The Maxillofacial Center for Diagnostics & Research

Abstract

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. In order to provide this evidence, two population-based incidence investigations were carried out in Rochester, Minnesota and the state of West Virginia (WV). Results: 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), while the incidence rate for all intraoral carcinomas was 3.6/100,000 (5.4 for males; 2.1 for females). Among males 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 WV residents was somewhat greater, 0.3/100,000 population, and demonstrated an even gender predilection (0.28/100,000 males; 0.29/100,000 females). The incidence rate for all oral/pharyngeal cancers in WV was 8.8 (13.4/100,000 males; 5.7/100,000 females), which was below the U.S. average. Conclusions: Oral verrucous carcinoma is a rare tumor of older individuals. It is diagnosed in only 1-3 of every 1,000,000 persons each year.

Introduction

A smokeless tobacco etiology for oral cancer was suggested by James Ewing,1 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 71-92% of all carcinomas 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 common 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 canal, vagina, penis, bladder, rectum, soles of feet, dentigerous cyst).6-11 It is, furthermore, now known that 16-51% 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 the majority of oral cases are found in persons who habitually chew 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 1-10% of all oral squamous cell carcinomas diagnosed by U.S. hospitals and dental schools.10 In India, approximately 7% of oral cancers are verrucous carcinomas.19

No population-based studies, however, have been reported and a significant facet of this disease is lacking, namely its epidemiologic characteristics. The epidemiologic characterization of verrucous carcinoma may be of timely importance to Western populations, where a significant increase in young users of smokeless tobacco has been reported.20-23 The purpose of the present investigation was, therefore, to determine incidence data for this disease. Because of the importance of microscopic confirmation of such an unusual neoplasm, a population-based investigation was undertaken in Rochester, Minnesota, where all oral and pharyngeal carcinomas could be reviewed histopathologically, where there is an excellent case ascertainment rate extending back to 1935, and were the demographics of the population are well defined. This has the additional characteristic of being 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, was 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 two populations have different advantages and disadvantages relative to epidemiologic investigation, but the author 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 one case per 1,000,000 persons each year. A secondary hypothesis was that the verrucous carcinoma experience in the two populations was considerably different, with the tobacco-chewing West Virginia population having a significantly higher incidence rate for this "snuff dipper's cancer."

Methods & Materials

Rochester, Minnesota data collection. The first community evaluated was Rochester, Minnesota. Rochester has a relatively small population (approximately 62,000 persons in 1990, but representing 2,003,228 person-years for the years 1935-1984). 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 that: 1) great care is taken to identify all cases of specific diseases, i.e. 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 and, in fact, growing up near Rochester, the present author was not even aware of the fact that tobacco could be chewed until he learned of the habit in dental school. A review of more than 4,800 medical records from this population identified only 18 tobacco chewers, all males. Recent surveys have indicated that only 2% of the Minnesota population chews tobacco, almost always males.34

Minimal referral bias is possible in Rochester studies because medical practice in the population has centered at the Mayo Clinic since the early part of the twentieth 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 two large regional tertiary care facilities in Minneapolis, Minnesota, 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 include in this database, including those residents who had moved away from Rochester by the time of their death.

All medical, surgical, histopathologic, and autopsy records of Rochester residents 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, Minnesota (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", "lesion", etcetera, were also reviewed. In total, the complete medical records of more than 4,800 residents were reviewed, including all microscopic material from head and neck lesions (benign or malignant), in order to assure that no cases of verrucous carcinoma were missed or misdiagnosed.

The anatomic areas investigated, with 9th Revision ICD codes,35 included: lip vermilion (ICD=140.1-2); oral cavity (ICD=140.3-5, 141, 143-145); major salivary glands (ICD=142); oropharynx (ICD=146); nasopharynx (ICD=147); hypopharynx (ICD=148); unspecified pharynx (ICD=149); nasal and paranasal sinuses (ICD=160, excepting 160.1); and larynx (ICD=161). For present purposes 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 at least one year prior to 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 re-examined by a single pathologist (JEB) 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 Tortoledo9 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. For 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 two known deaths of cancer incidence cases; neither of the latter was a verrucous carcinoma.

For calculation of carcinoma incidence, the entire population of Rochester was considered at risk and the denominator in age- and sex-specific incidence rate calculations was estimated from decennial census data. Age- and gender-adjustment of incidence rates was to the 1970 U.S. white population in order 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 therefore are actually incidence density measures.36 Incidence rates were calculated as the number of newly diagnosed cases per 100,000 person-years.

West Virginia data collection. The estimated population of West Virginia was 1,825,256 in 1995 and there were 5,545,598 person-years at risk for the observation years 1993-95.37 The state has long held the distinction of having the highest prevalence of smokeless tobacco use in the U.S.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 Cancer diagnoses are required by law to be sent to the registry, but under-reporting 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 eight free-standing pathology laboratories and two 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, and 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 in 1993-1995 with cancer listed as an underlying cause of death were matched against the WVCR data. Those cases which 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 mucosa (ICD 140, 141, 143-149). Major salivary glands (ICD 142) are excluded from the definition.

Results

Rochester, Minnesota. From January 1, 1935 through December 31, 1984, 339 cases of carcinoma of the upper aerodigestive tract were diagnosed among the residents of Rochester, Minnesota. Of these, 297 arose from oral (including lip vermilion), pharyngeal and laryngeal sites. All but one of the 297 malignancies were clinically and histopathologically classified during life; no case was identified via death certificates which had not been previously noted in antemortem medical records. The single case not classified prior to death was a nasopharyngeal carcinoma presenting as an occult cervical metastasis.

Only two verrucous carcinomas were diagnosed at upper aerodigestive tract sites during the 2,003,228 person-years of observation. Both lesions arose from the buccal mucosa of elderly males (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 teenage years.

These two 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 1). 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 males and 0.0/100,000 females). This compared to 3.6/100,000 for all primary invasive intraoral carcinomas (Table 2). When only older males were assayed, a considerable increase in incidence was noted, with the age-specific incidence rate for verrucous carcinoma for males older than 64 years of age rising to 3.2/100,000 person-years. Total intraoral carcinoma incidence in this male cohort also increased, from 1.8 for 35-44 year olds to 29.7 for men older than 64 years of age. For males older than 64 years of age 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 persons, 13.4/100,000 males and 5.1/100,000 females. This was somewhat less than the Rochester rate of 10.1 and the 1990-1994 average U.S. 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 a small proportion 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 1993-1995, all from the vestibular mucosa except for two 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 of age (64.7% were older than 64 years; 41.2% were older than 74 years). Additionally, seven 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 population (0.28/100,000 males; 0.29/100,000 females) for this "snuff dipper's cancer." For persons older than 64 years of age, the incidence rate increased to 1.3/100,000 (Table 3). For all practical purposes, these are rates for intra-oral disease, as no cases were identified from the lip vermilion or pharyngeal mucosa.

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 1-3 of every million persons. Assuming the present incidence rates to be reasonably representative, we would expect 250-750 cases of this cancer to be diagnosed each year among the entire U.S. population. This would explain why so few cases are accessioned in U.S. oral pathology biopsy services. Eisenberg et al15 could find, for example, only 17 verrucous carcinomas among 20,274 consecutive biopsies submitted to the University of Connecticut. The present author could find only 16 cases among 38,953 biopsy samples submitted to the two 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, more than 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 in order to capture misdiagnosed cases in the population.

While the total number of identified verrucous carcinoma lesions in the Rochester population is small, the author believes 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 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.41-43 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 state-wide incidence data. It may be that the three-fold increase in verrucous carcinoma incidence in the West Virginia population, when compared to the Rochester population, is due to the greater use of smokeless tobacco in the state population. This is the author's opinion. Moreover, the author believes that the considerably greater incidence in West Virginia females, when compared to Rochester females, is likely the result of the long-term use of smokeless tobacco by the older women of West Virginia.

The author's beliefs nonwithstanding, the data does 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 under-reporting 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 which 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 which arise from the mucosa of 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. The author encourages additional studies in light of the increasing popularity of these products, the recent suggestion to use smokeless tobacco as 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 most unique form of oral cancer.

CONCLUSIONS

This investigation's primary hypothesis that verrucous carcinoma is a rare tumor is proven correct by the data. Verrucous carcinoma of the oral mucosa was found annually in one to three of every million persons in two populations. This makes verrucous carcinoma among the most rare of all oral cancers. Although rare, the great majority of cases were found in persons older 64 years of age. For males over 64 years of age this cancer was found in one of every 31,000 persons. Verrucous carcinoma represented 3% of oral carcinomas in two population-based analyses, one of which allowed microscopic confirmation of all diagnoses and one for which microscopic confirmation was not available.

The secondary hypothesis that the verrucous carcinoma experience in these two populations with different tobacco chewing experiences would be significantly different cannot be rejected or proven by the data because of incompatible study designs.

_____________________________________

The author wishes to thank Dr. Leonard Kurland, former Director, Section of Clinical Epidemiology and Biostatistics, Department of Health Science Research, Mayo Clinic, Rochester, Minnesota, Dr. Louis Weiland, former Chairman, Department of Surgical Pathology, Mayo Clinic West, Scottsdale, Arizona, and Dr. Catherine Slemp and Ms. Beverly Keener, WV Office of Epidemiology and Health Promotion, Charleston, West Virginia, for their assistance in data collection and analysis.

References

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Table 1: Histopathologic types of upper aerodigestive tract (UAT) carcinomas diagnosed in Rochester, Minnesota residents, 1935-1984, ranked by frequency of intraoral lesions. Lesions of the major salivary glands and nasal/paranasal sinuses are excluded.

        * no primary cases were found of malignant melanoma, spindle cell carcinoma, basaloid squamous carcinoma, or                         adenosquamous carcinoma

Table 2: Average annual incidence rates for primary invasive carcinomas of the upper aerodigestive tract in the Rochester, Minnesota population, 1935-1984, age-adjusted to the 1970 U.S. white population. Totals in right-hand column are also gender adjusted to 1970 U.S. white population.

 * population base: 900,312 person-years for males, 1,102,916 person-years for females
** numbers in parentheses represent actual number of cases, not incidence rates; carcinomas in situ and metastases
    to the upper aerodigestive tract are excluded from the above data

Table 3: Age-specific annual incidence rates for verrucous carcinoma in the West Virginia population, 1993-1995, representing 5,465,598 person-years at risk. Numbers of cases were too small for meaningful rates according to gender.

             * age-adjusted to the 1970 U.S. white population