferlito A. Histological classification of larynx and hypopharynx cancers and their clinical manifestations. Pathologic aspects of 2052 malignant neoplasms diagnosed at the ORL Department of Padua University from 1966 to 1977. Acta Otolaryngol (Stockh) [suppl] 1976; 432:1-88.
17. Shafer WG. Basic clinical features of oral premalignant lesions. In: Mackenzie IC, Dabelsteen E, Squire CA. Oral premalignancy. Proceedings of the first Dows Symposium. Ames, Iowa: University of Iowa Press, 1980, 15-22.
18. Amagasa T, Yokoo E, Sato K, et al. A study of the clinical characteristics and treatment of oral carcinoma in situ. Oral
Surg 1985; 60:50-55.
19. Batsakis JG. Tumors of the head and neck. ed 4, Baltimore: Williams & Wilkins, 1979, 125-129.
20. Barnes L, Gnepp DR. Diseases of the larynx, hypopharynx, and esophagus. In: Barnes L (ed). Surgical pathology of the head and neck. New York: Marcel Dekker, 1985, 156-158.
21. Crissman JD, Gnepp DR, Goodman ML, et al. Preinvasive lessions of the upper aerodigestive tract. Histologic definitions and clinical implications (a sympsium). In: Rosen PP, Fechner RE (eds). Path Annual, vol 22 (1). Norwalk, CN: Appleton-Century-Crofts, 1987, 311-352.
22. Feinstein A. Clinical judgement. Baltimore: Williams & Wilkins, 1967, 53.
23. Melton LJ III. Selection bias in the referral of patients and the natural history of surgical conditions. Mayo Clin Proc
1985; 60: 880-889.
24. Bouquot JE. The epidemiology of head and neck tumors. In: Gnepp DR (ed). Pathology of the head and neck. New York: Churchill Livingston1988:263-314.
25. Kurland LT, Molgaard CA. The patient record in epidemiology. Sci Am 1981; 245:54-63.
26. Kurland LT, Elveback LR, Norbrega FT. Population studies in Rochester and Olmsted County, Minnesota, 1900-1968. In: Kessler IT, Levin ML (eds). The community as epidemiologic laboratory. Baltimore: Johns Hopkins Press, 1970, 47-69.
27. Kurland LT, Elveback LR, Nobrega FT. Mayo Clinic records linkage system in the Rochester-Olmsted Epidemiology Program Project. In: Davies AM (ed). Uses of epidemiology in planning health services. Belgrade: Savremena Adminstracija, 1973, 164-176 (Proceedings of the Sixth International Scientific Meeting, International Epidemiology Association, 1971).
28. Kurland LT, Molgaard CA, Schoenberg BS. Mayo Clinic records-linkage: contributions to neuroepidemiology. Neuroepid 1982; 1:102-114.
29. Kurland LT, Molgaard CA, Weigel KM. The minimum basic data set and epidemiologic research: the Mayo Clinic experience. In: Lambert PM, Rogers FH (eds). Hospital Statistics in Europe. Brussels, North-Holand Publ, 1982, 25-41.
30. The United States National Center for Health Statistics. International classification of diseases. ed 9, Clinical modification (ICD-9-CM). Vol. 1. Ann Arbor: Edwards Brothers, 1978, 82-86, 104.
31. Waldron CA. Oral epithelial tumors. In: Gorlin RJ, Goldman HM (eds). Thoma's oral pathology. ed 6, St. Louis: C.V. Mosby Co, 1970, 801-858.
32. Miller AH. Carcinoma in situ of the larynx: clinical appearance and treatment. In: Alberti PW, Bryce DP (eds). Centennial conference on laryngeal cancer. New York: Appleton-Century-Crofts, 1976, 161-113.
33. Mehregan AH. Pinkus' guide to dermatohistopathology. ed 4, Norwalk, Conn: Appleton-Century-Crofts, 1986, 443-451.
34. Seidman H, Kreiman SD. An analysis of the records of the Central Cancer Registry of the Calhoun County, Michigan, Medical Society, 1949-1961. New York: Amer Cancer Soc, Inc., 1964.
35. Breslow L. Incidence of cancer in Alameda County, California, 1960-1964. Berkeley: State of Calif Dept Pub Health, 1967.
36. Young JL Jr, Percey CL, Asire AJ, et al. Cancer incidence and mortality in the United States, 1973-1977. National Cancer Inst Monogr #57. Washington DC: U.S. Govt Print Off, 1981.
37. Bouquot JE, Gnepp DR. Carcinoma in situ of the upper aerodigestive tract: A necessary review with emphasis on epidemiology. Cancer 1988; 61:1685-1690.
38. Bouquot JE, Weiland LH, Kurland LT. Leukoplakia and carcinoma in situ synchronously associated with invasive oral/oropharyngeal carcinoma in Rochester, Minnesota, 1935-1984. Oral Surg Oral Med Oral Pathol 1988; 65:199-207..
39. Altmann F, Ginsberg I, Stout AP. Intraepithelial carcinoma (carcinoma in situ) of the larynx. Arch Otolaryngol 1952; 56:121-133.
40. McGavran MH, Bauer WC, Ogura JH. Isolated laryngeal keratosis. Its relation to carcinoma of the larynx based on a clinicopathologic study of 87 consecutive cases with long-term follow-up. Laryngoscope 1960; 70:932-951.
41. Miller AH, Fisher HR. Clues to the life history of carcinoma in situ of the larynx. Laryngoscope 1971; 81:1475-1480.
42. Mincer H, Coleman SA, Hopkins KP. Observations on the clinical characteristics of oral lesions showing histologic epithelial dysplasia. Oral Surg 1972; 33:389-392.
43. Banoczy J, Csiba A. Occurrence of epithelial dysplasia in oral leukoplakia. Oral Surg 1976; 42:766-774.
44. Pene F, Fletcher GH. Results in irradiation of the in situ carcinoma of the vocal cords. Cancer 1976; 37:2586-2590.
45. Pindborg, JJ, Deftary DK, Mehta FS. A follow-up study of sixty-one oral dysplastic precancerous lesions in Indian villagers. Oral Surg 1977; 43:383-390.
46. Doyle PJ, Flores A, Douglas GS. Carcinoma in situ of the larynx. Laryngoscope 1977; 87:310-316.
47. Elman AJ, Goodman M, Wang CC, et al. In situ carcinoma in the vocal cords. Cancer 1979; 43:2422-2428.
48. Hellquist H, Lundggen J, Olofsson J. Hyperplasia, dysplasia and carcinoma in situ of the vocal cords. A follow-up study. Clin Otolaryngol 1982; 7:11-23.
49. Hellquist H, Olofsson J, Grontoft O. Carcinoma in situ and severe dysplasia of the vocal cords. A clinicopathological and photometric investigation. Acta Otolaryngol 1981; 92: 543-555.
50. Silverman S Jr, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients.Cancer 1984; 53:563-568.
51. Norris CM, Peale AR. Keratosis of the larynx. J Laryngol 1963; 77:635-647.
52. Kleinsasser O. Uber den Krankheitsverlauf bei Epithel-hyperplasien der Kehlkopfschleimhaut und die Entstehung von Karzinomen. IV. Mitteilung. Z Laryng Rhinol Otol 1963; 42: 541-558.
53. Hintz BL, Kagon AR, Nussbaum H, et al. A "watchful waiting" policy for in situ carcinoma of the vocal cords. Arch Otolarngol 1981; 107:746-751.
54. Som ML. Discussion. In: Alberti PW, Bryce DP (eds). Centennial conference on laryngeal cancer. New York: Appleton-Century-Crofts, 1976, 166.
55. Slaughter DP, Southwick HW, Smejkal W. "Field cancerization" in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer 1953; 6:963-968.
Table 1: Gender- and site-specific average annual incidence rates for CIS of the UAT in Rochester, Minnesota, 1935-1984
(population bases: males=900,312 person-years; females= 1,102,916 person-years).
--------------------------------------------------------------
# CASES | # NEW CASES/100,000 PERSON-YEARS
-------------------------------------------------------------------------------
ANATOMIC SITE MALES FEMALES TOTAL | MALES FEMALES TOTAL
-------------------------------------------------------------------------------
Lip vermilion 18 (13)* 2 (2)* 20 (15)*| 2.0 (1.4)* 0.2 (0.2)* 1.0 (0.8)*
Oral cavity 9 (5) 3 (3) 12 (8) | 1.0 (0.6) 0.3 (0.3) 0.6 (0.4)
Pharynx 6 (3) 1 (1) 7 (4) | 0.7 (0.3) 0.1 (0.1) 0.4 (0.2)
Larynx 7 (6) 1 (1) 8 (7) | 0.8 (0.7) 0.1 (0.1) 0.4 (0.4)
Nasal/Paranasal 1 (1) 0 (0) 1 (1) | 0.1 (0.1) 0.0 (0.0) 0.1 (0.1)
-------------------------------------------------------------------------------
Total UAT 41 (28) 7 (7) 48 (35) | 4.6 (3.1) 0.6 (0.6) 2.4 (1.8)
-------------------------------------------------------------------------------
* numbers in parentheses refer to virgin CIS lesions only, that is, those unassociated with invasive carcinomas.
Table 2: Time trends in average annual incidence rates for CIS of the UAT in Rochester, Minnesota, 1935-1984, both genders (population bases: 1935-1964=913,305 person-years; 1965-1984=1,089,923 person-years).
|----------------------------------------------------|
| # NEW CASES PER 100,000 PERSON-YEARS * |
|------------------------|----------------------------------------------------|
| YEAR OF DIAGNOSIS | LIP VERMILION | INTERNAL MUCOSA | TOTAL |
|-----------------------------------------------------------------------------|
| 1935 - 1964 | 1.0 (8.0) ** | 0.6 (9.6) ** | 1.5 (17.6) **|
| 1965 - 1984 | 1.0 (3.2) | 2.1 (11.5) | 3.1 (14.7) |
|-----------------------------------------------------------------------------|
| ALL DECADES | 1.0 (6.0) | 1.4 (10.5) | 2.4 (16.5) |
|-----------------------------------------------------------------------------|
*includes both virgin and associated CIS lesions.
**numbers in parentheses refer to invasive carcinomas only.
Table 3: Various clinical features of combined virgin and microinvasive CIS lesions of the UAT in Rochester, Minnesota, 1935-1984, both genders. All proportions are determined using only cases with adequate information in medical records.
|----------------------------------------------
| VERMILION | MUCOSA | TOTAL |
| (n=17) | (n=24) | (n=41) |
|--------------------------------------------------------------------------|
|PATIENT CHARACTERISTICS: | | | |
| Males | 88.2 % | 79.2 % | 82.9 % |
| Average age | 69.8 years| 60.1 years| 64.9 years|
| Tobacco smoker | 80.0 % | 93.3 % | 90.3 % |
| Alcohol abuse * | 6.7 % | 68.4 % | 40.0 % |
| Outdoor occupation | 64.7 % | 20.0 % | 39.0 % |
|--------------------------------------------------------------------------|
|LESION CHARACTERISTICS: | | | |
| Average size | 1.3 cm. | 1.4 cm. | 1.4 cm. |
| Average duration | 3.4 years| 2.1 years| 2.7 years|
| With leukoplakia | 100.0 % | 66.7 % | 82.4 % |
| With erythroplakia | 0.0 % | 38.9 % | 25.0 % |
| With ulceration | 56.3 % | 16.7 % | 32.4 % |
| With mass ** | 25.0 % | 0.0 % | 11.8 % |
|--------------------------------------------------------------------------|
|PROGNOSTIC FEATURES: | | | |
| Average # years followed | 11.8 years| 9.6 years| 10.5 years|
| Rx=minor surgery | 100.0 % | 83.3 % | 90.2 % |
| Recurred | 0.0 % | 12.5 % | 7.3 % |
| Invaded (sq. cell ca.) @ | 11.8 % | 25.0 % | 19.5 % |
|--------------------------------------------------------------------------|
* identified as "alcoholic", "heavy drinker", or with a "drinking problem" in the medical record.
** cutaneous horns and actinic keratoses.
@ microinvasive at time of treatment (n=2 vermilion & 4 mucosal lesions) or became invasive on recurrence (n=2).
Table 4: Comparison of average annual incidence rates for virgin UAT CIS in the U.S. white population, 1973-1977 (36), and the Rochester, Minnesota population, 1935-1984, males and females.
|-------------------------------------------------------------
| # NEW CASES PER 100,000 PERSON-YEARS
|-------------------------------------------------------------
| MALES | FEMALES | TOTAL |
|-------------------------------------------------------------------------------|
| ANATOMIC SITE | U.S. ROCHESTER | U.S. ROCHESTER | U.S. ROCHESTER |
|-------------------------------------------------------------------------------|
|ORAL & PHARYNX | 0.4 2.3 (0.9)* | 0.1 0.5 (0.4)* | 0.2 1.4 (0.6)* |
|LARYNX | 0.5 0.7 | 0.1 0.1 | 0.3 0.4 |
|-------------------------------------------------------------------------------|
|TOTAL UAT CIS ** | 0.9 3.1 (1.6) | 0.2 0.6 (0.4) | 0.5 1.8 (1.0) |
|-------------------------------------------------------------------------------|
* numbers in parentheses refer to incidence rates with lip vermilion lesions excluded.
Table 5: A summary of transformation rates (into invasive carcinoma) from the largest reported series of virgin UAT CIS cases which provided adequate follow-up information, listed by year of publication.
--------------------------------------------------------------------
YEAR # CIS ANATOMIC %
AUTHOR(S) PUBL. CASES SITE TRANSFORMED
--------------------------------------------------------------------
TREATED CIS CASES:
Altman, et al (39) 1952 29 larynx 3.5
McGavran, et al (40) 1960 18 * larynx 11.1
Miller,Fisher (6,8,41) 1971 203 larynx 15.8
Mincer, et al (42) 1972 16 * oral 11.1
Banoczy, Csiba (43) 1976 68 * oral 13.2
Pene, Fletcher (44) 1976 26 larynx 4.0
Pinborg, et al (45) 1977 21 * oral 14.3
Doyle, et al (46) 1977 28 larynx 7.1
Elman, et al (47) 1979 81 * larynx 17.0
Hellquist, et al (48,49) 1982 20 * larynx 25.0
Silverman, et al (50) 1984 22 * oral 36.4
Amagasa, et al (18) 1985 12 oral 50.0
Bouquot, Kurland, Weiland 1987 41 UAT 4.9
UNTREATED CIS CASES:
Norris, Peale (51) 1963 16 larynx 33.3
Kleinsasser (52) 1963 20 larynx 90.0
Hintz, et al (53) 1981 27 larynx 63.0
--------------------------------------------------------------------
TOTAL, TREATED CASES 559 18.6 **
TOTAL, UNTREATED CASES 63 62.1 **
--------------------------------------------------------------------
* includes severe epithelial dysplasias in addition to CIS
** not weighed according to size of patient cohorts; exludes present data (i.e. from Bouquot, Kurland, Weiland).
Figure 1: Age-specific incidence rates per 100,000 person-years for total UAT CIS experience in Rochester, Minnesota, 1935-1984, for males and females.
Figure 2: Total UAT CIS age-specific incidence rates per 100,000 Rochester males, 1935-1984, for lip vermilion and internal mucosal UAT surfaces.
Figure 3: Age-specific incidence rates per 100,000 Rochester males, 1935-1984, comparing virgin UAT CIS lesions (dotted lines) with associated CIS lesions (i.e. those adjacent to invasive carcinoma or with small focus of microinvasion within them) (solid lines).
Figure 4: Duration of follow-up time after UAT CIS diagnosis for affected Rochester residents (n=47), 1935-1984. Striped portion of bars represents patients still alive at the last date of follow-up observation (n=20).
Figure 5: Age-specific incidence rates for UAT CIS in the U.S. population as represented by the SEER data; all races, both genders (36).