LARYNGEAL PRECANCER: A REVIEW OF THE
LITERATURE, COMMENTARY, AND COMPARISON
WITH ORAL LEUKOPLAKIA
Jerry E. Bouquot, DDS, MSD, and Douglas R. Gnepp, MD
Laryngeal keratosis (LK) is a precancerous mucosal change
with great similarity to oral leukoplakia. Its malignant transforma-
tion rate varies from 1% to 40%, with the highest rates being
found in patients microscopically diagnosed as “keratosis with
atypia” (KWA). Recent evidence indicates that even cases with
only mild or moderate epithelial dysplasias are at increased risk
for malignant transformation, with the highest rates occurring in
patients with more severe dysplasia or carcinoma in situ. Ap-
proximately 81Yoof LK patients are men and the average age at
diagnosis is 50 years, a decade younger than that for laryngeal
carcinoma patients. A high proportion of LK patients are tobacco
smokers (84%) and alcohol abusers (at least 35%). LK is almost
always found on the true vocal cords and is usually bilateral
(67%). Clinical signs of high risk include, in decreasing order of
importance: erythroplakia, surface granularity, increased keratin
thickness, increased size, recurrence after conservative re-
moval, and long duration. The annual incidence of LK in the
United States is 10.2 and 2.1 lesions per 100,000 males and fe-
males, respectively.
HEAD & NECK 1991;13:488-497
Tremendous advances have been made in the
understanding of oral leukoplakia (OL), since
Schwimmer’ first coined the clinical expression
From the Department of Oral Pathology West Virginia University School
of Dentistry and Department of Pathology (Dr Bouquot), West Virginia
University School of Medicine. Morgantown West Virginia, and Depart-
ments of Pathology and Otolaryngology-Head and Neck Surgery (Dr
Gnepp), St Louis University School of Medicine, St Louis, Missouri
Address reprint requests to Dr Bouquot at the Department of Oral Pa-
thology, WVU Health Sciences Center- North, Morgantown WV 26506
Accepted for publication May 20, 1991
CCC 0148-6403/91/060488-010 $04 00
0 1991 John Wiley & Sons, Inc
488 Laryngeal Precancer
in 1877. Today, such lesions are successfully
evaluated and managed as a routine facet of oral
health care. A parallel but completely indepen-
dent research effort has led to a less advanced
state relative to laryngeal leukoplakia or “kera-
tosis” (LK). Investigators and clinicians from ei-
ther field, however, seldom use or assimilate
hard-won facts and conclusions from the other
parallel field. This is due, in part, to an early and
erroneous assumption that keratotic plaques
from 1 anatomic site bear no significant similar-
ity to identical lesions of the other ~ i t e . ~It - ~
seems also a natural consequence of the simple
fact that benign lesions of each site have been
considered to be within the purview of 2 different
health professions, dentistry and medicine.
While several reviews are available for laryn-
geal precancers, none broadly synopsizes the var-
ied historical, clinicopathologic, histopathologic,
epidemiologic, and follow-up data available. The
present paper is an attempt to fill this void by
summarizing and analyzing past and current
concepts of laryngeal keratosis (LK), dysplasia,
and carcinoma in situ. It also provides compari-
sons with OL, because OL has been more exten-
sively studied and because there appears to be,
in fact, a marked similarity between OL and
LK.5-10
DEFINITIONS
The term “laryngeal keratosis” is used herein ac-
cording to the WHO “leukoplakia” definition,”
HEAD & NECK NovembedDecernber 1991
that is, a clinical white keratotic plaque that
cannot be given another diagnostic name. It is
used interchangeably with leukoplakia and has
no implication relative to the presence or ab-
sence of underlying microscopic atypia or dys-
plasia. “Erythroplakia” is used as a clinical
term to define a red mucosal plaque which does
not appear to arise from an obvious mechanical
or inflammatory etiology or which persists after
removal of obvious etiologic factors. “Erythro-
keratosis,” also known as speckled keratosis, is
a clinical term used to define a mucosal plaque
with areas of erythroplakia and leukoplakia in-
termixed.
A thin layer of surface keratin is accepted by
many authors under the definition of carcinoma
in situ (CIS), which otherwise requires “top-to-
bottom” epithelial dysplasia with little or no
other evidence of maturation and no invasion
through the basement membrane. The accep-
tance of surface keratin and/or maturation in
this lesion is neither encouraged nor espoused by
the present authors, but has been allowed by so
many investigators as t o make it a de fact0 fea-
ture of some CISs. It must be emphasized, there-
fore, that a strict separation of CIS from severe
epithelial dysplasia could not be attained in the
present review, and that the majority of lesions
reported as CIS may in reality be severe dyspla-
sias. This is of some concern, as CIS is considered
to be a preinvasive malignancy, whereas severe
dysplasia is a precancer. The terms “precancer”
and “premalignancy”define a physically or phys-
iologically altered tissue, benign in itself but
thought to carry a greater than normal risk of
transforming into malignancy.
ASSOCIATION WITH CANCER
The first reported case of LK appears to be Du-
rant’s12 1880 description of “white cicatrices” ad-
jacent to an assumed malignancy of the true vo-
cal cords. However, it was not until 1920 that
Pierce13 published the first English-language pa-
per dealing specifically with “leukoplakia laryn-
gis.” Shortly thereafter, Chevalier J a c k ~ o n l ~ ’ ~ ~NORRIS, PEALE (1963)
suggested an association between LK and carci-
noma of the larynx, a remarkable conclusion in
light of the fact that the very concept of prema-
lignancy was not yet accepted and such terms as
dysplasia and CIS had not yet been used to iden-
tify cells with a potential for malignant transfor-
mation or invasion.16-ls
Jackson metaphorically equated epithelial
atypia t o the “mobilization of a foreign army pre-
Laryngeal Precancer
paratory to invasion,”15 and pathologists of the
stature of James Ewing considered his cases to
represent the “earliest form” of laryngeal can-
cer.14It is perhaps significant that the long liter-
ature debate initiated by him commenced within
a decade of the ready availability and rapid pop-
ularity of inexpensive, mass-produced ciga-
rettes. 19,20
By 1942 Graham21 was able to report, after
review of the literature, that the precancerous
nature of LK was well established. The first com-
prehensive follow-up investigation, a decade
later, confirmed his assumption, finding that al-
most 40% of LK cases eventuated in car~inoma.~
Subsequent studies determined a much smaller
proportion of transforming cases (Figure 1).The
only population-based analysis of this question
found only 0.9%of LK lesions transforming after
diagnosis, although 17% contained carcinoma at
the time of diagnosis.23OL has demonstrated an
equally varied malignant transformation rate
(1%to 36%;average 4%)32and the single extant
population-based study has found that more than
10%become malignant after diagnosis.33
Acceptance of the precancerous nature of OL
preceded LK acceptance by several de-
Cades,4,32,34-36partly because OL has been noted
adjacent to as much as 100% of oral cancers,37
but also because of confusion resulting from a
lack of appropriate LK diagnostic criteria and
terminology. This has lead, literally, to chaos
and has prevented meaningful comparison be-
tween various research efforts and conclusions.
More than 20 different classification systems
have thus far been o h n using simi-
lar terms but with different meanings. Pierce13
HELLQUIST (1982)
GABRIEL, JONES (1973)
BOSATRA(1977)
KLEINSASSER (1959)
’UTNEY, OKEEFE (1953) 9
0 5 10 15 20 25 30 35 40
% LK WITH CARCINOMA AFTER DIAGNOSIS
FIGURE 1. Reported malignant transformation rates for 3,423
treated and followed LK case^?^**-^'
HEAD & NECK NovembedDecember 1991 489
believed that leukoplakia was the same as
pachyderma, a dermatologic term long used in
otolaryngology to describe a pebbled keratosis of
the posterior glottis. Jackson14 preferred the
term keratosis for the precancerous or suspicious
lesions, reserving leukoplakia for the much more
common thin keratotic plaques. Graham2’ pre-
ferred to use leukoplakia as a strictly micro-
scopic term and several authors have used leuko-
plakia and keratosis
Since 1959 there has been a trend toward the
use of 2 mutually exclusive microscopic names
dependent entirely on the presence or absence of
atypical epithelial cells: “keratosis without aty-
pia” (KWOA) and “keratosis with atypia”
(KWA).8*9*28930,3’ Such terms have true prognos-
tic significance. Treated KWA has been shown t o
transform into carcinoma in 5.6% to 40% of hos-
pital-based follow-up studies. This is consider-
ably more than the 0.0% to 16% rates for KWOA
(Figure 2). The great variability of these rates,
however, damages the credibility of any individ-
ual data and is probably as much dependent on
patterns of patient referral and selection as on
true differences between populations served by
hospitals. Such referral patterns tend to select
for more seriously affected patients, a feature
readily demonstrated by comparing the transfor-
mation rates of the 2 investigations which have
followed large numbers of untreated LK cases:
22.2% of such lesions became malignant in a pa-
tient cohort derived from a teaching hospital,
whereas only 0.9% did so in a general popula-
tion.23,41
The KWONKWA segregation has helped to
clarify the risk of malignant transformation in
SABRIEL, JONES (1962)
5.6 KWOA
W A
GABRIEL. JONES (1973)
73
McGAVRAN et al(l960)
11.1
NORRIS. PEALE (1963) h33 12.8
VELASCO el al (1987) & 19.5
HENRY (1979) 28,6
HOJSLET et al(1989)
0 5 10 15 20 25 30 35 40
Oh LK WITH CARCINOMA AFTER DIAGNOSIS
FIGURE 2. Comparison of malignant transformation rates for la-
ryngeal keratosis with (KWA) and without (KWOA) atypia or
dy~plaSia.”.27.28.30’38-40
490 Laryngeal Precancer
LK, but has several major flaws. First, it re-
quires a biopsy specimen and, therefore, does not
take into account the 53% of LK lesions which
are never b i ~ p s i e d Second,
.~~ the word “atypia”
encompasses a number of histologic changes not
associated with malignancy or premalignancy ;in
this light, “keratosis with dysplasia” would be
preferred. Third, a thin parakeratin layer is nor-
mal to the vocal cords, where most LK occurs,
and a white plaque of this site is, therefore, in-
dicative of a n excessive amount of keratin rather
than the mere presence of keratin. The term “hy-
perkeratosis” is more accurate as a histologic de-
scriptor. Finally, the term KWA does not take
into account the degree of cellular dysplasia
present . . . a feature that has long been consid-
ered to be among the most important aspects of
risk assessment for leukoplakias of other upper
aerodigestive tract (UAT) ~ i t e s ,and~ ,one
~ ~that
~ ~
will be discussed in a subsequent section of this
review.
CLINICAL FEATURES OF HIGH RISK
The emphasis on a simplistic, purely microscopic
lexicon for LK has resulted in a rather poor un-
derstanding of the clinical aspects of the disease.
In light of the large number of cases never bi-
opsied and the great stress placed on frequent
clinical follow-up of treated cases, this emphasis
is surprising. P ~ t n e ydid~ suggest,
~ as early as
1955,that LK lesions with surrounding inflam-
mation (erythroplakia?), surface granularity or
“papillarity,” long duration, or recurrence after
surgical removal were most likely to “degener-
ate” into malignancy. Other authorities have oc-
casionally agreed with him and added additional
high-risk
It wasn’t until the 1970s that Gabriel and
Jones27 successfully turned prevailing sentiment
toward the concept that the clinical appearance
of LK was as important as the microscopic ap-
pearance in determining treatment protocols.
These authorities recommended an international
committee to establish standards in both arenas.
Attempts to do so, unfortunately, have failed to
bring consensus and rather emphasize than di-
minish d i s p a r i t i e ~ . ~This
~~.~ ~ , ~ ~ forces
difficulty
the present authors to emphasize the importance
of microscopic evaluation of multiple LK sites.
45 Erythroplakia and erythrokeratosis, long con-
sidered the oral mucosal changes with the high-
est risk of malignant have
been largely ignored in the laryngeal literature
because they were confounded by the inflamma-
HEAD & NECK NovemberlDecember 1991
tory hyperemia which is an almost constant fea-
~ ~ - ~ ~ a few
ture of “smoker’s l a r y n ~ . ” Ironically,
authorities have actually included mucosal
erythema as a routine or required part of their
definition of LK.38 Several authors have warned
that the more heavily “inflamed LKs were at
greatest risk of malignant or dysplastic
change,4,10,21,43,48but only recently has the red-
ness associated with LK been considered to be a
feature of a dysplastic process rather than evi-
dence of differing intensities of i n f l a m m a t i ~ n . ~ ’ ~ments.
Erythroplakia in OL, by contrast, has long been
considered to be a high-risk precancer change
rather than an inflammatory ~ h a n g e . This
sign is noted in approximately 16%of LK lesions
and 1%to 3% of OL lesions.8*23*33,42
Figure 3 represents a composite illustration
of the various clinical appearances of LK with
expected underlying microscopic changes. Le-
sions become progressively more “severe” toward
the right, culminating in erythrokeratosis and
erythroplakia, which most frequently demon-
strate severe epithelial dysplasia and CIS when
studied histologically. It should be emphasized
that Figure 3 does not necessarily represent a
chronological change, but rather the potential
presentations of LK. It is not unusual for LK to
present with multiple appearances, in which
case the clinician should attempt to sample tis-
sue with the greatest chance of containing dys-
plastic cells, that is, those appearances to the
right in Figure 3 (right-shifted). It should fur-
ther be mentioned that the microscopic changes
indicated are only estimated and it is possible,
although unlikely, that dysplastic epithelium
could be found beneath all depicted clinical
changes. An identical model has been proposed
for OL as part of a precancer staging protocol
(J.E. Bouquot et al., submitted for publication).
Clinical signs are seldom noticed before
symptoms cause a patient to seek medical con-
sultation. Few papers, however, mention symp-
tomatology beyond broad introductory com-
~ Those few have indicated that the major
presenting symptom, found in 50.9%to 97.7% of
affected individuals, is hoarseness o r dysphonia
~ ~ . ~ ~of less than 7 months duration (range: 1 month
to 25 Duration of hoarseness ap-
pears to have little prognostic significance.
Almost all LK cases are found on the true vo-
cal cords and a large proportion, perhaps a ma-
jority, involve both cords.23 The average lesion
size at diagnosis is 1.2 cm and involves a large
portion of the affected cord, usually the central
and anterior lateral borders.23 There is no
present proof that LK of nontrue cord mucosa
carries a higher risk for malignant transforma-
tion, but 1 site, the aryepiglottic fold, appears to
carry an extremely low a situation
somewhat analogous to gingival leukoplakias,
which are most frequently simple frictional kera-
t~ses.~’
EPIDEMIOLOGY
The prevalence (proportion of persons affected) of
LK is not known. Autopsy investigations have

GRANULAR.
VERRUCIFORM ERYTHROKERATOSIS
KERATOSIS (SPECKLED KERATOSlSl

1 - Bulbous. elongated rele pegs Epithstidl atrophy Ion right1

I
1
- Moderaleiseveie dvsplasta
*Congested vessels
* Candida hyohae lmaybei

FIGURE 3. Representationof the various clinical presentations of LK, progressing from low-risk to high-risk malignant transformation
potential from the left to the right side. Probable underlying microscopic appearances are also depicted for each clinical presentation.
Fissured, nodular, and verruciform appearances are exaggerated for clarity. This model is derived from the LK literature and the au-
thors’ personal experience.

Laryngeal Precancer HEAD 8. NECK NovemberlDecember 1991 491

concluded that 19.6% of men, 80.7% of whom 0 KERATOSIS
were smokers, had LK at Even in non- CARCINOMA
smokers, 4.2% demonstrate LK. The incidence
(number of new cases per annum per 100,000
persons) of clinically diagnosed LK has only re-
cently been shown to be 10.2 for men and 2.1 for
women.23This compares to OL incidence rates of
16.0 and 8.6, respectively, in the same popula-
,---d
t i ~ n . ~ ~
The incidence rate for LK does not continue
to increase throughout life, as it does for OL,23950
but rather decreases after a peak in the 45- to
64-year age group (Figure 4). Bouquot et al.23
have demonstrated that laryngeal carcinomas
193544 1945-54 195564 1965-74 1975-84
are actually diagnosed more frequently than LK TIME PERIOD (DECADES)
after 64 years of age. Overall, however, LK is di-
agnosed 2.1 to 5.4 times more frequently than in- FIGURE 5. Time trends in average annual incidence rates for
LK and laryngeal carcinoma in a white population, both genders
vasive carcinoma of the larynx, depending on in~luded.'~
whether or not affected patients are taken from
the general population or a teaching hospi-
tal.22*23The annual incidence rate of diagnosed itive correlation between the proportion of men
LK is increasing much more rapidly than that and increasing lesion severity has recently been
for laryngeal carcinoma (Figure 5), predomi- demonstrated for OL lesions as well.50
nantly because of changing LK rates in There appears to be an additional positive
women.23 correlation between age at diagnosis and laryn-
Most patients with LK are men, accounting geal lesion severity or dysplasia.40 Mean ages for
for 63.5% to 93.6% of affected This first LK diagnosis vary from 48.0 to 56.5
male predilection becomes even more pro- years,4,17,22- 24,39.40,51
10 to 15 years younger
nounced with increasing dysplasia. Norris and than patients with laryngeal carcinoma (see also
Peale28 reported that 82% of KWOA patients Figure 4).9,23Norris and Peale,28 moreover, de-
were males, whereas 91% of KWA were male. termined that the mean age of patients with
Bouquot et al.23reported that 80.6% of 1commu- KWOA is less than that for patients with KWA,
nity's LK cases arose in males, whereas 83.3% of 48 and 53 years of age, respectively, although no
its laryngeal CIS cases and 94.3% of its invasive test for statistical significance was made by
laryngeal carcinomas were male. A strongly pos- them.
ETIOLOGY
''- KERATOSIS
Gender and age appear to be significant high-
risk features for LK but are not etiologic factors
v)
16-
CARCINOMA
per se. Virchow was probably the first to suggest
14- that voice and/or alcohol abuse could produce
g
n
12- pachyderms," and Jackson14 presumed that LK
was primarily produced by voice abuse. Surpris-
8 10-
ingly few investigators, however, have addressed
2
s 8- etiology in their research. Graham21 was first to
8 6-
report LK disappearance afier vitamin A ther-
2 - ~ ~ reported LK disappear-
apy, and W a l l n e ~ first
0 4- ance after smoking cessation; however, there
z*3 2- have been no follow-up investigations that have
specifically addressed vitamin therapy or habit
0 1
7
0-14
1 I 1
1524 25-34 35-44 45-54 55-64
I
65+ cessation. Current suggestions that carotene
AGE IN YEARS and/or retinoids are efficacious in reducing oral
FIGURE 4. Age-specific average annual incidence rates for LK 1eukoPlakia O r dYsPlasia tend to validate the use
and laryngeal carcinoma, both genders i n ~ l u q d e d . ~ ~ of beta-carotenes or cis-retinoic acid for LK.53*54

492 Laryngeal Precancer HEAD & NECK NovemberlDecember 1991

 Epidemiologic evidence has strongly impli-
cated tobacco smoking in the etiology of laryn-
geal and autopsy studies have
demonstrated a strong correlation between the
daily amount of tobacco consumed and the pres-
ence of LK or laryngeal d y ~ p l a s i a . ~ Per-~ , ~ ~ , ~ ~Laryngeal
sons smoking more than 20 cigarettes daily have
a 44.4% chance of developing LK and an even
greater chance, 47.2%, of developing dysplastic
vocal cord m u ~ o s a Light
. ~ ~ smokers (fewer than
10 cigarettedday) have a 12.4% risk of dysplastic
change, compared to 4.2% for nonsmokers. To-
bacco chewing appears to contribute significantly
to the risk of developing laryngeal cancer in In-
dia58 and to a much lesser extent in the United
but data are not detailed enough to
quantitate the relative risk of acquiring LK from
this habit.
Whether or not stopping the smoking habit
routinely returns the laryngeal mucosa to its
normal histology is uncertain,26*38*46*47*51,60 but
certainly many LK lesions are reversible if etio-
logic habits, such as tobacco, alcohol, and voice
abuse, are eliminated or if potential nutritional
deficiencies, especially vitamin A deficiencies,
are corrected. Occasional lesions disappear with-
out a change in smoking or other etiologic
habits61; re-biopsy of previously excised lesions
demonstrates normal mucosa in two thirds of
cases.4o
Alcohol abuse has been shown to have a syn-
ergistic association with tobacco abuse in the
production of laryngeal carcinoma,s5 but no sim-
ilar effect has been examined relative to laryn-
geal precancers. Only 1 investigation has pro-
vided statistics for this parameter, reporting that
35.2% of all LK patients are alcohol abusers
(listed in the medical records as heavy drinkers,
alcoholics, or having a “drinking problem”).23
Human papillomaviruses (HPV) have been
demonstrated in laryngeal carcinomas and pre-
cancerous p a p i ~ l o m a s ,as
~ ~well
’ ~ ~as in oral car-
cinomas and l e ~ k o p l a k i a s . ~Such
~’~~ data are
based on immunohistochemical demonstration of
HPV-antigen expression in such lesions, and on
DNA hybridization studies. The “high risk” HPV
type 16 DNA has been found in laryngeal verru-
cous carcinomas and HPV 6, 11, and 16 in non-
verrucous laryngeal carcinomas; 12.9% of the
latter contained the DNA of at least 1 HPV
type.“ No investigation has yet examined the
role of HPV in LK, nor do we know whether
HPV actually causes epithelial dysplasias rather
than being a secondary infection in previously
Laryngeal Precancer
altered cells. However, analysis of HPV-inocu-
lated normal cervical mucosa cells grown t o full
differentiation and maturity on collagen gels
seems to strongly suggest that HPV causes epi-
thelial dysplasias.66
,~~ keratosis has a multifactorial eti-
ology with tobacco smoking being of prime im-
p ~ r t a n c e $ ~ ~ , ~followed ~ * ~ ~closely
, ~ ~ ,by ~ ~ ~ ~ ~ ,
chronic mechanical trauma (voice
and more distantly by alcohol abuse10*23,30p51
and/or nutritional d e f i c i e n ~ i e s . ’ ~ ~It~ ~ is
~~~*~~
likely that LK lesions diagnosed in otolaryngol-
ogy clinics of large teaching hospitals have an
artificially high proportion of smoke-related le-
sions, as voice-related LK lesions would tend to
be selected out by the referral process. It should
also be emphasized that LK lesions without iden-
tifiable etiologies are considered more likely to
become dysplastic or malignant than other LK
lesions,* a characteristic of OL as well.’
DYSPLASIA AND CIS
The clinical presence of white keratosis, red
erythroplakia, verrucous hyperplasia, or surface
granularity is extremely important for identify-
ing and pin-pointing laryngeal mucosa at great-
est risk for containing or developing neoplastic
cells, but only the most innocuous LK lesions
should be exempt from biopsy, since the micro-
scopic appearance of the epithelial cells, with or
without overlying keratin, is the single most in-
fluential predictor of future transformation into
m a l i g n a n ~ y Figure
.~~ 2 emphasizes the impor-
tance of histologic evaluation using a simple
KWOMKWA classification. One should keep in
mind, however, that many authors have not pre-
sented clear microscopic definitions of atypia, es-
pecially with regard to the proper classification
of mild and moderate dysplasias. Most investiga-
tors, we believe, have included the latter diag-
noses under the KWA terminology, but several
have only included severe (“precancerous”) epi-
theilal dysplasia in this ~ a t e g o r y , ~ , ~ ~and
@ *a~ ’
few have included CIS as a KWA l e ~ i o n . ~ ~ , ~ ~
Recent studies have concluded that there is,
in fact, significant risk of malignant transforma-
tion in moderate epithelial dysplasia of laryn-
geal mucosa. Hojslet et al.40found that risk to be
the same (40%) as that of the combined group of
severe dysplasidCIS lesions. Investigations by
Hellquist et a1.26and Velasco et al.39 corroborate
this similarity of risk, although their transfor-
mation rates are lower (20%). Hojslet et al. cau-
tioned that even mild epithelial dysplasia bears
HEAD & NECK NovernberDecernber 1991 493
an increased risk (4%) of malignant transforma-
tion. Such results are contrary to the OL experi-
ence9v70,71 and would seem to dictate a more spe-
CT
-
- 4
MALES
FEMALES

cific subcategorization of epithelial dysplasias in

future LK research. Special emphasis, further-
more, should be placed on nuclear enlargement
and hyperchromatism in the assessment of that
dysplasia, as photometric analyses have demon-
strated that greatly increased DNA content was
the single strongest prognostic indicator.72
Laryngeal CIS received special and early at-
tention in the otolaryngologic literature. In fact,
the earliest review of nonlaryngeal UAT CIS, by
G~rlin'~ specifically emphasized oral and pha-
ryngeal lesions in order to counter the prevalent
belief that the larynx was the only UAT site af-
fected by this preinvasive malignancy. Recent
epidemiologic studies have justified the concern
of Gorlin, demonstrating that only one third to
one half of UAT CIS lesions are found in the lar-
ynx.74>75 The annual incidence rate for CIS of the
larynx is only 0.4 cases per 100,000 persons, a
rare neoplasm indeed. Even among total body
CIS cases, laryngeal lesions represent only 1%of
all cases. They also represent 6.5% of all laryn-
geal cancers, are much more common in males
than in females, and have a peak incidence in
the 65- to 69-year-old age group (Figure 6).
Although rarely diagnosed, CIS of the larynx
has been more extensively followed than CIS of
other UAT sites: three fourths of the 468 UAT
CIS patients thus far followed after diagnosis
have had laryngeal involvement. Table 1 demon-
strates that 29.0% of laryngeal CIS lesions even-
tuate in invasive disease, with untreated cases
* 20-24 30-34 4044 5054 60-64 70-74 80-84
2529 35-39 45-49 5559 65-69 75-79 85+
AGE (IN YEARS)
FIGURE 6. Age-specific average annual incidence rates for la-
ryngeal CIS,by gender.75
transforming at the highest rate (33.3% to
90.0%).
Because of differences in the definition and
criteria of KWA, severe dysplasia and CIS, we
strongly recommend a classification system simi-
lar to that used for tissue of the uterine cervix:
LIN I (laryngeal intra-epithelial neoplasm) for
mild epithelial dysplasia; LIN I1 for moderate
dysplasia; and LIN I11 for severe dysplasia or
CIS. This should ensure a more uniform diagnos-
tic protocol.
LK AND OL COMPARISON
By way of conclusion, Table 2 provides a sum-
mary of various clinicopathologic and epidemio-
logic characteristics of LK and compares each
characteristic with OL lesions. The similarity be-

Table 1. Results of follow-up investigations of laryngeal CIS

(listed by year of publication).

Year No. of 70transformed into

Aulhor(s) published CIS cases invasive carcinoma
Altman et al.76 1952 29 3.5
McGavran et a1.22 1960 18' 11.1
Norris and Peale2' 1963 1st 33.3
Klein~asser~~ 1963 20t 90.0
Miller and Fisher7' 1971 203 15.8
Pene and Fletcher7' 1976 26 4.0
Doyle et al.'' 1977 28 7.1
Elrnan et aL8' 1979 81* 17.0
Hintz el aLa2 1981 27t 63.0
Hellquist el a1.26 1982 20' 25.0
Total 468 29.0%*
'Includes severe epithelial dysplasias in addition to CIS
tCases were followed without treatment.
#Not weighed according to size of patient cohorts.

494 Laryngeal Precancer HEAD & NECK November/December 1991

 Table 2. Comparison of various characteristics of LK and OL.*
Laryngeal Oral
Characteristict keratosisS IeukoplakiaS
Patient characteristics
Average age at diagnosis 48-56 yrs (50y/o) 54-63% (60y/o)
Yo Males 64-94% (81%) 58-80% (60%)
Yo Smokers 84-94% (84%) 66-81% (66%)
Yo Alcohol abusers 35% (35%) N/A
Incidence (casedl 00,00O/yr) 6 (6) NIA
Prevalence (casedl ,000) N/A§ 20- 170 (20)
Lesion characteristics
Average lesion size 1-3 crn (1 cm) 1-2 crn (1 cm)
Average duration at diagnosis 7 rno (7rno) 1-40 rno (26 rno)
% With erythroplakia at diagnosis 16% (16%) 18-24% (18%)
% With carcinoma at diagnosis 4-67% (12%) 0.1-40% (7%)
Yo With carcinoma after diagnosis 1-40% (1%) 0.1-6% (4%)
% Recurred after treatment 16-30% (16%) 18-42% (18%)
% With dysplasia at diagnosis 3-100% (3%) 3-54% (14%)
Yo Carcinomas with adjacent LWOL 18-43% (33%) 10- 100% (34%)
% Biopsied 47% (47%) 26% (26%)
% Treated ’ 46% (46%) N/A (20%)
Typical histology Hyperkeratosis Hyperkeratosis
*References 4, 5,9. 13, 17. 22-24, 27, 28, 30.32-35, 39-42, 50, 51, 70.71. 83-86.
jRepresents 3857 LK and 4117 OL patients.
#Numbers in parentheses represent authors’ estimate of the most representative (unbiased) data.
§MA, data not available.

tween the 2 lesions would appear to justify the
contention that they are, in fact, the same entity.
Table 2 also illustrates the unfortunate variation
in results arising from clinicopathologic investi-
gations with their considerable patient referral
or case-selection biases. The authors recommend
that future investigators make every effort t o
minimize or at least identify such biases. In the
meantime we have suggested figures (in paren-
theses in Table 2) which we believe to be the
most representative for these lesions.

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