Oral verrucous carcinoma

Oral verrucous carcinoma Incidence in two US populations Jerry E. Bouquot, DDS, MSD, a Morgantown, W. Va. THE MAXILLOFACIALCENTERFOR DIAGNOSTICS& RESEARCH Much is known about the clinical appearance, biological behavior, and treatment of verrucous carcinoma of the oral cavity. However, the epidemiologic characteristics are completely unknown. This cancer is considered to be rare in Western cultures because it is not common in oral pathology biopsy services, but there is no epidemiologic evidence for this belief. To provide this evidence, 2 population-based incidence investigations were carried out, one in Rochester, Minn., and the other in the state of West Virginia. The results were as follows: the age-adjusted average annual incidence rate for oral verrucous carcinoma among Rochester residents was 0.1/100,000 person-years (0.2 for males, 0.0 for females), whereas the incidence rate for all intraoral carcinomas was 3.6/100,000 person-years (5.4 for males, 2.1 for females). Among men over 64 years of age, the incidence rate for verrucous carcinoma was increased to 3.2/100,000 person-years. Verrucous carcinoma was among the least common of the oral carcinomas in this population, representing only 3% of the total. The age-adjusted incidence rate for oral and pharyngeal verrucous carcinoma among West Virginia residents was somewhat greater, 0.3/100,000 person-years, and showed an even gender predilection (0.28 for males, 0.29 for females). The incidence rate for all oral/pharyngeal cancers in West Virginia was 8.8/100,000 person-years (13.4 for males, 5.7 for females), which was below the US average. The conclusion is that oral verrucous carcinoma is a rare tumor of older people, diagnosed in only 1 to 3 of every 1,000,000 persons each year. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:318-24)

A smokeless tobacco etiology for oral cancer was suggested by James E w i n g ] who noted that cancer in the mouths of tobacco chewers most often developed at the site of quid placement. Ewing's premise was reiterated in Western clinicopathologic reports published during the 1940s, with specific reference to verrucous carcinoma.2, 3 The high relative frequency of oral cancer (all types) in India, moreover, had focused attention on the causative role of chewing tobacco as early as 1908, when it was determined that an amazing 71% to 92% of all c a r c i n o m a s diagnosed in hospital outpatients arose from the oral mucosa.4, 5 Verrucous carcinoma, a low-grade variant of squamous cell carcinoma, is so closely aligned with the use of snuff and chewing tobacco that it has been called the "snuff dipper's cancer," even though it is not the most c o m m o n form of carcinoma resulting from this habit and even though it has been reported from numerous anatomic sites other than the oral mucosa (larynx, ear This investigation was supported in part by Research Grant AR30582, National Institutes of Health, U.S. Public Health Service, and by the Mary Babbs Randolph Cancer Center of West Virginia University. aDirector of Research, The Maxillofacial Center for Diagnostics & Research, Morgantown, W. Va.; Former Dental Director, West Virginia Bureau for Public Health, Charleston, W. Va. (Dr Bouquot was a Senior Visiting Scientist with the Department of Health Sciences Research, Section of Clinical Epidemiology, Mayo Clinic, Rochester, Minn., during part of this investigation.) Received for publication May 17, 1996; returned for revision July 2, 1996; accepted for publication May 18, 1998. Copyright © 1998 by Mosby, Inc. 1079-2104/98/$5.00 + 0 7/14/91902 318

canal, vagina, penis, bladder, rectum, soles of feet, dentigerous cyst). 6-11 Furthermore, it is now known that 16% to 51% of oral verrucous carcinomas are found in persons without tobacco habits. 10 Obviously, other etiologic agents may be involved, with immunosuppression, human papillomavirus, and other viruses being most recently implicated. 12-16 Nevertheless, it cannot be denied that the most common site of occurrence for this cancer remains the oral mucosa and that most oral cases are found in persons who habitually use chewing tobacco or snuff. The typical clinical presentation of oral verrucous carcinoma has long been known, as has its remarkably innocuous appearance and biological behavior when not associated with the devastating premalignancy, proliferative verrucous leukoplakia. 11,17,18 Relative frequency rates for biopsy service cases are also known: this cancer represents 1% to 10% of all oral squamous cell carcinomas diagnosed by US hospitals and dental schools. 10 In India, approximately 7% of oral cancers are verrucous carcinomas. 19 No population-based studies have been reported, however, and a significant facet of knowledge about this disease is lacking--namely, its epidemiologic characteristics. The epidemiologic characterization of verrucous carcinoma may be of timely importance to populations in the West, where a significant increase in young users of smokeless tobacco has been reported. 2°-23 The purpose of the present investigation, therefore, was to determine incidence data for this disease. Because of the importance of microscopic confirmation of such an unusual neoplasm, a population-based investigation was

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undertaken in Rochester, Minn., where all oral and pharyngeal carcinomas could be reviewed histopathologically, where there is an excellent case ascertainment rate extending back to 1935, and where the demographics of the population are well defined. This city has the additional characteristic of having a population in which tobacco chewing is not popular. For comparison, statewide tumor registry data from West Virginia, the state with the highest prevalence of smokeless tobacco use, were used to determine incidence in that population, even though identified cases could not be microscopically reviewed and the case ascertainment rate was presumably not as high as in the Rochester study. The 2 populations have different advantages and disadvantages relative to epidemiologic investigation, but it was felt that an analysis of both would provide meaningful information and interesting comparisons. The primary hypothesis of this study was that verrucous carcinoma incidence is extremely low, possibly less than 1 case per 1,000,000 persons each year. A secondary hypothesis was that the verrucous carcinoma experience in the 2 populations was considerably different, with the tobacco-chewing West Virginia population having a significantly higher incidence rate for this "snuff dipper's cancer."

MATERIAL AND METHODS Rochester data collection The first community evaluated was Rochester, Minn. Rochester has a relatively small population (approximately 62,000 persons in 1990, but representing 2,003,228 person-years for the years 1935 through 1984). Its suitability for epidemiologic investigations has been well established, and several previous studies of head and neck cancers have been reported. 24-33 The major advantages of Rochester population studies are as follows: (1) great care is taken to identify all cases of specific diseases--ie, there is minimal referral bias; (2) entire medical records are available for virtually all cases; (3) all microscopic cases are available for diagnostic confirmation and reevaluation. Anecdotal information indicates that smokeless tobacco use has not been common in this population; in fact, growing up near Rochester, I was not even aware of the fact that tobacco could be chewed until I learned of the habit in dental school. A review of more than 4800 medical records from this population identified only 18 tobacco chewers, all male. Recent surveys have indicated that only 2% of the Minnesota population chews tobacco and that chewers are almost always maleY Minimal referral bias is possible in Rochester studies because medical practice in the population has been centered at the Mayo Clinic since the early part of the

20th century. Approximately 90% of the entire population registers for primary or specialty health care during any given 3-year period, and such Clinic registration requires the entry and indexing of all diagnoses made during that registration. This type of health practice is unique in that residents use a single major medical center not only for secondary and tertiary health care but for primary care as well. Additionally, residents' diagnoses from smaller hospitals and independent health care providers in surrounding counties and those from the 2 large regional tertiary care facilities in Minneapolis, Minn., are periodically entered into the indexing and record retrieval system at the Mayo Clinic. Diagnoses listed on the death certificates of Rochester residents who died after 1935 are also included in this database, including those of residents who had moved away from Rochester by the time they died. All medical, surgical, histopathologic, and autopsy records of every Rochester resident who was given a diagnosis of neoplastic or precancerous disease of the mucous membranes and glands of the upper respiratory and digestive tracts from January 1, 1935, through December 31, 1984, were reviewed after retrieval from the files of the Mayo Clinic and its affiliated hospitals, the Olmsted Medical 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 (125 km distant). For purposes of thoroughness, all cases of sarcoma, neoplastic and inflammatory cervical lymph node disease, facial skin cancer, benign neoplasms and hyperplasias, and such nonspecific diagnoses as "ulcer," "mass," and "lesion" were also reviewed. In total, the complete medical records of more than 4800 residents were reviewed, including all microscopic material from head and neck lesions (benign or malignant), to assure that n o cases of verrucous carcinoma were missed or misdiagnosed. The anatomic areas investigated included the following (9th Revision International Classification of Diseases [ICD] codes are given in parentheses35): lip vermilion (140.1-2), oral cavity (140.3-5, 141, and 143-145), major salivary glands (142), oropharynx (146), nasopharynx (147), hypopharynx (148), unspecified pharynx (149), nasal and paranasal sinuses (160, with the exception of 160.1), and larynx (161). For purposes of the present study, only oral cavity (intraoral) lesions are germane, but pharyngeal, laryngeal, and lip vermilion data are included because verrucous carcinoma occasionally occurs at these sites. Only those patients who had resided in Rochester for

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September 1998 f a b l e I. Histopathologic types of upper aerodigestive tract (UAT) carcinomas diagnosed in Rochester, Minn., residents, 1935-1984, ranked by frequency of intraoral lesions No. lesions* Diagnosis Squamous cell carcinoma Carcinoma in situ Microinvasive squamous cell carcinoma Metastatic carcinoma to UAT Adenocarcinoma (minor glands) Verrucous carcinoma Lymphoepitlaelioma Basal cell carcinoma Totals*

Lip vermilion

Intraoral mucosa

65 15 7 0 1 0 0 10 98

50 8 6 4 2 2 1 0 73

Pharyngeal mucosa 46 5 3 2 4 0 7 0 67

Laryngeal mucosa 49 7 3 0 0 0 0 0 59

Total 210 35 19 6 7 2 8 10 297

*Lesions of major salivary glands and nasal/paranasal sinuses are excluded. tNo primary cases of malignant melanoma, spindle cell carcinoma, basaloid squamouscarcinoma, or adenosquamouscarcinoma were found.

at least 1 year before diagnosis were considered bona fide residents, and only cases of microscopically proven carcinoma were accepted. Few cases were excluded because of a lack of microscopic confirmation; all verrucous carcinomas and 99.4% of all identified upper aerodigestive tract malignancies were histologically confirmed at the time of diagnosis. These were reexamined by a single pathologist (J.E.B.) who was unaware of the original microscopic diagnoses during his review. All diagnoses presented herein were updated relative to terminology and histopathologic classification. The diagnostic criteria used for verrucous carcinoma were those delineated by Luna and Tortoledo 9 in their detailed and thoughtful review. Follow-up through January 1, 1992, was complete for all verrucous carcinomas and for 98.1% of all upper aerodigestive tract carcinomas. With respect to those in the cohort who died during the period of observation, death certificates were obtained regardless of the location or cause of death for all but 2 persons who were known to have had cancer; neither of these 2 cancer incidence cases was a verrucous carcinoma. For calculation of carcinoma incidence, the entire population of Rochester was considered at risk, and the denominator in age- and gender-specific incidence rate calculations was estimated from decennial census data. Age- and gender-adjustment of incidence rates was to the 1970 US white population to facilitate comparison with epidemiologic data from other sources. Incidence rates were based on the number of individual cancers, not the number of affected persons, and are actually therefore incidence density measures. 36 Incidence rates were calculated as numbers of newly diagnosed cases per 100,000 person-years.

West Virginia data collection The estimated population of West Virginia in 1995 was 1,825,256, and there were 5,545,598 person-years

at risk for the observation years 1993 through 1995. 37 The state has long held the distinction of having the highest prevalence of smokeless tobacco use in the United States.34, 38 Cancer-specific data have only recently become available in this state through a statewide cancer registry similar to those in other states.37,39,40 It is required by law that cancer diagnoses be sent to the registry, but underreporting likely results because a certain number of health care professionals do not submit their cases and because a certain number of state residents travel to out-of-state institutions for diagnosis and treatment. Diagnoses are not microscopically confirmed by the tumor registry. The West Virginia Department of Health and Human Resources, Bureau for Public Health, Office of Epidemiology and Health Promotion, Division of Surveillance and Disease Control, implemented a computerized, population-based central cancer registry in 1992. Data for the West Virginia Cancer Registry (WVCR) was collected from all hospitals (n = 61) within the state, from 8 free-standing pathology laboratories, and from 2 free-standing radiation treatment centers. Facilities without tumor registries provide access to medical records of cancer cases for the WVCR abstractors. Results were not available for oral carcinomas exclusively, and data include oral, lip vermilion, and pharynx cancers; information relative to patient habits was not available. To identify cases of cancer in residents who traveled outside West Virginia for diagnosis and treatment, the WVCR has reciprocal agreements for data exchange with the central registries of Ohio, Pennsylvania, Maryland, Kentucky, Virginia, the District of Columbia, North Carolina, Florida, Arkansas, and Mississippi. To identify cases not found by routine case-finding activities, all deaths among West Virginia residents during the period 1993 through 1995 with cancer listed as an underlying cause of death were

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Table II. Average annual incidence rates for primary invasive carcinomas of upper aerodigestive tract in the Rochester, Minn., population, 1935-1984, age-adjusted to 1970 US white population Anatomic site

Males

Lip vermilion Intraoral mucosa

8.2 (74)$ 5.4 (38)

Verrncous carcinoma

0.2 (2)

Pharyngeal mucosa Laryngeal mucosa Nasal/paranasal sinuses Major salivary glands All primary carcinomas

5.2 7.0 0.7 1.1

No. cases/lOO, OOOperson-years* Females

(38) (49) (6) (11)

30.0 (216)

0.8 (9)$ 2.1 (23) 0.0 (0) 2.0 (22) 0.3 (3) 0.6 (6) 1.3 (13) 7.2 (76)

Totalt 4. i 3.6 0.1 3.4 3.3 0.7 1.3 17.3

(83)$ (61) (2) (60) (52) (12) (24)

(292)

*Population base: 900,312 person-years for males, 1,102,916 person-years for females. tGender-adjusted to 1970 US white population. ~Numbers in parentheses represent actual numbers of cases, not incidence rates. Carcinomas in situ and metastases to upper aerodigesfive tract are excluded from these data.

matched against the W V C R data. Those cases that were verified to be reportable based on year of diagnosis were included in the WVCR. For purposes of the present study, the terms oral~pharyngeal and oral and pharyngeal, as applied to WV data, are defined as including lip vermilion, intraoral mucosa, and pharyngeal mncosa (ICD 140, 141, and 143-149). Major salivary glands (ICD 142) are excluded from the definition.

RESULTS Rochester From January 1, 1935, through December 31, 1984, 339 cases of carcinoma of the upper aerodigestive tract were diagnosed among the residents of Rochester. Of these, 297 arose from oral (including lip vermilion), pharyngeal, and laryngeal sites. All but 1 of the 297 malignancies were clinically and histopathologically classified during life; no case was identified by means of a death certificate that had not been previously noted in antemortem medical records. The single case not classified before death was a nasopharyngeal carcinoma manifesting itself as an occult cervical metastasis. Only 2 verrucous carcinomas were diagnosed at upper aerodigestive tract sites during the 2,003,228 person-years of observation. Both of these lesions arose from the buccal mucosa of elderly men (69 and 72 years of age at diagnosis). Both were treated by wide local resection and neither recurred, metastasized, or caused the death of the affected patient. One of the affected patients dipped snuff and the other smoked cigarettes. These habits had begun during their teenaged years. These 2 lesions represented 3.3% of all primary invasive carcinomas of the oral mucosa. The proportion of oral carcinomas represented by verrucous carcinoma was actually less than that represented by either oral carcinomas in situ or oral metastatic deposits from

extraoral carcinomas (Table I). Oral epithelial malignancies such as melanoma, spindle cell carcinoma, basaloid squamous carcinoma, and adenosquamous carcinoma are presumably even more rare, as they were not diagnosed in this population. The age-adjusted average annual incidence rate for intraoral verrucous carcinoma was 0.1/100,000 person-years (0.2/100,000 for males and 0.0/100,000 for females). This compares with 3.6/100,000 for all primary invasive intraoral carcinomas (Table II). When older men only were assayed, a considerable increase in incidence was noted, with the age-specific incidence rate for verrucous carcinoma for men older than 64 years rising to 3.2/100,000 person-years. Total intraoral carcinoma incidence in this male cohort also increased, from 1.8 for 35-to44-year-olds to 29.7 for men older than 64 years. For men older than 64 years, verrucous carcinoma represented 10.8% of all intraoral carcinomas.

West Virginia The average annual age-specific oral/pharyngeal cancer incidence rate for the state was 8.8/100,000 person-years (13.4/100,000 for males and 5.1/100,000 for females). This was somewhat less than the Rochester rate of 10.1 and the 1990-1994 average US rate of 11.1 for the same anatomic sites (oral and pharyngeal mucosa and lip vermilion).37, 39-42 This lesser incidence relative to the national average was seen at all ages and in both genders. The West Virginia malignancies (n = 610) were usually squamous cell carcinomas (85%), with small proportions being salivary adenocarcinomas (6%), lymphomas (5%), verrucous carcinomas (2.8%), and sarcomas (1%). Most cases (87%) were found in patients 50 or more years of age. A total of 17 oral verrucous carcinomas were identified during 1993

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through 1995; all were from the vestibular mucosa except for 2 each from the oral floor and hard palate. These tumors were evenly divided between males and females, with 9 from females and 8 from males, and 88.2% were found in persons older than 54 years (64.7% were older than 64 years; 41.2% were older than 74 years). Additionally, 7 extraoral verrucous carcinomas were diagnosed from the nasal sinus, larynx, anus, and penis. Oral/pharyngeal cases represented an average annual age-adjusted incidence rate of 0.3/100,000 personyears (0.28/100,000 for males and 0.29/100,000 for females) for this "snuff dipper's cancer." For persons older than 64 years, the incidence rate increased to 1.3/100,000 (Table III). For all practical purposes, these are rates for intraoral disease, as no cases were identified from the lip vermilion or pharyngeal mucosa.

l a b l e III. Age-specific annual incidence rates for verrucous carcinoma in West Virginia population, 1993-1995, representing 5,465,598 person-years at risk

DISCUSSION This investigation confirms the author's hypothesis that verrucous carcinoma of the oral and pharyngeal region is indeed a rare tumor, occurring annually in only 1 to 3 of every million persons. Assuming the present incidence rates to be reasonably representative, we would expect 250 to 750 cases of this cancer to be diagnosed each year among the entire US population. This would explain why so few cases are accessioned in US oral pathology biopsy services. Eisenberg et a1,15 for example, could find only 17 verrucous carcinomas among 20,274 consecutive biopsies submitted to the University of Connecticut. I could find only 16 cases among 38,953 biopsy samples submitted to the 2 oral pathology biopsy services in West Virginia. A tumor as rare and clinicopathologically unique as oral verrucous carcinoma presents a major problem to those examining its population parameters. Its diagnosis requires, to a greater extent than is true for most lesions, experience and close coordination between surgeon and pathologist. Our understanding of its diagnostic criteria and biological behavior has furthermore been constantly evolving. For such a malignancy it is especially important that all identified cases be microscopically reviewed to confirm the diagnosis. It is equally important that all other cases of oral malignancy and benign papillary oral tumors be reviewed for the sake of capturing misdiagnosed cases in the population. Although the total number of identified verrucous carcinoma lesions in the Rochester population is small, I believe that the excellent case ascertainment rate and the population size are adequate to the task of establishing acceptable incidence rates. The ability to confirm the diagnoses of all verruciform oral lesions, benign or malignant, through a review of the actual

Age in yr

No. cases

No. cases/lOO, OOOperson-years*

0-24 25-34 35-44 45-54 55-64 65-74 75+

0 1 1 0 4 4 7

0.00 0.14 0.12 0.00 0.76 0.84 1.95

Totals

17

0.28t

*Numbers of cases were too small for meaningful rates according to gender. tAge-adjusted to 1970 US white population.

medical records and microscopic materials is a powerful advantage of the Rochester data. This advantage is routinely lacking in state tumor registries, none of which have ever mentioned verrucous carcinoma. 4143 Population studies are typically so large that diagnoses must be accepted from a variety of pathologists with different levels of experience, training, and quality, as well as with different diagnostic criteria for verrucous carcinoma. This advantage does not, unfortunately, allow us to reasonably compare the Rochester results with those of statewide incidence data. It may be that the 3-fold increase in verrucous carcinoma incidence in the West Virginia population, when compared with the Rochester population, is due to the greater use of smokeless tobacco in the state population. This is my opinion. Moreover, I believe that the greater incidence in West Virginia females in comparison with Rochester females is likely the result of the long-term use of smokeless tobacco by the older women of West Virginia. My beliefs nonwithstanding, the data do not allow us to substantiate such conclusions. Small numbers of additional cases would greatly influence the established rates, and the incidence rates are, after all, not hugely different. They Could just as likely result from the inclusion of improperly diagnosed papillary carcinomas or large, benign verruciform tumors of the mouth in the West Virginia data or from another, completely unknown feature of the populations studied. The extent of underreporting in the West Virginia data, likewise, cannot be ignored or identified. The combined population base of more than 7.5 million person-years is evidently large enough to capture cases of verrucous carcinoma, but it does not allow us to make significant conclusions relative to etiologies or population trends, except to confirm that it is a disease with an incidence that increases dramatically with age. Finally, we must always keep in mind the fact that verrucous carcinoma only represents a small proportion of the oral cancers that arise from the mucosa of

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smokeless tobacco users. It does not represent the majority of associated cancers. There seems to be a definite association between smokeless tobacco use and oral carcinoma, 44,45 but the strength of this association is not addressed by the present investigation. I encourage additional studies in light of the increasing popularity of these products, the recent suggestion that the use of smokeless tobacco is a safer alternative to cigarette smoking,46, 47 and the close but confusing association between verrucous carcinoma and proliferative verrucous leukoplakia. There is much to learn about this unique form of oral cancer.

nomas of the oral cavity: a clinicopathologic study of 104 cases. Arch Otolaryngol 1984; 110:437-40. Tornes K, Bang G, Stromme Koppang H, Pedersen KN. Oral vermcous carcinoma. Int J Oral Surg 1985;14:485-92. Luna MA, Tortoledo ME. Verrucous carcinoma. In: Gnepp DR, editor. Pathology of the head and neck. London: ChurchillLivingstone; 1988. p. 497-515. Neville, BW, Datum DD, Allen CM, Bouquot JE. Oral and maxillofacial pathology. Philadelphia: WB Sannders; 1995. p. 304-6. Odell EW, Morgan R. Biopsy pathology of the oral tissues. London: Chapman & Hall Medical; 1998. p. 229-33. Kamath VV, Varma RR, Gadewar DR, Muralidhar M. Oral verrucous carcinoma: an analysis of 37 cases. J Craniomaxillofac Surg 1989;17:309-14. Turner JE, Hodge SJ, Callen JR Verrucous carcinoma in a renal transplant patient after long term immunosuppression. Arch Dermatol 1980;116:1074-6. Fisker AV, Philipsen HR Verrucous hyperplasia and verrucous carcinoma of the rat oral mucosa: experimental carcinogenesis using 4-nitroguinoline 1-oxide. Acta Pathotogica Microbiologica Immunologica Scandinavia 1984;92A:437-45. Eisenberg E, Rosenberg B, Krutchkoff DJ. Verrucous carcinoma: a possible viral pathogenesis. Oral Surg Oral Med Oral Pathol 1985;59:52-7. Shroyer KR, Greer RO, Frankhouser CA, McGuirt WE Marshall R. Detection of human papillomavirus DNA in oral verrucous carcinomas by polymerase chain reaction. Mod Pathol 1993;6:669-72. Kahn MA, Dockter ME, Hermann-Petrin JM. Proliferative verrucous leukoplakia: four cases with flow cytometry analysis. Oral Surg Oral Med Oral Pathol 1994;78:469-75. Murrah VA, Batsakis JG. Proliferative verrucous leukoplakia and verrucous hyperplasia. Ann Otol Rhinol Laryngol 1994; 103:660-3. Murti PR, Gupta PC, Bhonsle RB, Daftary DK, Mehta FS, Pindborg JJ. Smokeless tobacco use in India: effects on oral mucosa. In: Stotts RC, Schroeder KL, Burns DM, editors. Smokeless tobacco or health: an international perspective (NIH Publication No. 92-3461). Bethesda, Md.: US Department of Health and Human Services (NIH); 1992. p. 51-65. US Department of Health and Human Services, PHS. The health consequences of using smokeless tobacco: a report of the advisory committee of the Surgeon General (NIH Publication No. 86-2874). Washington, DC: The Department; 1986. Connolly GN, Winn DM, Hecht SS, Henningfield JE, Walker B Jr, Hoffmann D. The reemergence of smokeless tobacco. N Eng J Med 1986; 314:1020-7. US Department of Health and Human Services. Smokeless tobacco use in the United States: behavioral risk factor surveillance system, 1986. Morbid Mortal Wkty Rpt 1987;36:337-40. Glover ED, Glover PN. The smokeless tobacco problem: risk groups in North America. In: Stotts RC, Schroeder KL, Bums DM, editors. Smokeless tobacco or health: an international perspective (NIH Publication No. 92-3461). Bethesda, Md.: US Department of Health and Human Services (NIH); 1992. p. 3-10. Bouquot JE, Kurland L% Weitand LH. Primary salivary epithelial neoplasms in the Rochester, Minnesota population [abstract]. J Dent Res 1979;58:4t9. Bouquot JE, Kurland LT, Weiland LH. Forty-five years of oral carcinoma in a United States population [abstract]. J Oral Pathol 1985;11:81. Bouquot JE, Weiland LH, Kurland LT. Leukoplakia and carcinoma in situ synchronously associated with invasive oral/oropharyngeal carcinoma in Rochester, Minnesota, 19351984. Oral Surg Oral Med Oral Pathol 1988;65:i99-207. Bouquot JE, Kurland LT, Weiland LH. Carcinoma in situ of the upper aerodigest tract: incidence, time trends and follow-up in Rochester, Minnesota, 1935-1984. Cancer 1988;61:1691-8. Bouquot JE. Epidemiology. In: Gnepp DR, editor. Pathology of the head and neck. Philadelphia: Churchill-Livingstone; 1988. p. 263-314.

CONCLUSIONS The primary hypothesis of this investigation--that verrucous carcinoma is a rare tumor is proved correct by the data. Verrucous carcinoma of the oral mucosa was found annually in 1 to 3 of every million persons in 2 populations. This makes verrucous carcinoma among the rarest of all oral cancers. Despite its rarity, the great majority of cases were found in persons older than 64 years. For men over 64 years of age this cancer was found in 1 of every 31,000 persons. Verrucous carcinoma represented 3% of oral carcinomas in 2 population-based analyses, one of which allowed microscopic confirmation of all diagnoses; in the other analysis, microscopic confirmation was not available. The secondary hypothesis--that the verrucous carcinoma experience in these 2 populations with different tobacco chewing experiences would be significantly different---cannot be rejected or considered to be proved by the data because of incompatible study designs. I thank Dr Leonard Kurland, former Director, Section of Clinical E p i d e m i o l o g y and Biostatistics, D e p a r t m e n t o f Health S c i e n c e Research, M a y o Clinic, R o c h e s t e r ; Dr Louis Weiland, former Chairman, Department of Surgical Pathology, M a y o Clinic West, Scottsdale, Ariz.; and Dr Catherine Slemp and Ms. Beverly Keener, West Virginia Office o f E p i d e m i o l o g y and Health P r o m o t i o n , Charleston, W. Va., for their assistance in data collection and analysis.

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Reprint requests: J: E. Bouquot, DDS, MSD The Maxillofacial Center 165 Scott Avenue, Suite 101 Morgantown, WV 26505

CALL FOR REVIEW ARTICLES The January 1993 issue of Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics contained an Editorial by the Journal's Editor in Chief, Larry J. Peterson, that called for a Review Article to appear in each issue. These Review Articles should be designed to review the current status of matters that are important to the practitioner. These articles should contain current developments, changing trends, as well as reaffirmation of current techniques and policies. Please consider submitting your article to appear as a Review Article. Information for authors appears in each issue of Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology,

and Endodontics. We look forward to hearing from you.