Occurrence of epithelial dysplasia in oral leukoplakia Analysis
and
follow-up
Jo&in Bhdczy, M.D., Budapest, Hungary
C.Sc.,”
SEMMELWEIS
UNIVERSITY
MEDICAL
study
of
md iirpcid
SCHOOL
12 cases
Csiba, M.D.,“”
OF
DENTISTRY
The histologic material of 500 leukoplakia patients was analyzed in order to define the characteristics of epithelial dysplasia and to correlate the findings with the clinical data. Epithelial dysplasia was found in 120 cases (24 per cent) and was graded as mild, moderate, or severe. The occurrence of dysplasia was highest in the group of erosive leukoplakias. The majority of the severe dysplasias were found on the tongue and lips. Follow-up studies on sixty-eight leukoplakia patients with histologic dysplasia revealed carcinoma in nine cases (13.2 per cent) during the mean observation period of 6.3 years. Leukoplakias of the tongue showed the highest incidence of malignant change.
T
he precancerous character of oral leukoplakia today is generally accepted. According to various authors,’ the ratio of malignant transformation varies between 1 and 6 per cent. Recent studies have attempted to define the precancerous leukoplakias in a narrower sense by clinical and histologic methods.‘, *, 5 Leukoplakias showing histologically epithelial dysplasia are considered to have a greater disposition for malignant transformation. However, reports on the occurrence of epithelial dysplasia and longitudinal studies on the behavior of these lesions are few.“, 6, lo There is also no unanimity regarding the therapy of leukoplakias showing epithelial dysplasia. The purpose of the present study is to define the occurrence of epithelial dysplasia in a large group of oral leukoplakia patients and to report on our experiences with the follow-up observations of these patients. *Professor **Assistant and Dentistry.
766
and Chairman, Department of Conservative Professor, Division of Oral Pathology,
Dentistry. Department
of Maxillo-Facial
Surgery
Epithelial
Volume Number
-12
Table
I. Distribution
6
dysplasia
in oral leukopla.kia
767
of histologic characteristics of dysplasia in 120 cases
Histologic
Per cent o/specimens showing this change
change
Irregular epithelial stratification Hyperplasia of the basal layer D%p-shaped rete pegs Increased number of mitotic figures Loss of polarity of the basal cells Increased nuclear-cytoplasmic ratio Nuclear polymorphism Nuclear hyperchromatism Enlarged nucleoli Keratinization of single cells or cell groups Loss of intercellular adherence
in the prickle
75.0 43.3 68.3 2.5 23.3 13.3 IS.0 IO.0 12.5 35.8 18.3
layer
II. Correlation of the grade of dysplasia with the age and sex distribution of patients Table
Men Age 20 to 29 30 to 39 40 to 49 50 to 59 60 to 69 Over 70 Total
MATERIAL
Moderate
Mild
Women Severe
Total
Mild T 2: 3
1
I
II,
: 21 19 8 63
z
16
; 2 I9
:; I2 104
r 5 i 2 22
AND
Moderate
Total
Severe
Total
T T :2
2
Cases 2
r :3 :3 9
4
3: 4 7 16
t; 39 36 I2 I20
Per cent 1.7 10.0 15.8 32.5 30.0 10.0 100.0
METHODS
The clinical and histologic material of the present study originated from leukoplakia patients treated and followed up regularly at the Department of Maxillo-Facial Surgery and Conservative Dentistry. The term leukoplakia was employed in a clinical sense,meaning a white patch on the mucous membrane that cannot be removed by rubbing and cannot be classified as any other diagnosable disease. Hematoxylin-eosin-stained histologic sections of 500 casesdiagnosed clinically as leukoplakia were investigated. The sections were grouped according to whether they showed simple hyperkeratosis, epithelial dysplasia, or carcinoma (including invasive carcinomas and carcinoma in situ). Epithelial dysplasia was diagnosed when two or more of the following changes were present : irregular epithelial stratification, hyperplasia of the basal layer ; drop-shaped rete pegs; increased number of mitotic figures (a few abnormal mitoses may be present) ; increased nuclear-cytoplasmic ratio ; lossof polarity of the basal cells; nuclear polymorphism ; nuclear hyperchromatism ; enlarged nucleoli; keratinization of single cells or cell groups in the prickle-cell layer; and loss of intercellular adherence. Epithelial dysplasia was graded as mild when two of the above-listed histologic changes were present, moderate when two to four changes were noted, and severe when five or more of the changes were present.
768
Bdndczy
and Csiba
Oral December,
Surg. 1976
III. Correlation of the grade of dysplasia with the clinical type of leukoplakia Table
Grade Type of leukoplakia Leukoplakia Leukoplakia Leukoplakia Total
simplex verrucosa erosiva
Mild 1: 8 25
of dysplasia
Total
1 Moderate
Severe
:i 34 72
i 14 23
1
Cases
Per cent
z: 56 120
18.4 35.0 46.6 100.0
The clinical classification of leukoplakia was done according to previous reports,Q differentiating leukoplakia simplex, leukoplakia verrucosa, and leukoplakia erosiva types. The methods of treatment employed have been published previously.Q In the first part of our study, the occurrence and grade of epithelial dysplasia, as well as the frequency of the histologic characteristics, were analyzed. In the second part the correlation of epithelial dysplasia with age and sex of the leukoplakia patients and with the clinical type and location of leukoplakia was investigated and the subsequent clinical course of dysplasia caseswas analyzed. RESULTS
Analysis of 500 histologic sections, diagnosed clinically as leukoplakia, showed carcinoma in forty-eight cases (9.6 per cent), epithelial dysplasia in 120 cases (24 per cent), and keratosis without dysplasia in 332 cases (66.4 per cent). The grade of severity of the epithelial dysplasia caseswas classified as mild in twenty-five cases (20.6 per cent), moderate in seventy-two cases (60.0 per cent), and severe in twenty-three cases (19.5 per cent). The distribution of the histologic characteristics of dysplasia is shown in Table I. The most frequent changes were the irregular epithelial stratification, drop-shaped rete pegs, and hyperplasia of the basal layer. The distribution of the leukoplakia patients by age and sex and the correlation of these factors with the grade of epithelial dysplasia are shown in Table II. The 120 dysplasia patients include 104 men (86.7 per cent) and sixteen women (13.3 per cent). The frequency of dysplasia shows a rise after the age of 40. Most cases were observed in patients between the ages of 50 and 70 years (72.5 per cent). The distribution of the clinical types of leukoplakia in dysplasia casesand the correlation with the grade of the dysplasia are shown in Table III. The distribution of the clinical types shows a predominance of the erosive type (46.6 per cent), verrucous leukoplakia occurring in 35 per cent and simplex leukoplakias only in 18.4 per cent. Most severe and moderate dysplasias are observed in the erosive type, and the less severe atypias in the simplex type. Table IV shows the location of leukoplakia in correlation with the grade of dysplasia and in comparison with the percentage distribution of the total leukoplakia (all 500 cases) and carcinoma groups (48 cases) according to location. The occurrence of severe dysplasias on the tongue and on the lower lip was high.
Epithelial Table
Correlation
IV.
dysplnsia
of the grade of dysplasia
with
ix oral leukoplakia
the location of leukoplakia
1 Distribution
Commissures Buccal mucosa Lips Tongue Hard palate Soft palate Floor of mouth Alveolar ridge Total
Table
V.
11 i
30 13 16
2
9 2
1 25
Follow-up
: 1 2 23
12
results according
in percentage
Leukoplakia grow (500 cases)
39. I 20.8 20.0 14.1 1.7 0.9 1.7 1.7 100.0
6 I
2 -
of location
Dysplasia group (120 cases)
Total cases
769
Carcinoma group (48 cases]
36.5 26.3 6.5 x.5 8.5 1.3 5.8 6.6 100.0
to grade of dysplasia
9.1 9.7 16.1 38.8 6.4 3.2 9.1 6.4 100.0
and treatment
Treatment Surgical Grade of_ dysplasia . . Results
Mild 9 I 10
Cured Improved Unchanged Spread Carcinoma Total
Table
VI.
Moderate
Severe 4 -
23 6 29
&‘ollow-up
results
Conservative Grade of_ dvsplasia . . Mild -
T I 6
according
Moderate -
Severe -
Result Cured Improved Unchanged Spread Carcinoma Total
Table
VII.
Buccal mucosa
Lips
22 6 7
z
9 t
t 37
T 5
I
Per cent 53.0 14.7 14.7 4.4 13.2 100.0
T
:
z
T 3
: 14
4 6
; 69
to location Total
I1
Hard palate
Tongue
T 12
Cases 36 10 IO
Location Commissure
Total
I
3
2
T
1
.: 9
IT2
Soft palate
Floor of mouth
Aiveolar ridge
1
1
r
I
r -
I
36 10 10
I 1
I
Cases
i 68
Per cent 53.0 14.7 14.7 4.4 13.2 100.0
Follow-up results in correlation with the observation period Observation
Result Cured Improved Unchanged Spread Carcinoma Total
It02
1
2
to5
period 1
(years)
5tolO
Total
81
14 :
12.i
: 2
Cases 36 10 IO
9
< 24
: 25
: 10
G 68
-
1
lOto
[
Per cent 53.0 14.7 14.7 4.4 13.2 100.0
770
B6ndczy
Fig. 1. T. L., the tongue.
and Csiba
50.year-old
Oral I)ecember,
woman.
Verrucous-erosive
leukoplakia
ou the inferior
surface
Surg. 1976
of
Follow-up investigations could be performed on sixty-eight leukoplakia patients with dysplasia. The observation period varied from 1 to 20 years, with a mean observation period of 6.3 years. The follow-up results, according to the grade of dysplasia, are shown in Table V, with cases separated into surgically and conservatively treated groups. (Conservative treatment consisted of the elimination of possible etiologic factors, accompanied by vitamin A and/or antimycotic treatment.) Best results were achieved in the surgically treated cases, where in the majority of the moderate and severe dysplasias no recurrence was observed. Of the nine carcinoma cases (13.2 per cent) developed from dysplasia% eight cases originated in the nonsurgically treated group (Figs. 1 and 6). The clinical outcome of dysplasia cases according to location is shown in Table VI. Of the nine carcinoma cases, four were observed on the tongue. The highest ratio of cured and improved cases could be found in dysplasias located in the commissures. An analysis of the subsequent clinical course of dysplasia cases in correlation with the observation period (Table VII) shows a higher ratio of cured and improved cases after a short observation period. The number of unchanged, spread, and carcinoma cases rises with the observation time. DISCUSSION The ratio of epithelial dysplasia found in present study is relatively high. Mehta and associates3 in their studies of 723 oral leukoplakia cases in India, found epithelial dysplasia in 10.7 per cent. Pindborg and tied-Petersen,” in 345 Danish leukoplakias, noted a 15.4 per cent incidence of dysplasia. Waldron
Volume Number
42 6
Epithelial
dysplasia
in oral leukoplakia
Fig. 8. Biopsy specimen from lesions shown in Fig. 1, showing severe epithelial (Hematoxylin and eosin stain. Magnification, x150.) Fig. 3. Biopsy specimen from lesion shown in Fig. 1 after 1 year of conservative showing invasive c-arcinoma. (Hematoxylin and eosin stain. Magnification, x150.)
771
dysplasia. treatment,
and Shafer,“’ in their extensive study of 3,256 cases diagnosed clinically as leukoplakia, found squamous-cell carcinoma, carcinoma in situ, or severe epithelial dysplasia in 7.6 per cent and mild to moderate epithelial dysplasia in 12.2 per cent of all specimens. In our previous studies8 of 184 leukoplakia cases, dysplasia was observed in 28.8 per cent, which is close to the present 24 per cent. The higher occurrence of epithelial dysplasia in our material might be explained partly by geographic factors ( Waldron and ShafeP observed significant regional differences in the character of oral leukoplakia within the United States) and partly by smoking habits and by the different indications of biopsy. In contrast to other authors’, 3 who perform biopsy routinely on the first visit of the leukoplakia patient, we take biopsy specimens, except in the clinically suspect cases, only in cases in which the leukoplakia had not disappeared after the removal of local irritants and/or cessation of smoking. As probably the clinically irreversible lcukoplakias might show more severe histologic changes, this fact may be responsible for the higher occurrence of dysplasia as well as of carcinoma in the present material. The relatively high occurrence of moderate and severe dysplasias compared with the results of other investigation@ might be due also to the different biopsy indications or the investigators’ subjective assessment. The frequency of the histologic changes of dysplasia is partly identical with
772
R6ndczy
and
Csiba
Pig. 4. S. I
and
follow-up
Jo&in Bhdczy, M.D., Budapest, Hungary
C.Sc.,”
SEMMELWEIS
UNIVERSITY
MEDICAL
study
of
md iirpcid
SCHOOL
12 cases
Csiba, M.D.,“”
OF
DENTISTRY
The histologic material of 500 leukoplakia patients was analyzed in order to define the characteristics of epithelial dysplasia and to correlate the findings with the clinical data. Epithelial dysplasia was found in 120 cases (24 per cent) and was graded as mild, moderate, or severe. The occurrence of dysplasia was highest in the group of erosive leukoplakias. The majority of the severe dysplasias were found on the tongue and lips. Follow-up studies on sixty-eight leukoplakia patients with histologic dysplasia revealed carcinoma in nine cases (13.2 per cent) during the mean observation period of 6.3 years. Leukoplakias of the tongue showed the highest incidence of malignant change.
T
he precancerous character of oral leukoplakia today is generally accepted. According to various authors,’ the ratio of malignant transformation varies between 1 and 6 per cent. Recent studies have attempted to define the precancerous leukoplakias in a narrower sense by clinical and histologic methods.‘, *, 5 Leukoplakias showing histologically epithelial dysplasia are considered to have a greater disposition for malignant transformation. However, reports on the occurrence of epithelial dysplasia and longitudinal studies on the behavior of these lesions are few.“, 6, lo There is also no unanimity regarding the therapy of leukoplakias showing epithelial dysplasia. The purpose of the present study is to define the occurrence of epithelial dysplasia in a large group of oral leukoplakia patients and to report on our experiences with the follow-up observations of these patients. *Professor **Assistant and Dentistry.
766
and Chairman, Department of Conservative Professor, Division of Oral Pathology,
Dentistry. Department
of Maxillo-Facial
Surgery
Epithelial
Volume Number
-12
Table
I. Distribution
6
dysplasia
in oral leukopla.kia
767
of histologic characteristics of dysplasia in 120 cases
Histologic
Per cent o/specimens showing this change
change
Irregular epithelial stratification Hyperplasia of the basal layer D%p-shaped rete pegs Increased number of mitotic figures Loss of polarity of the basal cells Increased nuclear-cytoplasmic ratio Nuclear polymorphism Nuclear hyperchromatism Enlarged nucleoli Keratinization of single cells or cell groups Loss of intercellular adherence
in the prickle
75.0 43.3 68.3 2.5 23.3 13.3 IS.0 IO.0 12.5 35.8 18.3
layer
II. Correlation of the grade of dysplasia with the age and sex distribution of patients Table
Men Age 20 to 29 30 to 39 40 to 49 50 to 59 60 to 69 Over 70 Total
MATERIAL
Moderate
Mild
Women Severe
Total
Mild T 2: 3
1
I
II,
: 21 19 8 63
z
16
; 2 I9
:; I2 104
r 5 i 2 22
AND
Moderate
Total
Severe
Total
T T :2
2
Cases 2
r :3 :3 9
4
3: 4 7 16
t; 39 36 I2 I20
Per cent 1.7 10.0 15.8 32.5 30.0 10.0 100.0
METHODS
The clinical and histologic material of the present study originated from leukoplakia patients treated and followed up regularly at the Department of Maxillo-Facial Surgery and Conservative Dentistry. The term leukoplakia was employed in a clinical sense,meaning a white patch on the mucous membrane that cannot be removed by rubbing and cannot be classified as any other diagnosable disease. Hematoxylin-eosin-stained histologic sections of 500 casesdiagnosed clinically as leukoplakia were investigated. The sections were grouped according to whether they showed simple hyperkeratosis, epithelial dysplasia, or carcinoma (including invasive carcinomas and carcinoma in situ). Epithelial dysplasia was diagnosed when two or more of the following changes were present : irregular epithelial stratification, hyperplasia of the basal layer ; drop-shaped rete pegs; increased number of mitotic figures (a few abnormal mitoses may be present) ; increased nuclear-cytoplasmic ratio ; lossof polarity of the basal cells; nuclear polymorphism ; nuclear hyperchromatism ; enlarged nucleoli; keratinization of single cells or cell groups in the prickle-cell layer; and loss of intercellular adherence. Epithelial dysplasia was graded as mild when two of the above-listed histologic changes were present, moderate when two to four changes were noted, and severe when five or more of the changes were present.
768
Bdndczy
and Csiba
Oral December,
Surg. 1976
III. Correlation of the grade of dysplasia with the clinical type of leukoplakia Table
Grade Type of leukoplakia Leukoplakia Leukoplakia Leukoplakia Total
simplex verrucosa erosiva
Mild 1: 8 25
of dysplasia
Total
1 Moderate
Severe
:i 34 72
i 14 23
1
Cases
Per cent
z: 56 120
18.4 35.0 46.6 100.0
The clinical classification of leukoplakia was done according to previous reports,Q differentiating leukoplakia simplex, leukoplakia verrucosa, and leukoplakia erosiva types. The methods of treatment employed have been published previously.Q In the first part of our study, the occurrence and grade of epithelial dysplasia, as well as the frequency of the histologic characteristics, were analyzed. In the second part the correlation of epithelial dysplasia with age and sex of the leukoplakia patients and with the clinical type and location of leukoplakia was investigated and the subsequent clinical course of dysplasia caseswas analyzed. RESULTS
Analysis of 500 histologic sections, diagnosed clinically as leukoplakia, showed carcinoma in forty-eight cases (9.6 per cent), epithelial dysplasia in 120 cases (24 per cent), and keratosis without dysplasia in 332 cases (66.4 per cent). The grade of severity of the epithelial dysplasia caseswas classified as mild in twenty-five cases (20.6 per cent), moderate in seventy-two cases (60.0 per cent), and severe in twenty-three cases (19.5 per cent). The distribution of the histologic characteristics of dysplasia is shown in Table I. The most frequent changes were the irregular epithelial stratification, drop-shaped rete pegs, and hyperplasia of the basal layer. The distribution of the leukoplakia patients by age and sex and the correlation of these factors with the grade of epithelial dysplasia are shown in Table II. The 120 dysplasia patients include 104 men (86.7 per cent) and sixteen women (13.3 per cent). The frequency of dysplasia shows a rise after the age of 40. Most cases were observed in patients between the ages of 50 and 70 years (72.5 per cent). The distribution of the clinical types of leukoplakia in dysplasia casesand the correlation with the grade of the dysplasia are shown in Table III. The distribution of the clinical types shows a predominance of the erosive type (46.6 per cent), verrucous leukoplakia occurring in 35 per cent and simplex leukoplakias only in 18.4 per cent. Most severe and moderate dysplasias are observed in the erosive type, and the less severe atypias in the simplex type. Table IV shows the location of leukoplakia in correlation with the grade of dysplasia and in comparison with the percentage distribution of the total leukoplakia (all 500 cases) and carcinoma groups (48 cases) according to location. The occurrence of severe dysplasias on the tongue and on the lower lip was high.
Epithelial Table
Correlation
IV.
dysplnsia
of the grade of dysplasia
with
ix oral leukoplakia
the location of leukoplakia
1 Distribution
Commissures Buccal mucosa Lips Tongue Hard palate Soft palate Floor of mouth Alveolar ridge Total
Table
V.
11 i
30 13 16
2
9 2
1 25
Follow-up
: 1 2 23
12
results according
in percentage
Leukoplakia grow (500 cases)
39. I 20.8 20.0 14.1 1.7 0.9 1.7 1.7 100.0
6 I
2 -
of location
Dysplasia group (120 cases)
Total cases
769
Carcinoma group (48 cases]
36.5 26.3 6.5 x.5 8.5 1.3 5.8 6.6 100.0
to grade of dysplasia
9.1 9.7 16.1 38.8 6.4 3.2 9.1 6.4 100.0
and treatment
Treatment Surgical Grade of_ dysplasia . . Results
Mild 9 I 10
Cured Improved Unchanged Spread Carcinoma Total
Table
VI.
Moderate
Severe 4 -
23 6 29
&‘ollow-up
results
Conservative Grade of_ dvsplasia . . Mild -
T I 6
according
Moderate -
Severe -
Result Cured Improved Unchanged Spread Carcinoma Total
Table
VII.
Buccal mucosa
Lips
22 6 7
z
9 t
t 37
T 5
I
Per cent 53.0 14.7 14.7 4.4 13.2 100.0
T
:
z
T 3
: 14
4 6
; 69
to location Total
I1
Hard palate
Tongue
T 12
Cases 36 10 IO
Location Commissure
Total
I
3
2
T
1
.: 9
IT2
Soft palate
Floor of mouth
Aiveolar ridge
1
1
r
I
r -
I
36 10 10
I 1
I
Cases
i 68
Per cent 53.0 14.7 14.7 4.4 13.2 100.0
Follow-up results in correlation with the observation period Observation
Result Cured Improved Unchanged Spread Carcinoma Total
It02
1
2
to5
period 1
(years)
5tolO
Total
81
14 :
12.i
: 2
Cases 36 10 IO
9
< 24
: 25
: 10
G 68
-
1
lOto
[
Per cent 53.0 14.7 14.7 4.4 13.2 100.0
770
B6ndczy
Fig. 1. T. L., the tongue.
and Csiba
50.year-old
Oral I)ecember,
woman.
Verrucous-erosive
leukoplakia
ou the inferior
surface
Surg. 1976
of
Follow-up investigations could be performed on sixty-eight leukoplakia patients with dysplasia. The observation period varied from 1 to 20 years, with a mean observation period of 6.3 years. The follow-up results, according to the grade of dysplasia, are shown in Table V, with cases separated into surgically and conservatively treated groups. (Conservative treatment consisted of the elimination of possible etiologic factors, accompanied by vitamin A and/or antimycotic treatment.) Best results were achieved in the surgically treated cases, where in the majority of the moderate and severe dysplasias no recurrence was observed. Of the nine carcinoma cases (13.2 per cent) developed from dysplasia% eight cases originated in the nonsurgically treated group (Figs. 1 and 6). The clinical outcome of dysplasia cases according to location is shown in Table VI. Of the nine carcinoma cases, four were observed on the tongue. The highest ratio of cured and improved cases could be found in dysplasias located in the commissures. An analysis of the subsequent clinical course of dysplasia cases in correlation with the observation period (Table VII) shows a higher ratio of cured and improved cases after a short observation period. The number of unchanged, spread, and carcinoma cases rises with the observation time. DISCUSSION The ratio of epithelial dysplasia found in present study is relatively high. Mehta and associates3 in their studies of 723 oral leukoplakia cases in India, found epithelial dysplasia in 10.7 per cent. Pindborg and tied-Petersen,” in 345 Danish leukoplakias, noted a 15.4 per cent incidence of dysplasia. Waldron
Volume Number
42 6
Epithelial
dysplasia
in oral leukoplakia
Fig. 8. Biopsy specimen from lesions shown in Fig. 1, showing severe epithelial (Hematoxylin and eosin stain. Magnification, x150.) Fig. 3. Biopsy specimen from lesion shown in Fig. 1 after 1 year of conservative showing invasive c-arcinoma. (Hematoxylin and eosin stain. Magnification, x150.)
771
dysplasia. treatment,
and Shafer,“’ in their extensive study of 3,256 cases diagnosed clinically as leukoplakia, found squamous-cell carcinoma, carcinoma in situ, or severe epithelial dysplasia in 7.6 per cent and mild to moderate epithelial dysplasia in 12.2 per cent of all specimens. In our previous studies8 of 184 leukoplakia cases, dysplasia was observed in 28.8 per cent, which is close to the present 24 per cent. The higher occurrence of epithelial dysplasia in our material might be explained partly by geographic factors ( Waldron and ShafeP observed significant regional differences in the character of oral leukoplakia within the United States) and partly by smoking habits and by the different indications of biopsy. In contrast to other authors’, 3 who perform biopsy routinely on the first visit of the leukoplakia patient, we take biopsy specimens, except in the clinically suspect cases, only in cases in which the leukoplakia had not disappeared after the removal of local irritants and/or cessation of smoking. As probably the clinically irreversible lcukoplakias might show more severe histologic changes, this fact may be responsible for the higher occurrence of dysplasia as well as of carcinoma in the present material. The relatively high occurrence of moderate and severe dysplasias compared with the results of other investigation@ might be due also to the different biopsy indications or the investigators’ subjective assessment. The frequency of the histologic changes of dysplasia is partly identical with
772
R6ndczy
and
Csiba
Pig. 4. S. I
