The Journal of Laryngology and Otology May 1979. Vol. 93. pp. 447-459.
The transformation of laryngeal leucoplakia to cancer* By R. C. HENRY (Manchester) THE purpose of this paper 'the transformation of laryngeal leucoplakia to cancer' is to determine whether or not leucoplakia can be considered precancerous. Another transformation will take place—that of the title itself. The word leucoplakia is derived from the Greek Leucos (XCVKOV) meaning white and Plax (wAal) a flat stone or slab. Leucoplakia has, therefore, become an apt and widely used, albeit somewhat misleading, clinical description of white patches which may affect the laryngeal mucous membrane, especially that of the true vocal cords. Another definition is hyperkeratosis. This term which is often used to describe exuberant keratinization of the surface of the vocal cord is, however, erroneous. The true vocal cord is normally non-keratinized and so with keratin production it can only exhibit keratosis. In contradistinction, the squamous epithelium of the skin is keratinized and deposition of more keratin does indeed lead to hyperkeratosis. At the Section of Laryngology Meeting at the Royal College of Surgeons on 4 December 1953 there was a discussion on the 'keratoses of the larynx'. Mr. Munro Black defined hyperkeratosis as a change which occurs in squamous epithelium commonly as a response to some irritant, and leucoplakia as the appearance of white plaques which is the clinical picture produced by this change. He went on to say 'the rather generic term "the keratoses" is useful but tends to confusion now as limited in meaning to keratosis pharyngis, a condition of different nature and outlook. Accordingly, in so far as the larynx is concerned, it would seem wise to avoid the term.' Twenty-five years later one might suggest that to lessen confusion now the terms to be avoided are leucoplakia and hyperkeratosis, with substitution of the correct clinical and pathological term namely, keratosis of the larynx. The title of this paper should, therefore, be!amended to that of 'the transformation of laryngeal keratosis to cancer'. Histology The clinical appearance of keratosis of the larynx is well known but, like an iceberg, the ominous part lies beneath the surface. In keratosis this can only be discerned by the histopathologist. * Paper read to the Section of Laryngology, Royal Society of Medicine, on 5 May 1978. 447
R. C. HENRY
FIG. 1 High power view of a section of keratinized stratified squamous epithelium of the true vocal cord showing regular maturation and a granular cell layer.
Fig. 1 is a high-power view of a section of keratinized stratified squamous epithelium of the true vocal cord showing the basal or germinal cells arranged perpendicular to the basement membrane and maturing in a regular fashion to become more ovoid in the prickle cell layer until finally the cells flatten out in the superficial layer. Also present, just below the surface, is a granular cell layer, the granules being composed of keratohyaline, the precursor of keratin. It may be useful at this stage to define some other histological terms: Acanthosis: means thickening of the prickle cell layer. Dyskeratosis: is premature keratinization in this layer. Parakeratosis: is retention of the nuclei within the keratinized cells (Fig. 2). Keratosis, parakeratosis, dyskeratosis and acanthosis are not particularly remarkable epithelial changes. There may, however, be a further alteration which should be cause for concern. This is epithelial dysplasia or cellular atypia (Fig. 3). Cellular atypia denotes not only faulty maturation, whereby the cells have the appearance of being jumbled up, but also individual cell alterations including such nuclear aberrations as enlargement, irregularity, hyperchromatism and abnormal mitoses. These changes affect, to a greater or lesser extent, the partial
THE TRANSFORMATION OF LARYNGEAL LEUCOPLAKIA TO CANCER
449
FIG. 2 Low power view of a section of keratinized stratified squamous epithelium of the true vocal cord demonstrating parakeratosis.
FIG. 3 High power view of an area of the epithelium shown in Fig. 2 exhibiting cellular atypia.
450
FIG. 4 Low power view of the epithelium of the true vocal cord, the full thickness of which is occupied by atypical cells without evidence of regular maturation.
FIG. 5 High power view of Fig. 4. The spindle-shaped atypical cells are seen extending up to the surface.
THE TRANSFORMATION OF LARYNGEAL LEUCOPLAKIA TO CANCER
451
thickness of the epithelium. To this histological picture the descriptive term 'restless epithelium' has been applied. More alarming is the appearance of the full thickness of the epithelium between the intact basement membrane and the surface occupied by atypical cells with total loss of the cytological architecture (Figs. 4 and 5). This is carcinoma-in-situ. An invasive carcinoma occurs when the basement membrane is disrupted and the malignant cells spread down into the underlying stroma (Fig. 6). Dr. Albert C. Broders, who is best known for his grading of carcinoma of the colon, published a paper in 1932 on carcinoma-in-situ which included one case affecting the larynx. He wrote 'it seems pertinent to state that the day has passed when epithelium can be considered non-caircinomatous or, at the most, only precarcinomatous because it is within the confines of the basement membrane and, conversely, carcinomatous because it has penetrated beyond this barrier. It is, therefore, imperative that the microscopist take into consideration the character of the epithelial cells above everything else in order to arrive at a correct diagnosis'. At the Section of Laryngology meeting held at the Royal Society of Medicine on 7 November 1930, there was a discussion on precancerous conditions of the larynx which was opened by Dr. Chevalier Jackson. He spoke of the state of the tissues prior to the development of cancer by saying 'metaphorically it might be described as a large number of the citizens across the border leaving their regular daily routine and mobilizing preparatory to invasion. Similar misbehaviour on the part of the cells that have not yet crossed the border is often seen adjacent to an area where invasion, constituting cancer, has already occurred. Occasionally it is seen without any subsequent invasion'. These mobilized citizens to whom Dr. Chevalier Jackson referred would appear to be the atypical cells. Norris and Peale (1963) pursued this metaphor a little farther and likened the disbanding of the mobilized citizens to reversal of the supposed pre-malignant keratosis. - As a further explanation of the histological changes of keratosis, ; carcinoma-in-situ and invasive carcinoma, Dr. Chevalier Jackson's metaphor may be illustrated as follows: Fig. 7 shows the citizens going about their regular daily routine; i in other words the normal epithelial cells between the basement membrane, represented by the barbed wire, and the surface keratosis represented \ by the shrubbery. This, therefore, is keratosis without cellular atypia. When some of these citizens are mobilized they become soldiers or the atypical cells (Fig. 8). This is keratosis with atypia. Should a large number of the citizens be mobilized preparatory i to invasion and they occupy the full thickness of the epithelium between
452
R. C. HENRY
FIG. 6 High power view of an invasive squamous cell carcinoma of the true cord showing the malignant cells streaming down into the stroma.
THE TRANSFORMATION OF LARYNGEAL LEUCOPLAKIA TO CANCER
FIG. 7 Pictorial representation of keratosis without atypia.
FIG. 8 Keratosis with atypia.
453
454
R. C. HENRY
the still intact basement membrane and the surface, a carcinoma-in-situ occurs (Fig. 9). If, however, there is invasion of the neighbouring territory or underlying stroma by breaching of the basement membrane this becomes an invasive carcinoma (Fig. 10). It would seem that, in the transformation of laryngeal keratosis to cancer, the villains of the piece are the atypical cells. In an attempt to implicate them in this process I conducted a survey of patients suflFering from keratosis of the larynx who had been seen at the Royal Infirmary and Christie Hospital, Manchester, between 1957 and 1977, the majority of whom I personally reviewed. The specific laryngeal conditions of singer's nodes, polyp, papilloma, contact ulcer and pachydermia, all of which may be associated with keratosis, were excluded. Also excluded were keratosis in the presence of a carcinoma, carcinoma which was detected within six months of the initial biopsy and, not in the context of this discussion, atypia in the absence of keratosis. Clinical study
Of fifty-five patients suffering from laryngeal keratosis, seven could not be contacted and five died of unrelated disease during the period 1957 to 1977 and were not included. Thus forty-three patients, thirty-eight male and five female, were traced and considered. All these patients
FIG. 9 Carcinoma-in-situ.
THE TRANSFORMATION OF LARYNGEAL LEUCOPLAKIA TO CANCER
455
were untreated except by biopsy and medically by avoidance of irritant factors such as tobacco, alcohol and vocal abuse. The age of the patients was as anticipated. The highest incidence
FIG. 10 Invasive carcinoma.
12
AGE INCIDENCE
HI
< a. 4
20
40 60 AGE ( years )
80
FIG. 11 Histogram of the age distribution of 43 patients with laryngeal keratosis.
456
R. C. HENRY
of laryngeal keratosis was found in the fifth, sixth and seventh decades. The youngest patient was twenty-five and the oldest was eighty years of age (Fig. 11). Hoarseness was the presenting symptom except in one patient who denied any alteration in his voice (Table I). TABLE I THE DURATION OF HOARSENESS PRIOR TO THE INITIAL CONSULTATION AS SHOWN IN MONTHS OR YEARS
Months
1-3
4-6
7-9
10-12
Patients
18
8
2
3
Years
1-2
2-3
3^
5
6
25
5
1
2
1
1
1
Patients
In no case was the keratosis situated on other than the true vocal cords. In two instances the lesion was initially unilateral but later affected both vocal cords. Nine patients were non-smokers amongst whom was included a pipe smoker who gave an assurance that he did not inhale the smoke. Sixteen patients smoked up to twenty cigarettes per day and eighteen patients admitted to smoking more than twenty cigarettes per day. The forty-three patients were followed up for a minimum of one year and a maximum of twenty years. Thirty-eight patients showed no change from laryngeal keratosis to cancer. These cases were classified according to the presence or absence of cellular atypia and the persistence of the condition was recorded separately (Table II). Two cases of keratosis without atypia were proven histologically to have progressed to keratosis with atypia. TABLE II THE FOLLOW-UP OF 3 8 PATIENTS WITH LARYNGEAL KERATOSIS WHO DID NOT DEVELOP CARCINOMA
Years 1 2 3 4
5-10 >11
Total
Without atypia
Persisting
With atypia
Persisting
0 3 3 7 9 6 2
0 1 2 2 1 0 •
2 0 0 0 5 1 2
2 0 0 0 0 0 1
28
10
THE TRANSFORMATION OF LARYNGEAL LEUCOPLAKIA TO CANCER
457
In addition to these thirty-eight patients a further five developed squamous carcinoma (Table III). Only a third instance of a change from keratosis without to keratosis with atypia is noted. It can be seen that of the five carcinomas, four developed from keratosis with atypia and four were shown to be invasive. TABLE III THE DETAILS OF 5 CASES OF LARYNGEAL KERATOSIS WHICH CHANGED TO CARCINOMA. THE FINAL COLUMN SHOWS THE INTERVAL OF TIME BETWEEN THE INITIAL BIOPSY AND THE DIAGNOSIS OF CANCER
Histological pattern Keratosis without atypia Keratosis Keratosis without • with Atypia atypia Keratosis with atypia
Carcinoma
Time interval
Invasive
1| yrs.
Invasive
4i yrs.
Invasive Invasive In Situ
8 mths. 11 mths. 3 yrs.
There have been three previous reports of laryngeal keratosis in which the distinction was made between keratosis without and keratosis with atypia (Table IV). Of the one hundred and sixteen cases studied by Norris and Peale (1963), only two were known to have changed from keratosis without atypia to keratosis with atypia. The three carcinomas TABLE IV A SUMMARY OF THE REPORTED SERIES OF KERATOSIS WITHOUT AND KERATOSIS WITH CELLULAR ATYPIA TABULATING THE NUMBER OF PATIENTS IN EACH GROUP WHO DEVELOPED LARYNGEAL CARCINOMA
Keratosis • Carcinoma atypia
Sex M
F
Without
With
McGavran et al. (1960)
84
74
10
1/66
2/18 11-1 per cent
Gabriel and Glyn-Jones (1962)
30
25
5
0/13
Norris and Peale (1963)
116
1/17 5-9 per cent 11/86 12-8 per cent 4/14 28-4 per cent
Henry (1978)
43
1/30 38
5
1/29
in the series of McGavran, Bauer and Ogura (1960) and the one in that of Gabriel and Glyn-Jones (1962) were all invasive. Norris and Peale found twelve carcinomas of which six were invasive, four were in-situ
458
R. C. HENRY
and in two, there was equivocal evidence of invasion. In the present review, as already indicated, four of the carcinomas were invasive. Summation of the final column of Table IV reveals a total of eighteen carcinomas in one hundred and thirty-five cases of keratosis with atypia (13-3 per cent). Twelve of these carcinomas were invasive. Gabriel and Glyn-Jones (1973) conducted a further survey of one hundred and five patients with laryngeal 'hyperkeratosis'. In fifty there was said to be no real evidence of cellular atypia and in fifty-five atypia was described. Of the former number three patients developed carcinoma and of the latter, four. It is not indicated whether these carcinomas were in-situ or invasive. Summary
In the transformation of laryngeal keratosis to cancer what one may be witnessing is a progression from normal epithelium to keratosis without cellular atypia, through varying degrees of atypia to the stage of carcinoma-in-situ when the full thickness of the epithelium is occupied by atypical cells until finally, with breaching of the basement membrane, an invasive carcinoma occurs (Fig. 12). Although this is, in theory, an attractive sequence, in practice it seems rare to detect an alteration in the epithelium from keratosis without atypia to keratosis with atypia and furthermore most of the carcinomas which developed were not in-situ but invasive. Therefore NON KERATINIZING STRATIFIED SQUAMOUS EPITHELIUM
KERATOSIS WITHOUT ATYPIA
KERATOSIS WITH ATYPIA
CARCINOMA IN SITU
INVASIVE CARCINOMA FIG. 12 Diagram indicating the possible pathway of transformation of laryngeal keratosis to cancer. Both keratosis without and keratosis with cellular atypia are reversible.
THE TRANSFORMATION OF LARYNGEAL LEUCOPLAKIA TO CANCER
459
he significant pathway is probably a change from normal non-keratinizing itratified squamous epithelium via keratosis with atypia to invasive jarcinoma (Fig. 13). NON - K£RKTW\ZWtti SQUAMOUS EPITHELIUM
KERATOSIS WITH ATYPIA
INVASIVE CARCINOMA FIG. 13 Diagram showing the probable relationship between laryngeal keratosis and carcinoma.
Conclusions
It is important to document keratosis of the larynx as being with or without cellular atypia. In the present state of our knowledge, or indeed our ignorance, it is keratosis with atypia which should be the more closely observed because, on the evidence presented, it can be considered pre-carcinomatous. Acknowledgements
I wish to thank Mr. Kenneth Harrison, Director of the Department of Otolaryngology, Manchester Royal Infirmary, for his encouragement whilst I was preparing this study and both him and Mr. N. W. Gill, Consultant Otolaryngologist, The University Hospital of South Manchester, for allowing me to review their patients. My thanks also to Dr. I. Wright, Consultant Pathologist at the Manchester Royal Infirmary, for her assistance with the histological sections. I am grateful to the members of the Department of Medical Illustration at Manchester Royal Infirmary for their help and to Miss L. S. Parkinson for typing this manuscript. REFERENCES BLACK, J. MUNRO (1954) Proceedings of Royal Society of Medicine, 47, 245. BRODERS, A. C. (1932) Journal of the American Medical Association, 99,1670. GABRIEL, C. E., and GLYN-JONES, D. (1962) Journal of Laryngology and Otology, 76, 947. GABRIEL, C. E., and GLYN-JONES, D. (1973) Journal of Laryngology and Otology, 87, 129. JACKSON, C. (1930) Proceedings of the Royal Society of Medicine, 24, 301. MCGAVRAN, M. H., BAUER, W. C , and OGURA, J. H. (1960) Laryngoscope, 70, 932.
NORRIS, C. M., and PEALE, A. R. (1963) Journal of Laryngology and Otology, 77, 635. Withington Hospital, West Didsbury, Manchester M20 8LR.
The transformation of laryngeal leucoplakia to cancer* By R. C. HENRY (Manchester) THE purpose of this paper 'the transformation of laryngeal leucoplakia to cancer' is to determine whether or not leucoplakia can be considered precancerous. Another transformation will take place—that of the title itself. The word leucoplakia is derived from the Greek Leucos (XCVKOV) meaning white and Plax (wAal) a flat stone or slab. Leucoplakia has, therefore, become an apt and widely used, albeit somewhat misleading, clinical description of white patches which may affect the laryngeal mucous membrane, especially that of the true vocal cords. Another definition is hyperkeratosis. This term which is often used to describe exuberant keratinization of the surface of the vocal cord is, however, erroneous. The true vocal cord is normally non-keratinized and so with keratin production it can only exhibit keratosis. In contradistinction, the squamous epithelium of the skin is keratinized and deposition of more keratin does indeed lead to hyperkeratosis. At the Section of Laryngology Meeting at the Royal College of Surgeons on 4 December 1953 there was a discussion on the 'keratoses of the larynx'. Mr. Munro Black defined hyperkeratosis as a change which occurs in squamous epithelium commonly as a response to some irritant, and leucoplakia as the appearance of white plaques which is the clinical picture produced by this change. He went on to say 'the rather generic term "the keratoses" is useful but tends to confusion now as limited in meaning to keratosis pharyngis, a condition of different nature and outlook. Accordingly, in so far as the larynx is concerned, it would seem wise to avoid the term.' Twenty-five years later one might suggest that to lessen confusion now the terms to be avoided are leucoplakia and hyperkeratosis, with substitution of the correct clinical and pathological term namely, keratosis of the larynx. The title of this paper should, therefore, be!amended to that of 'the transformation of laryngeal keratosis to cancer'. Histology The clinical appearance of keratosis of the larynx is well known but, like an iceberg, the ominous part lies beneath the surface. In keratosis this can only be discerned by the histopathologist. * Paper read to the Section of Laryngology, Royal Society of Medicine, on 5 May 1978. 447
R. C. HENRY
FIG. 1 High power view of a section of keratinized stratified squamous epithelium of the true vocal cord showing regular maturation and a granular cell layer.
Fig. 1 is a high-power view of a section of keratinized stratified squamous epithelium of the true vocal cord showing the basal or germinal cells arranged perpendicular to the basement membrane and maturing in a regular fashion to become more ovoid in the prickle cell layer until finally the cells flatten out in the superficial layer. Also present, just below the surface, is a granular cell layer, the granules being composed of keratohyaline, the precursor of keratin. It may be useful at this stage to define some other histological terms: Acanthosis: means thickening of the prickle cell layer. Dyskeratosis: is premature keratinization in this layer. Parakeratosis: is retention of the nuclei within the keratinized cells (Fig. 2). Keratosis, parakeratosis, dyskeratosis and acanthosis are not particularly remarkable epithelial changes. There may, however, be a further alteration which should be cause for concern. This is epithelial dysplasia or cellular atypia (Fig. 3). Cellular atypia denotes not only faulty maturation, whereby the cells have the appearance of being jumbled up, but also individual cell alterations including such nuclear aberrations as enlargement, irregularity, hyperchromatism and abnormal mitoses. These changes affect, to a greater or lesser extent, the partial
THE TRANSFORMATION OF LARYNGEAL LEUCOPLAKIA TO CANCER
449
FIG. 2 Low power view of a section of keratinized stratified squamous epithelium of the true vocal cord demonstrating parakeratosis.
FIG. 3 High power view of an area of the epithelium shown in Fig. 2 exhibiting cellular atypia.
450
FIG. 4 Low power view of the epithelium of the true vocal cord, the full thickness of which is occupied by atypical cells without evidence of regular maturation.
FIG. 5 High power view of Fig. 4. The spindle-shaped atypical cells are seen extending up to the surface.
THE TRANSFORMATION OF LARYNGEAL LEUCOPLAKIA TO CANCER
451
thickness of the epithelium. To this histological picture the descriptive term 'restless epithelium' has been applied. More alarming is the appearance of the full thickness of the epithelium between the intact basement membrane and the surface occupied by atypical cells with total loss of the cytological architecture (Figs. 4 and 5). This is carcinoma-in-situ. An invasive carcinoma occurs when the basement membrane is disrupted and the malignant cells spread down into the underlying stroma (Fig. 6). Dr. Albert C. Broders, who is best known for his grading of carcinoma of the colon, published a paper in 1932 on carcinoma-in-situ which included one case affecting the larynx. He wrote 'it seems pertinent to state that the day has passed when epithelium can be considered non-caircinomatous or, at the most, only precarcinomatous because it is within the confines of the basement membrane and, conversely, carcinomatous because it has penetrated beyond this barrier. It is, therefore, imperative that the microscopist take into consideration the character of the epithelial cells above everything else in order to arrive at a correct diagnosis'. At the Section of Laryngology meeting held at the Royal Society of Medicine on 7 November 1930, there was a discussion on precancerous conditions of the larynx which was opened by Dr. Chevalier Jackson. He spoke of the state of the tissues prior to the development of cancer by saying 'metaphorically it might be described as a large number of the citizens across the border leaving their regular daily routine and mobilizing preparatory to invasion. Similar misbehaviour on the part of the cells that have not yet crossed the border is often seen adjacent to an area where invasion, constituting cancer, has already occurred. Occasionally it is seen without any subsequent invasion'. These mobilized citizens to whom Dr. Chevalier Jackson referred would appear to be the atypical cells. Norris and Peale (1963) pursued this metaphor a little farther and likened the disbanding of the mobilized citizens to reversal of the supposed pre-malignant keratosis. - As a further explanation of the histological changes of keratosis, ; carcinoma-in-situ and invasive carcinoma, Dr. Chevalier Jackson's metaphor may be illustrated as follows: Fig. 7 shows the citizens going about their regular daily routine; i in other words the normal epithelial cells between the basement membrane, represented by the barbed wire, and the surface keratosis represented \ by the shrubbery. This, therefore, is keratosis without cellular atypia. When some of these citizens are mobilized they become soldiers or the atypical cells (Fig. 8). This is keratosis with atypia. Should a large number of the citizens be mobilized preparatory i to invasion and they occupy the full thickness of the epithelium between
452
R. C. HENRY
FIG. 6 High power view of an invasive squamous cell carcinoma of the true cord showing the malignant cells streaming down into the stroma.
THE TRANSFORMATION OF LARYNGEAL LEUCOPLAKIA TO CANCER
FIG. 7 Pictorial representation of keratosis without atypia.
FIG. 8 Keratosis with atypia.
453
454
R. C. HENRY
the still intact basement membrane and the surface, a carcinoma-in-situ occurs (Fig. 9). If, however, there is invasion of the neighbouring territory or underlying stroma by breaching of the basement membrane this becomes an invasive carcinoma (Fig. 10). It would seem that, in the transformation of laryngeal keratosis to cancer, the villains of the piece are the atypical cells. In an attempt to implicate them in this process I conducted a survey of patients suflFering from keratosis of the larynx who had been seen at the Royal Infirmary and Christie Hospital, Manchester, between 1957 and 1977, the majority of whom I personally reviewed. The specific laryngeal conditions of singer's nodes, polyp, papilloma, contact ulcer and pachydermia, all of which may be associated with keratosis, were excluded. Also excluded were keratosis in the presence of a carcinoma, carcinoma which was detected within six months of the initial biopsy and, not in the context of this discussion, atypia in the absence of keratosis. Clinical study
Of fifty-five patients suffering from laryngeal keratosis, seven could not be contacted and five died of unrelated disease during the period 1957 to 1977 and were not included. Thus forty-three patients, thirty-eight male and five female, were traced and considered. All these patients
FIG. 9 Carcinoma-in-situ.
THE TRANSFORMATION OF LARYNGEAL LEUCOPLAKIA TO CANCER
455
were untreated except by biopsy and medically by avoidance of irritant factors such as tobacco, alcohol and vocal abuse. The age of the patients was as anticipated. The highest incidence
FIG. 10 Invasive carcinoma.
12
AGE INCIDENCE
HI
< a. 4
20
40 60 AGE ( years )
80
FIG. 11 Histogram of the age distribution of 43 patients with laryngeal keratosis.
456
R. C. HENRY
of laryngeal keratosis was found in the fifth, sixth and seventh decades. The youngest patient was twenty-five and the oldest was eighty years of age (Fig. 11). Hoarseness was the presenting symptom except in one patient who denied any alteration in his voice (Table I). TABLE I THE DURATION OF HOARSENESS PRIOR TO THE INITIAL CONSULTATION AS SHOWN IN MONTHS OR YEARS
Months
1-3
4-6
7-9
10-12
Patients
18
8
2
3
Years
1-2
2-3
3^
5
6
25
5
1
2
1
1
1
Patients
In no case was the keratosis situated on other than the true vocal cords. In two instances the lesion was initially unilateral but later affected both vocal cords. Nine patients were non-smokers amongst whom was included a pipe smoker who gave an assurance that he did not inhale the smoke. Sixteen patients smoked up to twenty cigarettes per day and eighteen patients admitted to smoking more than twenty cigarettes per day. The forty-three patients were followed up for a minimum of one year and a maximum of twenty years. Thirty-eight patients showed no change from laryngeal keratosis to cancer. These cases were classified according to the presence or absence of cellular atypia and the persistence of the condition was recorded separately (Table II). Two cases of keratosis without atypia were proven histologically to have progressed to keratosis with atypia. TABLE II THE FOLLOW-UP OF 3 8 PATIENTS WITH LARYNGEAL KERATOSIS WHO DID NOT DEVELOP CARCINOMA
Years 1 2 3 4
5-10 >11
Total
Without atypia
Persisting
With atypia
Persisting
0 3 3 7 9 6 2
0 1 2 2 1 0 •
2 0 0 0 5 1 2
2 0 0 0 0 0 1
28
10
THE TRANSFORMATION OF LARYNGEAL LEUCOPLAKIA TO CANCER
457
In addition to these thirty-eight patients a further five developed squamous carcinoma (Table III). Only a third instance of a change from keratosis without to keratosis with atypia is noted. It can be seen that of the five carcinomas, four developed from keratosis with atypia and four were shown to be invasive. TABLE III THE DETAILS OF 5 CASES OF LARYNGEAL KERATOSIS WHICH CHANGED TO CARCINOMA. THE FINAL COLUMN SHOWS THE INTERVAL OF TIME BETWEEN THE INITIAL BIOPSY AND THE DIAGNOSIS OF CANCER
Histological pattern Keratosis without atypia Keratosis Keratosis without • with Atypia atypia Keratosis with atypia
Carcinoma
Time interval
Invasive
1| yrs.
Invasive
4i yrs.
Invasive Invasive In Situ
8 mths. 11 mths. 3 yrs.
There have been three previous reports of laryngeal keratosis in which the distinction was made between keratosis without and keratosis with atypia (Table IV). Of the one hundred and sixteen cases studied by Norris and Peale (1963), only two were known to have changed from keratosis without atypia to keratosis with atypia. The three carcinomas TABLE IV A SUMMARY OF THE REPORTED SERIES OF KERATOSIS WITHOUT AND KERATOSIS WITH CELLULAR ATYPIA TABULATING THE NUMBER OF PATIENTS IN EACH GROUP WHO DEVELOPED LARYNGEAL CARCINOMA
Keratosis • Carcinoma atypia
Sex M
F
Without
With
McGavran et al. (1960)
84
74
10
1/66
2/18 11-1 per cent
Gabriel and Glyn-Jones (1962)
30
25
5
0/13
Norris and Peale (1963)
116
1/17 5-9 per cent 11/86 12-8 per cent 4/14 28-4 per cent
Henry (1978)
43
1/30 38
5
1/29
in the series of McGavran, Bauer and Ogura (1960) and the one in that of Gabriel and Glyn-Jones (1962) were all invasive. Norris and Peale found twelve carcinomas of which six were invasive, four were in-situ
458
R. C. HENRY
and in two, there was equivocal evidence of invasion. In the present review, as already indicated, four of the carcinomas were invasive. Summation of the final column of Table IV reveals a total of eighteen carcinomas in one hundred and thirty-five cases of keratosis with atypia (13-3 per cent). Twelve of these carcinomas were invasive. Gabriel and Glyn-Jones (1973) conducted a further survey of one hundred and five patients with laryngeal 'hyperkeratosis'. In fifty there was said to be no real evidence of cellular atypia and in fifty-five atypia was described. Of the former number three patients developed carcinoma and of the latter, four. It is not indicated whether these carcinomas were in-situ or invasive. Summary
In the transformation of laryngeal keratosis to cancer what one may be witnessing is a progression from normal epithelium to keratosis without cellular atypia, through varying degrees of atypia to the stage of carcinoma-in-situ when the full thickness of the epithelium is occupied by atypical cells until finally, with breaching of the basement membrane, an invasive carcinoma occurs (Fig. 12). Although this is, in theory, an attractive sequence, in practice it seems rare to detect an alteration in the epithelium from keratosis without atypia to keratosis with atypia and furthermore most of the carcinomas which developed were not in-situ but invasive. Therefore NON KERATINIZING STRATIFIED SQUAMOUS EPITHELIUM
KERATOSIS WITHOUT ATYPIA
KERATOSIS WITH ATYPIA
CARCINOMA IN SITU
INVASIVE CARCINOMA FIG. 12 Diagram indicating the possible pathway of transformation of laryngeal keratosis to cancer. Both keratosis without and keratosis with cellular atypia are reversible.
THE TRANSFORMATION OF LARYNGEAL LEUCOPLAKIA TO CANCER
459
he significant pathway is probably a change from normal non-keratinizing itratified squamous epithelium via keratosis with atypia to invasive jarcinoma (Fig. 13). NON - K£RKTW\ZWtti SQUAMOUS EPITHELIUM
KERATOSIS WITH ATYPIA
INVASIVE CARCINOMA FIG. 13 Diagram showing the probable relationship between laryngeal keratosis and carcinoma.
Conclusions
It is important to document keratosis of the larynx as being with or without cellular atypia. In the present state of our knowledge, or indeed our ignorance, it is keratosis with atypia which should be the more closely observed because, on the evidence presented, it can be considered pre-carcinomatous. Acknowledgements
I wish to thank Mr. Kenneth Harrison, Director of the Department of Otolaryngology, Manchester Royal Infirmary, for his encouragement whilst I was preparing this study and both him and Mr. N. W. Gill, Consultant Otolaryngologist, The University Hospital of South Manchester, for allowing me to review their patients. My thanks also to Dr. I. Wright, Consultant Pathologist at the Manchester Royal Infirmary, for her assistance with the histological sections. I am grateful to the members of the Department of Medical Illustration at Manchester Royal Infirmary for their help and to Miss L. S. Parkinson for typing this manuscript. REFERENCES BLACK, J. MUNRO (1954) Proceedings of Royal Society of Medicine, 47, 245. BRODERS, A. C. (1932) Journal of the American Medical Association, 99,1670. GABRIEL, C. E., and GLYN-JONES, D. (1962) Journal of Laryngology and Otology, 76, 947. GABRIEL, C. E., and GLYN-JONES, D. (1973) Journal of Laryngology and Otology, 87, 129. JACKSON, C. (1930) Proceedings of the Royal Society of Medicine, 24, 301. MCGAVRAN, M. H., BAUER, W. C , and OGURA, J. H. (1960) Laryngoscope, 70, 932.
NORRIS, C. M., and PEALE, A. R. (1963) Journal of Laryngology and Otology, 77, 635. Withington Hospital, West Didsbury, Manchester M20 8LR.
