VERRUCOUS CARCINOMA

Clinical and Pathologic S t u d y of 105 Cases Involving Oral Cauity,

L a r y n x and Genitalia
FREDERICK
T. KRAUS,M D , * AND CARLOS
PEREZ-hfESA, AID

Verrucous carcinoma, a distinctive variant of epidermoid carcinoma,

was found i n the oral cavity (77 cases), larynx (12 cases), nasal fossa ( 4 cases),
glans penis (8 cases), vulva (1 case), vagina (1 case), scrotum (1 case). A relation-
ship between the use of chewing tobacco and oral cavity lesions was evident i n
this indigent, predominantly r u r a l patient group. Locally aggressive behavior
with bone invasion occurred i n 15 instances. Lymph node metastases were not
found except in 4 patients treated by radiation, apparently as a result of alter-
ation of the biologic character of t h e lesion. Radiation therapy (17 patients)
failed t o control the lesion i n all instances. The response to surgical excision (88
patients) was excellent.

EKKUCOUS CARCINOMA, A CLEARLY DEFINED
variant of epidermoid carcinoma, first was
described as an entity by Ackerman.2 H e em-
phasized the predilection of this tumor for
the buccal mucosa and lower gingiva, its indo-
lent course, the rarity of metastases and the
distinctive gross and microscopic pattern. T h e
majority of the patients were elderly people;
many had extremely poor oral hygiene or
poorly fitting dentures and more than half of
the patients with lesions of the buccal mucosa
were tobacco chewers. I n a recent study of
55 patients with oral verrucous carcinoma
Goethals et a1.S noted that this lesion also may
occur on the glans penis, in the larynx and on
the vulva.
Many writers have emphasized the impor-
tance of snuff, chewing tobacco, or other types
of tobacco products as an etiologic factor in
oral carcinoma.', 2, 4, 8. 9, 12, 15-18, 20 Peacock,13
on the other hand, found a significant rela-
tionship only in those patients more than 60
From the Division of Surgical Pathology, Barnes
Hospital, St. Louis, Mo., and Department of Pathology,
Ellis Fischel State Cancer Hospital, Columbia, Mo.
* Present address: Department of Pathology, St.
Luke's Hospital, St. Louis, Mo. 63112.
Supported in part by U.S. Public Health Service
grant CA-09741 from the National Cancer Institute.
The 12 cases of laryngeal verrucous carcinoma were
contributed by Dr. Walter C. Bauer, Department of
Surgical Pathology, Barnes and McMillan Hospitals,
St. Louis, Mo.
The comments of Dr. Lauren V. Ackerman were of
great assistance in the completion of this manuscript.
Received for publication May 28, 1965.
26
years old and in low economic groups. T h e use
of chewing tobacco has been considered sig-
nificantly related to the development of ver-
rucous carcinoma of the oral cavity by most
writers.2, 9, 17, 18
T h e purpose of this study is to delineate
the distinctive appearance and natural history
of this peculiar form of carcinoma in the vari-
ous sites in which it is found and to analyze
the results obtained by different methods of
treatment.
hIATERIALS AND METHODS
A total of 105 patients constitute the case
material examined. Twenty-nine were treated
at Barnes Hospital, St. Louis, from 1948 to
1962 and 64 were treated at Ellis Fischel State
Cancer Hospital, Columbia, Missouri from
1942 to 1962. T h e great majority of these 2
groups oE patients had lived in rural Missouri
or Arkansas most of their lives in poor eco-
nomic circumstances. Twelve additional cases
of verrucous carcinoma of the larynx from
McMillan Hospital, Washington University
Medical Center, were contributed by Dr. Wal-
ter C. Bauer, from the period 1948 to 1962.
During this period of time 600 patients with
laryngeal carcinoma were treated at McMillan
Hospital. T h e clinical charts, roentenograms,
photographs, pathologic reports and micro-
scopic slides were examined in all instances.
Gross material in the form of fixed tissue or
photographs was examined when available.
No. 1 VERRUCOUS
CARCINOMAKraus a n d Perez-illcsa 27
TABLE1. Age Incidence of Oral Cavity Lesions TABLE2. Symptoms of Oral Cavity Lesions
No. KO.
Age man patients Symptom patients

30-39 1 Presence of mass 31

40-49 4 Presence of sore or ulcer 29
50-59 13 Pain or tenderness 19
26 Blister 5
60-69 4
70-79 26 Hard white patch
SO-89 7 Fistula 5
Bleeding 3
Loose teeth 1
Range: 34-85 years.

Additional microscopic sections were cut when
necessary. T h e clinical history, gross appear-
ance, microscopic appearance, method of ther-
apy and follow-up were tabulated from this
data. Some small irradiated lesions represented
pathologically by biopsy alone with inade-
quate gross or clinical description were not
included even though the microscopic pattern
of the biopsy suggested the diagnosis of ver-
rucous carcinoma.
Clinical data: Age-The youngest patient
was 34 years old; the oldest was 85. Seventy-
five patients (7173 were older than 60 (Table
1). Sex-Ninety patients were men; 15 were
women. Race-There were 100 Caucasian and
5 Negro patients.
Symptoms: Characteristically a sore or
blister grew slowly for a few years, became a
sinall warty mass, then grew more rapidly in
a few months to produce an indolent painful
3.0 to 5.0 cm cauliflower-like lesion. T h e initial
sjmptoms or complaints, when recorded, are
listed in Table 2 . T h e laryngeal lesions were
manifested in all instances by hoarseness; 6 of
the 12 had respiratory difficulty which re-
quired tracheostomy in 3 instances. T h e penile
lesions became evident first by the discovery
of an enlarging mass. T h e vaginal lesion was
associated with a yellow discharge.
FINDINGS
PATHOLOGIC
Gross appearance: These lesions were almost
invariably described as warty fungating ulcer-
ated masses measuring between 2.0 and 10.0
cm (Table 3). Regardless of the size of the
lesion or its site, it tended to have a bulky
elevated fungating appearance (Fig. 1-5, 8, 9).
On cut section the tumors had a sharply cir-
cumscribed deep margin composed of festoons
and bulbous masses of grey tissue that ap-
peared to compress and push against the sur-
rounding tissue rather than infiltrate (Fig. 4 B).
Bone invasion: When confronted with bony
structures such as the mandible, the tumor
tended to destroy the bony tissue on a broad
front, eroding with a sharp margin rather than
infiltrating into the marrow spaces (Fig. 1 B,

FIG. 1. A, verrucous carcinoma of the buccal mucosa that has invaded through the skin of the
cheek and floor of the mouth. B, the mandible has been invaded and eroded extensively as shown
by x-ray examination.
 CANCERJanuary 1966
2 K). Such bone invasion was encountered in
15 instances.
Aietast~sis: T h e only metastases demon-
strated in this study were in 4 lesions after
*",'I( 1'.
i'ition therapy. Lymph node enlargement
;IS an inflammatory reaction was common in
association with large bulky infected lesions.
I n 19 neck dissections done in association with
the excision of large lesions of the oral cavity
no lymph node metastasis was encountered.
Occasional lymph node biopsies per1ornied
in other patients showed only hyperplastic
changes.
Microscopic appearance: T h e characteristic
histologic pattern was formed by an undulat-
ing outer densely keratinized layer covering
large fungating papillary fronds and a sharply
circumscribed deep margin composed of rows
of bulbous extremely well-oriented rete ridges
(Fig. 6). These bulbous rete ridges, composed
FIG.2. A, advancing border of verrucous carcinoma
of the floor of the mouth, extending onto tongue. Now
the warty filiforni keratotic appearance.
Vol. 19
FIG. 1 (continlied).
C, extensive surgical i e -
section including right
hcmi-mandible, cheeh,
floor of mouth and
neck dissection encom-
passed the lesion. KO
tumor was found in
the IJniph nodes ex-
amined. T h e patient,
a tobacco chewer for
50 years. remained well
B )ears following this
resection.
ot la1ge well-differentiated squamous epithelial
e l l s , were present in all cases. (This pattern is
t o be distinguished from the rows of narrow,
uneven, sharp pointed, elongated and jagged
rete ridges so charactelistic of pseudoepithelio-
matous hyperplasia.) Anaplasia was lacking in
all instances; the individual cells had uniform
vesicular nuclei and abundant cytoplasm (Fig.
7). Inflammation of the adjacent stroma was
likewise invariably present t o variable degrees.
Inflammation was most pronounced in those
instances in which escape of keratin deep in
the tissues had occurred, producing foreign
body granulomata.
Associated leszons and conditions: Eight pa-
tients with lesions of the oral cavity also tle-
velopecl at other times a relatively anaplastic
oral epidermoid carcinoma. I n 3 patients dis-
tinctly separate verrucous carcinomas a p -
peared. T h e finding of extensive oral leuko-
plakia was noted by the examining physician
in 17 instances (Table 4).
Location: T h e commonest location of vei--
rucous carcinoma was the oral cavity. Less
frequently, the tumor originated in the larynx
o r the squamous mucosa o r skin of the geni-
talia (glans penis, vulva, vagina, scrotum, peri-
neum and nasal fossa) (Table 5).
T h e buccal mucosa and gingiva accounted
for the site of origin of 50 of the 77 oral cavity
TABLE3. Size (Largest Diameter) of
Oral Cavity Lesions
No.
Sise patients
1.0- 1 . 9 c m 19
2.0- 4.9 cm 36
5 0-10.0cm 15
Not recorded 7
so. 1 CARCINOMAKraus a n d Perez-illcsa
VERRUCOUS 29

FIG. 2 continued. B, the mandible is invaded characteristically by erosion and encroachment

of a large tumor mass, which has a sharply circumscribed margin (x35).

lesions (Table 5). Most of the larger more POSSIBLE ETIOI.OGIC FACTOKS
aggressive lesions spread to involve adjacent
structures so that eventually the floor of mouth, Oral cavity: T h e use of chewing tobacco
tongue, hard palate and even paranasal sinuses and/or snuff was common among patients
became involved secondarily. with oral cavity lesions (Table 6). Often the
T h e laryngeal lesions were distributed fairly lesion developed at the site where the tobacco
evenly. Four were infraglottic; 4 were ti-ans-
glottic; 2 were supraglottic and 2 were limited
to the glottis.
Of the 12 lesions of the genital mucous
membranes, the glans and prepuce of the penis
were involved most frequently. T h e vulva, va-
gina, scrotum and perineum were encountered
as primary sites only once each during the
period of this study.

TABLE
4. Neoplasms and Related Lesions Associated
with Oral Cavity Verrucous Carcinoma
No.
,hsociated lesion patients
More anaplastic epidermoid carcinoma S
Another distinctly separate verrucous carcinoma 3
Basal cell carcinoma of the skin 6
Adenocarcinoma of the cecum 1
Bladder papilloma FIG. 3. Verrucous carcinoma of the lip and anterior
Postradiation fibromatosis buccal mucosa. Note the associated leucoplakia of the
Leu koplakia ~ left commissure.
SO CANCER
January 1966 VOl. 19

FIG. 4. A, verrucons carcinoma of the larynx that has obliterated the right vocal cord and extended
into the subglottis. B, cross section shows extensive undertnining of suhglottic ninccisa and the convoluted
festoons o f well-differentiated squamous epithelium.

habitually hdd been placed. Described IS hav-
ing strikingly poor oral hygiene with ill-fitting
dentures o r decaying fractuied snag teeth
weie 17 of the 36 tobacco chewers. An addi-
tional group of 17 denied the use of tobacco
and had similai obvious and advanced dental
lesions. All but 2 of the 10 heavy smokers used
pipes most of the time. I n 13 instances there
was no mention of the state of oral hy,wene
or tobacco habits. Of the 9 wornen with oral
cavity verrucoi~scarcinoma 5 chewed tobacco
or used snuff; 3 had exceedingly poor oral
hygiene or poorly fitting dentures and one
smoked mole than 2 packs of cigaiettes pei
day. I n n o instance was theie a history of ex-
cessive alcoholic intake.
I,arynx: Information about smoking habits
was available in only 2 patients, both of whom
were smokers.
Genital mucous membmnes and skin: Of
the 8 men with verrucous carcinoma of the
penis 6 were uncircumcised; inforination con-
cerning circumcision was lacking in the other
2. Four had a history of syphilis and other
venereal diseases, chiefly gonorrhea. T h e pa-
tients with scrotal, vaginal, perineal and vulva
lesions had no history oE venereal disease.
IH1s.KAPY
Siirgicul excision: This was the most com-
mon initial therapeutic approach (Table 7).
Two patients with laryngeal verrucous carci-
noma were treated by excision biopsy only.
This procedure involved the piecemeal re-
moval of the entire visible lesion in both in-
stances; the lesions did not recur during a
3-year follow-up period. Some form of local

5. Location of Verrucous Carcinoma

TABLE
No.
Location patients
._
Oral cavity 77
Buccal niucosn 50
Gingiva 21
Tongue 3
Anterior tonsillar pillar 1
Hard palate 2
Larynx 12
Nasal Fossn 4
Genitalia 12
Penis (glans) 8
Vagina *1

Vulva I
FIG. 5 . Glans and prepuce of penis have been covered Scrotum 1
by this large mass. Involvement was superficial, without Perineum 1
invasion of corpora cavernosa. TOTAL 105
No. 1 VERRUCOUS CARCINOMAKraus and Perez-Mesa 31
TABLE6. Possible Etiologic Factors-Oral 7. Type of Therapy (All Lesions)
TABLE
____
Cavitv Lesions ___
No.
SO. Therapy patients
__ ____ _ _ - _ _ _ _ _ _ _ _ ___
_ Etiologic factor patients ~ ~

_ _ ___ ~ ---- ~ _ _ _ Surgery 88

Tobacco chewers
Snuff dippers
Heavy smokers
Unknown
_- - -- -----
excision of the lesion was done in 67 patients;
19 patients with oral cavity lesions were treated
by excision with neck dissection. T h e excision
included hemimandibulectomy when roent-
genographic evidence of bone involvement was
demonstrated. T h e effectiveness of surgical
therapy is shown in Table 8.
Recrudescence occurred in 9 patients, all
of whom had oral cavity lesions. T w o patients
have died with extensive postsurgical recru-
descent verrucous carcinoma. I n both instances
the lesions appeared on a background of ex-
tensive oral leukoplakia of several years dura-
tion and there were multiple recurrences
Excision biopsy 2
36 Local excision 67
3 Excision with neck dissection
10 (oral lesions) 19
13 Radiation therapy 17
___ -
requiring 5 subsequent excisions each. T h e
generally white thickened oral mucosa made
selection of a surgical margin virtually im-
possible. One postsurgical recrudescence was
treated by radiation therapy without response;
this patient died with verrucous carcinoma.
T h e 3 deaths occurred away from medical ob-
servation, without autopsy. There had been
no clinical evidence of metastases. Recrudes-
cence was controlled by re-excision in 5 pa-
tients. N o subsequent recurrence or recrudes-
cence was evident in 79 patients at follow-up.
R a d i a t i o n therapy: This was the initial form
of treatment in 17 patients and was unsuccess-

FIG. 6. Microscopic pattern of verrucous carcinoma of the scrotum. T h e bulbous rete pegs ant1 extensive hy-
perkeratosis with keratin cysts produce a very characteristic pattern. T h e advancing margin of the tumor is
sharply circumscribed. The absence of a connective tissue core in the papillary processes distinguishes this
lesion from condyloma aculninatum ( ~ 1 5 ) .
32 CANCER
Jnnwrry 1966 VOl. 19

TABLE
8. Results of Surgical Treatment TABLE
9. Results of Radiation Therapy
No. No.
Results patients Results patients
Oral cavity Oral cavity
+
No recrudescence 5 years* 26
25
Recrudescence, excision, well 3-6 years*
No response, dead with.verrucous-carcinorna
7
No recrudescence 2-5 years* 1
No recrudescence, < 2 years* 4 Anaplastic transformation, dead in <1 year 3
Recrudescence, re-excision, well 4 years
+
Recrudescence, re-excision, well 5 years* 4
1
Recrudescence, excision, recrudescence, dead
with verrucous carcinoma 1
Recrudescence, alive with verrucous Recrudescence, reradiation, mandibular
carcinoma (refused treatment) 1 necrosis (excised) well 8 years 1
Recrudescence, x-ray therapy, no response, Nasal fossa
dead with verrucous carcinoma 1 Anaplastic transformation, dead in < 1 year 1
Recrudescence multiple re-excisions, recru- Recrudescence, no therapy, dead with
descence, dead with verrucous carcinoma 2 verrucous carcinoma 1
Larynx Vagina
No recrudescence, 3-13 years* 12 No response. excision, well 5 years 1
Penile lesions Penis
+
No recrudescence 5 years 1 Recrudescence, reradiation, recrudescence,
No recrudescence 2-5 years 4 excision, well 1 year 1
No recrudescence <2 years 1
IJnknown 1 * Includes patients dead of intercurrent disease after
Vulva (clitoris) time interval indicated.
No recrudescence, 10 years 1
Nasal fossa
No recrudescence, 8 years 1 ful in all (Table 9). I n one instance no signifi-
No recrudescence, 1.5 years 1 cant regression of the tumor was obtained and
Scroturn the patient died with progressive verrucous
N o recrudescence, 6 years 1
Perineum carcinoma. I n 11 patients local recrudescence
Unknown 1 of verrucous carcinoma occurred. Eight of these
__
* Or dead of intercurrent disease. patients were retreated successfully by surgical

FIG. 7. Microscopic pattern of verrucous carcinoma of the vagina showing bulbous masses of extremely well-
differentiated squanious epithelial cells. Note the complete absence of anaplasia and the inflammatory reaction
in adjacent connective tissue (x85). N o regression was produced by radiation therapy, consisting of 7,000 mg
hours applied with a radium mold, over a 5-day period. The patient is well 5 years after excision.
No. 1 CARCINOMAKrazis a n d Pere;-,\lcsa
VERRUCOUS
FIG. 8. A, large verrucous carcinoma of buccal mu-
cosa, lower gum and floor of mouth. T h e patient had
habitually placed snuff in this area for more than 50
)ears. T h e lesion regressed completely after a midline
radiation dose of 5,500 rads (Betatron), in 43 days. One
month later a larger tumor mass had regrown.

excision for a follow-up period of 3 to 6 years.

Recrudescence in an additional patient was
successfully treated but with only 18 months
follow-up. Excision of one recrudescent lesion
failed and the patient died of respiratory tract
infection and debilitation secondary to the
large verrucous carcinoma.

FIG. 8 (continued). B,
original biopsy showed
typical pattern of ver-
rucous carcinoma
(x85).
 January 1966
CANCER Vol. 19
34

FIG.8 (continued). C , the tumor appearing after the radiation therapy was poorly differen-
tiated epidermoid carcinoma ( ~ 3 0 0 ) Surgical
. excision with neck dissection failed to control the
undifferentiated carcinoma; the patient died of disseminated carcinoma and local infection in
the neck 9 months after the initial radiation thcrap!.

A recrudescent lesion responded to a second 6 weeks. T h e details of radiation therapy $yen

course of radiation in one patient with a tu-
mor involving the alveolar ridge and buccal
mucosa. He received 6,280 rad tumor dose
first; one year later the recrudescent lesion was
given 3,640 rad tumor dose. T h e second course
of radiation was followed by disappearance of
the tumor and by necrosis and osteomyelitis
of the mandible, with draining sinus tracts.
Mandibulectomy was done to control the lat-
ter. No tumor was found and patient has re-
mained well for 8 years after initial treatment.
AnapEastic change in tumors following ra-
diation therapy: T h e tumor in 4 patients un-
derwent a startling change to a highly malig-
nant anaplastic lesion following irradiation.
I n each patient, a typical verrucous carcinoma
of the oral cavity was found (Fig. 8 A, 9 A).
T h e diagnosis was confirmed in each instance
by biopsy (Fig. 8 B, 9 B). Following radiation
therapy initial regression of the tumor mass
was described over a period of approximately
to 3 patients are described e1~ewhere.l~A rapid
change in the character of each lesion then was
seen; the primary lesion enlarged with ex-
plosive swiftness; metastases appeared and all
died, 4, 7, 8 and 9 months respectively, after
the initial treatment. In each instance there
had been no evidence of metastatic disease
prior to radiation. At the time of death and
autopsy metastases were extensive and widely
distributed in 2 patients. Large cervical metas-
tases were present in one. N o metastases were
demonstrated in one patient, who died im-
mediately after excision and radical neck dis-
section. T h e microscopic pattern of these
lesions was that of anaplastic epidermoid car-
cinoma (Fig. 8 C, 9 C).
DISCUSSION
T h e findings in this paper extend the ob-
servations of verrucous carcinoma as a clinical
so. 1 VERRUCOUS
CARCINOMAh'raus a n d Perez-Mesa

FIG. 9. A, verrucous carcinoma of Roor of mouth and

tongue of a 77-year old man who had chewed tobacco
for more than 20 years. Radiation therapy consisted of
4,230 rad tumor dose a t 250 KV given in 40 days and
single plane radium implant delivering 3,000 rads at
0.5 cm.As a 1.0 cm ulcerated tumor remained 4 months
later, a n additional 3,350 rads (250 KV) was admin-
istered. During this period the tumor enlaigecl to a
diameter of 3.0 cm.

FIG.9 (continued). B,
original biopsy showing
verrucous carcinoma
(X85).
36 CANCERJnnziary 1966 VOl. 19

FIG.9 (continued). C, anaplastic pattern following radiation therapy ( ~ 2 7 5 ) .Excision with

hemiglossectomy, hemi-mandibulectomy and neck dissection was done. The patient died immedi-
ately postoperatively. The 41 cervical nodcs in the neck dissection contained no tumor and no
residual primary or metastatic tumor was demonstrated at autopsy.

and pathologic entity, not limited to the oral
cavity. This is a peculiarly slow evolving but
relentlessly expanding variant of epidermoid
carcinoma that is extremely reluctant to me-
tastasize. Although the majority seemed to be
slow-growing lesions there were many instances
in this series in which recurrent lesions grew
rapidly. Occasionally a primary lesion which
maintained a nearly constant size for some
years suddenly grew a t a n accelerated rate
from a small innocuous nodule to a large
fungating mass, apparently in a few months.
T h e high incidence of using chewing to-
bacco or snuff by patients with verrucous carci-
noma suggests an important relationship. T h e
most common site of occurrence of verrucous
carcinoma is in the buccal gutter or buccal
mucosa adjacent to the site where tobacco or
snuff had been kept. Furthermore, the usual
high male preponderance among patients with
oral carcinoma is lost among populations where
women chew tobacco and use snuff.12.15, I n
one study of bucco-gingival carcinoma among
snuff dippers all of the patients were women.12
Peacock was unable to demonstrate a relation-
ship between chewing tobacco and oral cancer
except among aged patients of lower economic
status.13 Certainly most of the patients in this
study would fit into this category; most were
indigent and 71% were older than 60. Many
of the tobacco chewers in the present study
indicated that they had begun this habit in
childhood.
Tobacco chewing may be important in the
development of many cases of verrucous carci-
noma but, if it is, decades of exposure to to-
bacco will be required. I n view of the apparent
importance of the patients economic circum-
stances, inadequate dental care and poor nutri-
tion may be contributory. T h e frequent oc-
currence of extensive leukoplakia as well as
additional carcinomas suggests that in the oral
cavity lesions at least, some sort of carcinogenic
stimulus is operating to affect large areas oE
the oral mucosa.
T h e etiologic importance of lack of circum-
cision is evident in verrucous carcinoma of the
penis as it is in the more common relatively
anaplastic epidermoid carcinoma of the penis.
Our experience with verrucous carcinoma of
No. 1 CARCINOMA
VERRUCOCS * Kratis atid Perez-Mesa
the penis suggests that it is identical to the
lesions previously reported as giant condyloma
(Buschke-Lowenstein tumor)53 8 or papillary
tumor.10 T h e natural history here, as in the
oral cavity, is one of slow locally aggressive
growth without metastasis.
T h e diagnosis of verrucous carcinoma re-
quires both examination of the lesion in the
patient and careful histologic study. An ade-
quate biopsy must show not only a well-differ-
entiated hyperkeratotic warty superficial sur-
face but an equally well-differentiated bulbous
rete-ridge pattern at the base of the lesion.
Failure to include the latter can make it im-
possible to distinguish verrucous carcinoma
from a well-differentiated epidermoid carci-
noma that is forming much keratin superfici-
ally but may be relatively anaplastic and in-
filtrating in its deeper layers. While i t is true
that the total picture is so distinctive that it
can be recognized easily, we have found that
the diagnosis frequently will be missed by one
who attempts to identify the lesion without
having the necessary information. A large
fungating verrucous carcinoma, perhaps invad-
ing bone or having extended entirely through
the cheek, easily will be overestimated as ana-
plastic cancer with metastases by the clinician
ivlio first sees it, especially if inflammation in
the lesion has led to hyperplasia of the re-
gional lymph nodes. On the other hand the
biopsy almost invariably will be underesti-
mated as benign hyperplasia when it is seen
by a pathologist who has no knowledge of the
gross appearance of the lesion. T h e result may
be a sort of impasse during which the clinician,
sure of his ground, doggedly performs biopsy
after biopsy which the pathologist doggedly
refuses to recognize as carcinoma. This impasse
usually is not broken until the pathologist has
been induced to visit the patient and discover
that the lesion he regards as benign half fills
the mouth, has destroyed the mandible or per-
haps has obliterated the glans penis.
Verrucous carcinoma must be distinguished
from well-differmtiated epidermoid carcinoma.
Some well-differentiated epidermoid carci-
nomas may have a warty or papillary external
surface. T h e presence of small columns and
clusters of cells with anaplastic cytologic fea-
tures signifies the presence of an epidermoid
carcinoma of the conventional sort regardless
of how warty its surface may be. A totally
different natural history, with lymph node
metastases and the possibility of successfuI
radiotherapy then is to be expected. Lesions
37
in the genital area are distinguished from con-
dyloma acuminata by the absence of a central
connective tissue support in the papillary proc-
esses of a verrucous carcinoma (Fig. 6).
An important consideration in planning
therapy of verrucous carcinoma is its extreme
reluctance to metastasize. We have been un-
able to demonstrate metastases of any sort in
our series, except in those instances of ana-
plastic change following radiation therapy. A
similar rarity of metastases is reported by
Goethals et al.9 in their series of 55 patients.
They mention 2 patients, each apparently
with a single involved lymph node, one prior
to treatment and one noted after initial treat-
ment. I n both of these patients histologic
proof of metastasis apparently was lacking.
Ackermanz reports on one patient with a his-
tologically proven nearby lymph-node metas-
tasis. Duckworth likewise encountered a sin-
gle adjacent lymph node involved by tumor in
one of his 3 patients with verrucous carcinoma.
We have not encountered a single instance of
distant metastasis in the present study o r in
our review of the literature. It would seem,
therefore, that lymph node dissection in the
treatment of verrucous carcinoma should be
confined to the immediately adjacent lymph
node groups only. Where any possibility of in-
creased morbidity or mortality might be ex-
pected as a result of including node dissection
with surgical excision, it would appear most
desirable to omit it entirely.
I n those patients whose original verrucous
carcinoma apparently is controlled by sur-
gery the later development of a second carci-
noma with a more anaplastic pattern is not
at all unusual. Indeed, the subsequent or si-
multaneous appearance of a distinctly sepa-
rate epidermoid carcinoma elsewhere in the
oral cavity was found as often as recrudes-
cence of the original verrucous carcinoma at
the site of excision. It is possible that such
lesions may account for the rare lymph-node
metastases reported in verrucous carcinoma.
T h e striking failure of radiation therapy to
control verrucous carcinoma contrasts with
the effectiveness of this mode of therapy in
the treatment of conventional oral-cavity
epidermoid carcinoma.14 Although x-ray is
nearIy always unsuccessful, the reponse of
verrucous carcinoma to x-ray is certainly not
uniform. We have encountered (I.) partial
response, with some shrinkage of the tumor;
(2.) total lack of any effect on the tumor; and
(3.) the apparent alteration of the nature of
38 CANCER
January 1966
the tumor to a highly malignant rapidly me-
tastasizing poorly differentiated epidermoid
carcinoma. While we cannot completely e x
clude the possibility that a poorly differen-
tiated epidermoid carcinoma was lurking
beneath an apparent verrucous carcinoma in
these 4 patients, we have not encountered
such a lesion in the 90 excised specimens. Al-
though Ackerman2 has indicated that radia-
tion therapy controlled some small and su-
perficial verrucous carcinomas, significant long
term success (from 3 to 7 years) was obtained
in only 4 of 7 patients with small lesions. All
7 patients with larger lesions had local recur-
rences necessitating subsequent surgical ex-
cision. A similar experience was reported by
Goethals et al., who encountered local recur-
rence in 7 of 10 patients in whom radiation
therapy formed some part of the treatment of
the primary lesion. T h e results of the present
study plus those of other writers support sur-
gical excision which is adequate to encom-
pass the primary lesion as the most satisfactory
form of therapy.
SUMMARY
Verrucous carcinoma is a distinctive well.
differentiated slow-growing variant of epider-
REFERENCES
1. Abbe, R.: Cancer of m o u t h x a s e against tobacco.
N.Y. J . Med. 102:l-2, 1915.
2. Ackerman, L. V.: Verrucous carcinoma of the oral
cavity. Surgery 23:670-678, 1948.
3. -, and McGavran, M. H.: Proliferative be-
nign and malignant epithelial lesions of the oral cavity.
J. Oral Surg. 16:400-413, 1958.
4. Chapman, I., and Redish, C. H.: Tobacco-induced
epithelial proliferation in the human subject. A.M.A.
Arch. Path. 70:133-140, 1961.
5. Dawson, D. F., Duckworth, J. K., Bernhardt, H.,
and Young, J. M.: Giant condyloma and verrucous
carcinoma of the genital area. Arch. Path. 79:225-231,
1965.
6. Dreyfuss, W., and Neville, W. E.: Buschke-Lowen-
stein tumors (giant condyloma accuminata). A m . J.
Surg. 90:146-150, 1955.
7. Duckworth, R.: Verrucous carcinoma presenting
as mandibular osteomyelitis. Brit. J . Surg. 49:332-337,
1961.
8. Friedell, H. L., and Rosenthal, L. M.: T h e eti-
ologic role of chewing tobacco in cancer of the mouth.
JAMA 116:2130-2135, 1941.
9. Goethals, P. L., Harrison, E. G., and Devine, K. D.:
Verrucous squamous carcinoma of the oral cavity. Am.
J. SUrg. 106:845-851, 1963.
10. Goldstein, M. B.: Besondere Verlaufsformen der
rein Papillomatosen Geschwulste des Penis. Hautartzt.
13:25-28, 1962.
VOl. 19
moid carcinoma. I n this study i t was found
most commonly in the oral cavity (77 cases)
but tumors with an identical pattern and
natural history occurred in the larynx (12
cases), the nasal fossa (4 cases), the glans penis
(8 cases) and the vulva, vagina, scrotum and
perineum (one case each).
There seems to be a striking relationship
between the use of chewing tobacco or snuff
and oral verrucous carcinoma and between
lack of circumcision and verrucous carcinoma
of the glans penis.
Lymph node metastases are extremely rare
in patients when first seen, regardless of the
size or local spread of the tumor. Aggressive
local behavior with invasion of bone, cartilage
and all contiguous structures eventually will
occur.
T h e response to radiation therapy is poor.
No lesion was controlled by the initial course
of radiotherapy. I n 4 of the 17 patients ini-
tially treated by radiotherapy a sudden al-
teration of the character of the lesion to an
anaplastic pattern occurred. These lesions
grew rapidly, with distant metastases, and
death attributable to the tumor rapidly fol-
lowed in 3 patients.
T h e response to adequate surgical excision
is excellent.
11. Khanolkar, V. R.: Oral cancer in India. Acta U n .
Int. Cancr. 15:67-77, 1959.
12. Landy, J., and White, H. J.: Bucccgingival car-
cinoma of snuff dippers. Am. Surg. 27:442-447, 1961.
13. Peacock, E. E., Greenberg, B. G., and Brawley,
B. W.: T h e effect of snuff and tobacco on the produc-
tion of oral carcinoma-An experimental and epidemi-
ological study. Ann. Surg. 151:542-550, 1960.
14. Perez, C. A., Powers, W. A., Kase, J. P., Evans,
J: C., and Kraus, F. T.: Radiotherapy of verrucous car-
cinoma of the oral cavity. To be published.
15. Rosenfeld, L., and Callaway, J.: Snuff dippers
cancer. A m . J . Surg. 1063340-844,1963.
16. Shanta, V., and Krishnamurthi, S.: Further study
i n aetiology of carcinomas of upper alimentary tract.
Brit. J. Cancer 17:8-23, 1963.
17. Sorger, K., and Myrden, J. A.: Verrucous car-
cinoma of the buccal mucosa in tobacco chewers.
Canad. Med. Assn. J . 83:1413-1417, 1960.
18. Stecker, R. H., Devine, D. D., and Harrison,
E. G.: Verrucose snuff dippers carcinoma of the oral
cavity-A case of self-induced carcinogenesis. JAMA
189:838-840, 1964.
19. Vogler, W. R., Lloyd, J. W., and Milmore, B. K.:
.4 retrospective study of etiological factors in cancer of
the mouth, pharynx and larynx. Cancer 15:246-258,
1962.
20. Wynder, E. L., Bross, I. J., and Feldman, R. M.:
Study of etiological factors in cancer of the mouth.
Ibid. 10:1300-1323, 1957.