Oral verrucous carcinoma

J. Cranio-Max.-Fac. Surg. 17 (1989) j. Cranio-Max.-Fac. Surg. 17 (1989) 309-314 © Georg Thieme Verlag Stuttgart • New York

Oral Verrucous Carcinoma An Analysis of 37 Cases Venkatesh V. Kamath x, Ravi R. Varrna2, Dilip R. Gadewar 1, Mupparapu Muralidhar 3 1 Dept. of Oral Pathology (Head: Dr. D. R. Gadewar, M. D. S.) 2 Dept. of Community Dentistry (Head: Prof. R. R. Varma, B. sc. (Hon.), M.D.S.) 3 Dept. of Oral Diagnosis and Radiology (Head: Prof. M. R. Vijay Raghavan, M. D. S.) College of Dental Surgery, Manipal, India

Submitted 11.6.88; accepted 8.11.88

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Summary 37 cases of oral verrucous carcinoma, occurring over a period of six years from 1981-1986, were analysed in respect of the clinical, radiological and histological findings. A delineation of the clinical presentation of this tumour, and the relation of habits to the occurrence of the lesion, has been clarified. The connotation of the term verrucous hyperplasia and its differences from verrucous carcinoma, have been discussed. Surgery and radiotherapy both seem to give good results as methods of treatment, especially when coupled with adequate nutrition and cessation of harmful habits.

Key words Verrucous carcinoma -- V e r r u c o u s Treatment methods

hyperplasia -

Introduction The term verrucous carcinoma was coined by Ackerman in 1948 to describe a morphological variant of squamous cell carcinoma with distinctive clinical and pathological features. Since then there have been many reports of the lesion in the literature, and it is estimated that over 400 cases of verrucous carcinoma have been reported up to 1982 (Tornes et al., 1985). Clinically, the tumour manifests itself as a warty, fungating, ulcerated growth, either papillomatous or verrucous in appearance and is a slow growing lesion that seldom metastasizes. Apart from the oral cavity, its appearance in other sites such as the larynx (Rock and Fisher, 1960; Nostrand and Olofsson, 1972; Ferlito and Recher, 1980), oesophagus (Minielly et al., 1967), nasal cavity (Duckworth, 1961), skin (Brownstein and Shapiro, 1976) and genitalia (Kraus and Perez-Mesa, 1966) have also been reported. Histologically, verrucous carcinoma manifests itself as a hyperplastic lesion with hyperortho- and/or parakeratosis. This papillary exophytic lesion may show blunt intrusion of well polarised epithelial ridges. Keratin plugs may be present in the centre of the epithelial invaginations, but are not obligatory. Nuclear anaplasia is minimal but mitotic figures can be seen, often just above the juxtabasal area. Verrucous carcinoma is closely related to the habits of tobacco chewing and especially snuff-dipping. Though uncommon in the Scandinavian countries (Tornes et al., 1985), the habits of tobacco chewing and smoking being more common in Southern India, it was decided to analyse the patients with verrucous carcinomas in respect of the association of habits, age, sex and other clinical and histological parameters. As some authors have reported a variety of mucosal lesions co-existing with verrucous carcinoma (Kraus and Perez-Mesa, 1966), we also decided to observe and record the findings.

and histological examination according to the criteria mentioned above. Detailed histories were recorded and the association of habits, age, sex, site, presence of other mucosal lesions and the most common presenting complaints, were noted. The incidence of verrucous carcinomas in the patients attending the dental out-patient department, and the ratio of squamous cell carcinoma to verrucous carcinoma were also compared. Biopsies from all the patients were fixed in 10 % phosphate-buffered formalin. After routine processing procedures, 5-micron-thick paraffin sections were cut, stained with haematoxylin and eosin and examined.

Results The sex, age of the patients and the site and size of the tumour and evidence of bony destruction are shown in Table 1. Most of the patients were over 40 years of age and the average age of the group was 58.45 years. Amongst the 37 cases, 30 were male patients and the rest were female, giving a male-female ratio of 4.29:1.

Materials and Methods 37 cases of oral verrucous carcinoma obtained from our files, over a period from 1981-1986, were studied. The diagnosis of verrucous carcinoma was verified by clinical

Fig.1 Intraoral photograph of patient with verrucous carcinoma of the right buccal mucosa extending to the angle of the mouth showing the typical cauliflower-like growth.

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V. V. Kamath et al. fable2 a sis

Clinical presentation of the lesion at the time of diagno-

Clinical appearance

No. of cases

1. Warty, fungating mass, ulcerated and with a p s e u d o m e m b r a n o u s slough 2. Exophytic, papillomatous, sessile non-ulcerated growth 3. White, keratotic patch with or without erythematous base

67.57 % (25/37)

fable 2 b nosis

Table 1 Age, sex, location of lesion, size of tumour and bone destruction in patients with oral verrucous carcinoma Patient No.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37

Age

56 65 50 63 50 50 60 68 70 66 55 57 78 40 40 50 46 60 51 61 55 71 58 50 80 57 61 70 50 65 60 50 55 67 43 70 65

Sex

F M F M M M M M F M M M M M M M M M M M M M M M M F F F F M M F F M M M F

Location of tumour

Buccal vestibule Ant. ~ r d tongue Buccal m u c o s a Palate Buccal m u c o s a Mandibular alveolus Buccal m u c o s a Buccal m u c o s a Buccal m u c o s a Buccal m u c o s a Buccal vestibule Buccal m u c o s a Buccal m u c o s a Retromolar area Angle of mouth Buccal m u c o s a Ant. ~ r d of tongue Retromolar Buccal m u c o s a Buccal m u c o s a Buccal m u c o s a Retromolar Buccal m u c o s a Buccal m u c o s a Buccal m u c o s a Buccal m u c o s a Palate Retromolar area Buccal m u c o s a Buccal m u c o s a Buccal m u c o s a Buccal m u c o s a Angle of mouth Buccal m u c o s a Maxillary alveolus Lip Buccal m u c o s a

Size of tumour (cms)

Bone destruction

7x4 4x2 4x2 5x4 5x3 2x2 5x5 3x3 5x2 6x4 5x3 3x3 4x2 4x2 4x 1 5x2 3xl 3x2 3x2 2x 1 3x4 2x4 3x3 2x2 3x2 4x2 3x2 2x2 2x 1 3x2 3x 1 2x 1 2x 1 3x2 3x2 2x 1 3x2

+ + + + + + -

10.81% (4/37)

S y m p t o m s exhibited by the patient at the time of diag-

Symptoms*

Pig. 2 Radiograph (lateral oblique view) of a patient with verrucous carcinoma of the alveolar ridge showing superficial erosion of the bone.

21.62 % (8/37)

1. Pal n 2. Burning sensation 3. Xerostomia 4. Excessive salivation 5. Bleeding 6. Foul smell 7. Trismus

No. of cases 19/37 5/37 1/37 8/37 6/37 13/37 9/37

* It is to be noted that a patient had more than one symptom

The buccal mucosa (cheek) was the most common site of occurrence of the tumour (22/37), followed by the retromolar region (4/37), palate, buccal vestibule, anterior twothirds of the tongue and the angle of the mouth (2 cases each), with solitary cases occurring on the lip, mandibular and maxillary alveolus. Although many of the larger lesions extended to adjacent anatomical sites, the most probable site of origin was determined (Fig. 1). Bone destruction, in most cases occurring as superficial erosion, was evident in five of the cases, but in none of the cases was it so severe as to cause a pathological fracture (Fig. 2). Table 2 gives an idea of the three main forms of clinical presentation of the turnout as well as the symptoms elicited from the patient. The duration of the tumour at the time of diagnosis, oral habits, the oral hygiene status, details of associated lesions and the state of the dentition are categorised in Table 3. Chewing of tobacco and slaked lime wrapped in a betel leaf, or tobacco chewing with or without betel nut was the most common habit practised, following by "beedi" smoking ( a local preparation of tobacco wrapped in a dry "temburi" leaf, (Diospyros malanoxylon), cigarettes and consumption of alcohol. Alcohol consumption in most patients was mostly in the form of "arrack", a local brew concocted from the fermentation of rice and jaggery. The oral hygiene status of the patients was classified as good, fair or poor according to the Simplified Oral Hygiene Index (Greene and Vermillion, 1964). Histologically, all the cases showed hyperplasia of the epithelium in a papillomatous form. The epithelium was mostly hyperparakeratinised, but cases of hyperorthokeratinisation, as well as both combined, were also evident (Fig. 3). The epithelium extended in an intruding fashion deep into the connective tissue with broad bulbous rete pegs. Crypts lined with parakeratin were a variable finding

Oral Verrucous Carcinoma

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Fig.4

Fig.3 Photomicrograph of a case of oral verrucous carcinoma showing papillary outgrowth of epithelium with cleft lined by parakeratin (HE x 200).

Photomicrograph of verrucous carcinoma showing hyperplastic epithelium with orthokeratinisation. Note the intraepithelial infolding at the top half of the epithelium filled with parakeratotic cells and keratin (HE x 100).

(Fig. 4). Inflammatory cell infiltration, chiefly consisting of lymphocytes, plasma cells and a few mononuclear cells was found in varying degrees in all the cases. The epithelium in most cases was well differentiated with minimal nuclear anaplasia (Fig. 5). Some cases showed intraepithelial keratinisation and also pearl formation, a moderately increased amount of mitotic activity, and cellular and nuclear pleomorphism (Fig. 6). Basilar hyperplasia was also seen in a few cases (Fig. 7). All the patients were treated either by surgery or radiation therapy. Of the 37 patients, 20 had their lesions surgically excised, 7 were treated with radiation, 6 were treated with a combined approach of surgery and radiotherapy, while 4 patients discontinued treatment at an early stage and did not report back. Of the 20 patients treated surgically, no recurrences were noted to the date of publication while of the 7 treated by radiation, 3 cases recurred. A case treated by surgical intervention in our hospital (No. 35), had been treated previously for the same tumour at a different hospital, recurrence occurring after a period of approximately five years. Table 4 lists the number of cases of recurrence and their relevant details. One case (No. 22), had previously been treated by cryosurgery for leukoplakia, subsequently developing verrucous carcinoma at the same site.

Table3

Discussion Verrucous carcinoma is considered to be a mild variant of squamous cell carcinoma, in terms of morphology and histopathology. In our series, most of the patients were in the fifth decade and later, which is in keeping with other reports (Shafer, 1972; Slootweg and Miiller, 1983; Tornes et al., 1985). Predominance of the male gender to be affected by this tumour is also well-documented (Jacobson and Shear, 1972). Sundstrom et al., 1982; Slootweg and Miiller, 1983), though some reports state otherwise (McCoy and WaIdron, 1981; Arendorfand Aldred 1982; Tomes et al., 1985). There is general agreement about the buccal mucosa (cheek) being the most common site (BohmfaIk and Zallen, 1982) and though most reports state that the alveolar mucosa is the next most common site (Tomes et al., 1985), we

Habits, oral hygiene status, associated lesions, time lapse to time of diagnosis and state of dentition of the patient

Habits Smoking Chewing tobacco Alcohol consumption Abstainers

No. of cases (37) 11 11 24 4

Oral Hygiene Status** Good Fair Poor

(out of 35, two patients were edentulous) 4 31

Associated Lesions Hyperkeratosis - Mild dysplasia Moderate dysplasia Severe dysplasia Angular cheilitis Squamous cell carcinoma Time lapse to time of diagnosis 0- 6 months 7-12 months 13-24 months 25 months and above State of dentition Fully dentate Partially dentate edentulous a) Denture wearers b) Non denture wearers

4 1 1 2 1 15 7 7 8 26 9 2

0 2

**(Greene and Vermillion Index, 1967)

Table4 Period and mode of treatment of recurrent cases of oral verrucous carcinoma Case No.

Age

Time interval before recurrence

Previous mode of treatment

4 6 16 35

63/M 50/M 50/M 43/M

3 years 8 months 2 years 5 years

Radiation Radiation Radiation Surgery

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Fig.5 Photomicrograph of hyperplastic epithelium in verrucous carcinoma showing dysplastic features such as loss of stratification and intraepithelial keratin formation (HE x 300).

Fig,7 Photomicrograph of verrucous carcinoma showing dense inflammatory infiltrate chiefly consisting of lymphocytes, plasma cells in the subepithelial zone of connective tissue. Infiltration of chronic inflammatory cells in the suprabasal layers is also seen (HE x 200).

found the retromolar region to be more afflicted, followed by the palate, angle of the mouth, anterior two-thirds of the tongue, buccal vestibule, lip and the alveolar processes. Clinical appearance of the lesion as an exophytic growth that has a papillomatous or a verrucous base and as a warty, fungating mass, partly ulcerated, is in keeping with the general description of the lesion in various reports (Ackerman, 1948; Fonts et al., 1969; Bohmfalk and Zallen, 1982). The appearance of the carcinoma as a thickened leukoplakic patch is to the best of our knowledge not reported in the literature. It is our opinion that this appearance signifies the fact that verrucous carcinoma may also develop as a leukoplakia before progressing to the more common exophytic growth. This presumption was supported by the observation that these cases showed the mildest dysplastic features of the lot. A case of verrucous carcinoma lasting for nearly eight years depicts the slow growth and the indolent nature of the lesion. However, there was one case diagnosed within thirty days of occurrence. The delay in detection may be

V.V. Kamath et al.

Fig.6 Photomicrograph of verrucous carcinoma showing hyperplastic epithelium with loss of stratification, intraepithelial abscess filled with keratin flakes and micro-organisms (HE x 200).

due to the fact that these lesions do not cause any discomfort to the patient, apart from their mass. Invasion of bone and soft tissues is one of the characteristic features of malignant lesions. Though most cases of verrucous carcinoma occur in the soft tissues, bone destruction by invasion or pressure is reported in the literature (Fonts et al., 1969). There were five cases in our series, causing superficial erosion and destruction of the bone. Though cases do occur of oral verrucous carcinoma causing bone destruction resulting in osteomyelitis and pathological fracture (Fonts et al., 1969; Tomes et al., 1985), these are more the exception than the rule, this is in keeping with the mild destructive potential of the lesion. Tobacco usage and snuff-dipping are thought to be the main predisposing factors for oral verrucous carcinoma (Cooke, 1969; Claydon and Jordan, 1978; Sundstrorn et al., 1982; Tomes et al., 1985). Contradictory reports regarding the association of habits with oral verrucous carcinoma being a predisposing factor or a coincidental finding, exist. Landy and White (1961) reported oral verrucous carcinoma in twenty-five females all of whom were confirmed snuff-dippers. Winn et al. (1981) also found a strong relationship between the chronic use of snuff and the increased incidence of the tumour, though Tomes et al. (1985) and Duckworth (1961), also found a strong relationship between the chronic use of snuff and the increased incidence of the tumour consider it only to be a coincidental finding. We found a 90.28 % (33/37) to have one form of the habit or another, tobacco chewing being the most common followed by smoking of tobacco and alcohol consumption. No patient gave a history of snuff dipping as this habit is not in vogue in this part of the country. Though we are of the opinion that association of habits may play a very strong role either in the causation or predisposition to the lesion, it is very difficult to pinpoint exactly the causative factor as many patients have more than one habit, and the frequency and duration of habits varies from patient to patient. The concurrent existence of poor oral hygiene in almost all the patients is also a significant finding. Oral sepsis as a predisposing or a modifying factor in cases of squamous cell carcinoma of the oral cavity is well known. In our series, except for four cases, all had poor oral hygiene.

Oral Verrucous Carcinoma Whether this was a preexisting feature or an end-result of the habits, could not be ascertained, nevertheless the significance is stressed. Most of the patients reported to the clinics with the specific complaint of a swelling or a growth. Some were asymptomatic but on questioning such specific symptoms as pain (halitosis, trismus, bleeding on probing of the lesion, excessive salivation etc.) were present in varying degrees of intensity. One case exhibited xerostomia (No. 18) as he had been previously treated for verrucous carcinoma with radiation. The occurrence of the symptoms could be attributed either to the lesion per se (trismus, excessive salivation) or to the presence of secondary infection (pain, burning sensation, foul smell, bleeding etc.). The presence of ill-fitting dentures was a feature of the series of cases reported by Tomes et al. (1985). None of our patients wore dentures. Verrucous carcinoma is very often associated with other lesions. Goethals et al. (1963) reported the occurrence of more than one verrucous carcinoma in 30.9 % of their patients; in 23.6 % there was also a squamous cell carcinoma, either co-existing or associated. Kraus and Perez-Mesa (1966) found an occurrence of squamous cell carcinoma in 8 % and separately occurring, other verrucous carcinomas in 3 ~ of their series. Fonts et al. (1969) reported that in almost all of their patients, there were loci of atypical squamous epithelium in parts of the mucosa not involved by the neoplasm. Finally, Shear and Pindborg (1980) reported 66 % associated epithelial dysplasias and 10 % associated squamous cell carcinomas. This tendency to development of multiple mucosal lesions was also evident in our series. Out of thirty-seven cases, one case had a concomitant squamous cell carcinoma (No. 14), six cases had leukoplakia clinically and two had angular cheilitis. The six cases clinically seen as white patches (leukoplakia) were found histologically to exhibit hyperkeratosis with mild dysplasia (4 cases), moderate dysplasia (1 case) and severe dysplasia (1 case). The occurrence of multiple mucosal lesion in 24.5 ~ (9/37) of our cases, is slightly less than the figures of Slootweg and Miiller ( 1 9 8 3 ) - 48 %. This only substantiates the need to carry out a thorough follow-up ot the patients with the lesion, as other malignancies develop in a high percentage of cases. In this regard, we are in total agreement with the opinion of Slootweg and Miiller (1983) that "the presence of verrucous carcinoma has to be interpreted as an expression of an ubiquitious premalignant change in the whole oral epithelium". Histologically, diagnosing verrucous carcinoma, requires a considerable amount of experience on the part of the oral pathologist. The mild nature of the lesion, the lack of appreciable mitotic activity and absence of a breach in the basement membrane, make differentiation between a hyperplasia and carcinoma very difficult. Shear and Pindborg (1980) reported sixty-eight cases of verrucous hyperplasia that were clinically indistinguishable from verrucous carcinoma. It was stated by the authors that the essential part of the differentiation between the two lesions, was the location of the thickened epithelium. In verrucous hyperptasia, most of the hyperplastic broadened retepegs lie above the normal adjacent epithelium. Verrucous carcinoma on the contrary, exhibits a downward growth pattern of otherwise similar fete pegs. In an excellent review of 27 cases of verrucous carcinoma and hyperplasia, Slootweg

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and Miiller (1983), categorically stated that it is very difficult to draw a sharp demarcation between the two. In fact, many cases of verrucous hyperplasia exhibited features of verrucous carcinoma, a feature also pointed out by Shear and Pindborg (1980). The only point of differentiation, according to Slootweg and Miiller (1983) was the site of the lesion; verrucous carcinoma occurred with greater regularity in the mucoperiosteal regions, while verrucous hyperplasias occurred more on the soft tissue areas. The authors therefore conclude that verrucous hyperplasia may be the first stage in the progression to verrucous carcinoma. In our present series we were unable to find this distinction. Almost all the cases showed an ingrowth of epithelial rete ridges into the underlying connective tissue stroma. We also believe that a diagnosis of verrucous carcinoma is more justifiable than that of verrucous hyperplasia, in view of the slow indolent growth of the tumonr. A report of hyperplasia may lull the clinician into taking an easy and non agressive attitude to the lesion, which may prove harmful in the long run. The thirty-seven cases of oral verrucous carcinoma, occurred in a total of 170,031 patients from 1981-86, giving an incidence figure of 0.021%, which is definitely indicative of the not-so-rare occurrence of the lesion. Though this figure cannot be interpreted to be representative of the country or the region, yet it is significant that in a region where 7 5 - 8 0 % of the populace indulges in deleterious oral habits, the occurrence of tumours like verrucous carcinoma is cause for concern. The ratio of verrucous carcinoma to squamous cell carcinoma in the same time interval was about 12.25 Y0 (37/380). This conforms closely to the reports of McCoy and Waldron (1981), who reported this incidence to be 9 %. The incidence was reported to be 4.5 % by Goethals et al. (1963), 20 ~ by Fonts et al. (1969), and 2.2 % by Jacobson and Shear (1972). These differences can be explained on the basis of regional variations and also the distribution of patients to medical and dental departments varies considerably in many countries. Various treatment modalities have been attempted, chief amongst them being surgery, radiotherapy and chemotherapy. Most authors agree that verrucous carcinoma is best treated by radical excision of the diseased mucosa (Kraus and Perez-Mesa, 1966; Jacobson and Shear, 1972; McCoy and Waldron 1981). Treatment with radiotherapy is considered very controversial and cases of recurrence have been reported (Kraus and Perez-Mesa, 1966; Fonts et al., 1969). Amongst our series, there were four cases of recurrence, and of these, three had been previously treated by radiotherapy and one was surgically excised. Recent reports, however, indicate a reverse trend. In an excellent analysis of 52 cases of oral verrucous carcinoma treated by radiotherapy, Nair et al. (1988) reported that the 3 year survival rate compared favourably with that of well-differentiated squamous cell carcinoma treated during the same period (44 % versus 36 %). They further state that the results with radium implant treatment (86 ~, 3 year survival rate) were better when compared with external radiation. The above results compare favourably with those reported in the literature regarding anaplastic transformation of verrucous carcinoma after irradiation, 30 % (Kraus and Perez-Mesa, 1966; Perez et al., 1966; Fonts et al., 1969). The mean interval from the date of radiotherapy to anaplastic transformation appears to be 6 months. It is in-

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teresting to note that the results of recurrence after radiotherapy are similar to those of post-surgical reports, which range from 3 0 % to 5 0 % (Demian et al., 1973; Elliot et al., 1973; Schwade et al., 1976). Various reasons have been postulated regarding the anaplastic transformation of oral verrucous carcinoma. One view suggests that the anaplastic t r a n s f o r m a t i o n is a result o f the initiation o f a highly aggressive new neoplasm due to disregulation of the cell lines of a slow-growing turnout resulting from radiation injury (Profitt et al., 1970). It is also suggested that occult undifferentiated areas in verrucous carcinoma may be present which start to proliferation at a later date under the action of an inciting factor, most possibly the radiation therapy (Demian et al., 1973; Schwade et al., 1976). Cytostatics have given g o o d results (Dame et al., 1974). A case o f verrucous carcinoma, t o o extensive for surgery, was treated with Bleomycin and showed good regression (Kapstead and Bang, 1976). But this same patient, subsequently included in the series of Tornes et al. (1985), suffered a recurrence five years later. It does appear from the above reports that both surgery and radiotherapy have a role to play in the treatment of oral verrucous carcinoma. Treatment plans for each case should be drafted based on the histological nature of the lesion, site, accessibility, lymph node enlargement etc. Supportive treatment in the form of adequate nutrition and cessation of adverse oral habits should be incorporated in the scheduled therapy.

References

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Dr. V. V. Kamath, M. D. S. Collegeof Dental Surgery Dept. of Oral Pathology Manipa1576119 India