Transformation of the Common Wart into Squamous Cell

Carcinoma in a Patient with Primary Lymphedema

WALTER B.SHELLEY, MD, AND MARGARET G. WOOD, MD

A patient is reported in whom treatment-resistant periungual and subungual warts underwent malig-
nant transformation into squamous cell carcinoma. Similar changes were observed in multiple warts of
the vulvar, perianal, and intravaginal as well as cervical area. The tumors that developed were in many
instances microinvasive but did not metastasize. The remarkable conversion of a common wart into a
squamous cell carcinoma further implicates the human papovavirus in oncogenesis. The specific factors
accountable for the malignant change remain completely unknown, but the patient’s lymphedema prae-
cox, as well as her severe reaction to vaccinia, and her development of a disseminate systemic Mycobuc-
terium scrofulaceum infection suggest that the critical factor may be one of immunity.
Cancer 48:820-824, 1981.

T HE SKIN provides a remarkable observatory for the

genesis and natural course of disease. It is of spe-
cia1 value in the study of cancer where origins and se-
quences can be directly observed b y the clinician. T h e
present report details seven years of such observation
on a patient with verrucae vulgaris that regularly un-
derwent malignant transformation.
Case Report
A 25-year old white woman first came to us in July 1972 for
the treatment of recalcitrant periungual warts of her fingers,
wrist, left fifth toe, and left sole, as well as the entire vulvar
and perianal area. The warts, first noted in the vulvar and
perianal region in 1969, had shown only transient response to
intensive treatment which included topical podophyllin, 5-
fluorouracil, electrodesiccation, systemic vitamin A in large
dosage, and surgical excision.
The patient had massive bilateral lymphedema of the lower
extremities and pubic area, as previously rep01-ted.l~It first
appeared when she was 9, increasing in degree until age 16.
She experienced repeated attacks of cellulitis, on one occa-
sion with septicemia. Reparative surgery on the left leg had
been done on repeated occasions with limited success. There
was no family history of lymphedema, and her husband had
From the Department of Dermatology, University of Pennsylva-
nia School of Medicine, Philadelphia, Pennsylvania.
The patient was referred to the authors by Arthur Randelman, MD.
Gynecologic surgery was performed by John Mikuta, MD, and hos-
pital medical studies were supervised by Robert Mayock, MD, and
Manfred Goldwein, MD.
Accepted for publication July 23, 1980.
no warts. On the left upper arm, she also had a deep 2-cm
scar that followed a violent reaction to vaccination in 1970.
She was admitted to the University of Pennsylvania Hos-
pital for what was to be the first of 13 hospitalizations over
the next seven years. At that time general medical and labo-
ratory studies were within the normal range. A 3-cm plaque
of wart removed from the left sole and a 6-mm wart from the
dorsum of the left hand showed the patterning of verruca vul-
garis. All of the periungual verrucae were removed by curet-
tage. The one from the right middle finger subjected to histo-
logic study showed a vermca with evidence of bowenoid
change (squamous cell in situ). Verrucous lesions excised
from the vulva showed a mixture of condyloma acuminata
and multiple areas of noninvasive squamous cell carcinoma,
possibly arising from preexisting condyloma.
By the end of 1972, medical attention was directed to a
persistent low-grade fever and malaise. A lung biopsy
showed granuloma formation, but not until 1974 was it possi-
ble to culture and identify the causative organism-Myco-
bucterium scrofuluceum -in each of two cervical lymph
node biopsies. By 1976 the infection was disseminate. At lap-
arotomy, nodules were found over the entire small bowel,
omentum, and liver. The lymphatics were grossly dilated and
this had been noted in the lung biopsy as well. Numerous
studies, including lymphocyte transformation response, im-
munoglobulin levels, and skin tests, were done to document
an immune defect but without success.
By 1974 the warts on the vulva had increased to the point
where a vulvectomy had to be done. Study of the excised tis-
sue showed verrucae, focal carcinoma insitu, and microinva-
sive squamous cell carcinoma. Again, numerous dilated lym-
phatics were seen.
The verrucae of the sole and hands did not recur until
1975, at which time liquid nitrogen therapy, as well as topical
retinoic acid, was used without success on subungual verru-

0008-543)</8 I /0801/0820 $0.80 0 American Cancer Society

820
 10970142, 1981, 3, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(19810801)48:3<820::AID-CNCR2820480325>3.0.CO;2-H, Wiley Online Library on [21/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
No. 3 . Shelley and Wood
WARTTRANSFORMATION 82 1

FIG.1. Subungual wart removed with nail plate. Note on the (left) the typical pattern of verruca with dense orthokeratotic scale, thickened
granular layer, and an orderly arrangement of the rete cells. There is an abrupt transition to intraepidermal cancer on the right with parakera-
totic scale, loss of granular layer, and disarray of the rete cells (H & E, X 82).

cae of the thumbs. The fingers at this time were clubbed and
the nail plates yellow.
Further surgery of the thumbs and vulvar and anal areas
was done in 1977 and in 1978. At this time, vaginal and cervi-
cal condylomata were also removed and a diagnosis of mi-
croinvasive squamous cell carcinoma in the presence of ver-
rucae was made.
In February 1979 both the right and left thumb nails again
showed large subungual warts. The nail plates were removed
and radical curettage done on the verrucous tissue of the nail
bed. Histologic study showed epidermal rnultinucleated and
dyskeratotic cells with atypical mitotic figures, as well as bi-
zarre hyperchromatic nuclei in areas in direct contact with
the cells showing the typical changes of a benign verruca vul-
garis (Fig. 1-4). Finally, in April 1979 further vulvar and
perianal condylomas were removed, again showing focal
dysplasia with microinvasive squamous cell carcinoma.
Discussion
Certain types of viral warts of the skin may undergo
malignant transformation into squamous cell carci-
noma so consistently as to be a model for the study of
oncogenesis.8 The prototype for this is the wide-
spread, small, flat, reddish-brown or achromic warts
seen in patients with epidermodysplasia verruci-
formis.6 These lesions due to the specific human papil-
loma virus (HPV, Type 5)9 become squamous cell
epitheliomas, showing the characteristic changes of
Bowen's disease, as well as invasion and metastasis.
The malignant change is a delayed one occurring only
after a period of years, and is always associated with a
disappearance of the viral particles.
Another typical example implicating the human pap-
illoma virus with cancer is the veneral wart or condy-
loma acuminatum.'O Less well studied, but well-
known clinically, is the fact that a small percentage of
veneral warts both large and small may show malig-
nant change. Thus, the recently delineated bowenoid
papules of the penis may have antecedent or asso-
ciated viral warts,'5 or viral particles within the area of
epidermal ~ h a n g e . ~
In sharp contrast, the common wart, the verruca
vulgaris, is considered to be incapable of malignant
transformation.'8 No authentic examples appear in the
literature, although metaplasia and bowenoid change
have been seen but recorded with doubt and reserva-
tion.3 The present patient is the first reported example
of a closely studied patient in whom common warts re-
peatedly underwent malignant change over a period of
years.
Not only did our patient's common viral warts of the
fingers undergo malignant change, the anogenital and
intravaginal, as well as cervical, warts also showed the
same change. We do not have an explanation for her

822 CANCERAugust I 1981
widespead malignant change but an analysis of her
unique medical experience suggests several possibili-
ties.
The first is the role of chronic lymphedema. Primary
lymphedema does favor malignant change as seen in
the associated angiosarcoma. l7 Although gross edema
was evident only on the lower half of the patient's
body, it is likely that the process was universal. This is
supported by the presence of (1) gross lymphangiecta-
sia seen at laparotomy, (2) dilated lymphatics ob-
served on a lung biopsy specimen, and (3) yellow nails,
one of the signs of lymphedema. Significantly, intesti-
nal 1ymphangiectasis has been reported in association
with extensive viral warts and malignant lymphoma,
both possibly related to the cell-mediated immune def-
10970142, 1981, 3, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(19810801)48:3<820::AID-CNCR2820480325>3.0.CO;2-H, Wiley Online Library on [21/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Vol. 48
FIG.2. Higher magnification of transitional area de-
picted in Figure 1. Note the disorganization and atypy
of the cells and their nuclei. A mitotic figure is present
in the left lower quadrant (H & E, x 350).
icit produced by excessive loss of lymphocytes into the
gut.16
A second factor is that of immune deficiency, an ac-
knowledged concomitant of both the unusual exten-
sive viral wart of adult^^^^^'^ and of intraepithelial carci-
noma of the vuiva.13 Our patient had no clear
laboratory evidence of cell-mediated immune defi-
ciency, but clinically she showed poor defense against
diseases that can be immunologically controlled. Her
warts had been exuberant and failed to respond to in-
tensive medical and surgical approaches. Her re-
sponse to vaccination was atypical and severe. Her de-
velopment of a disseminate mycobacterial infection
also speaks for a failing immune system.
A third possibility is that our patient has a specific

No. 3
WARTTRANSFORMATION
FIG. 3. Malignant tissue removed from nail bed.
Note the parakeratotic scale, disorientation of normal
stratification of rete, and presence of vacuolated cells
and cells with highly atypical hyperchromatic nuclei.
Lymphocytes are present in tips of papillae (H & E,
X 88).
oncogenic human papilloma virus. No longer is the
wart virus a singular species, but rather appears in at
least five distinct types. Recent studies suggest HPV
Type 1 is most commonly the cause of plantar warts,
Type 2 with vermca vulgaris, Type 3 with plane juve-
nile warts, and Types 3 and 5 with epidermodysplasia
verruciformis. Type 5 is specifically identified in the
warty lesions of epidermodysplasia verruciformis
which undergo malignant change .s The facilities for
hybridization and immunofluorescent typing of the
papilloma virus were not available to us. Thus the pos-
sibility remains that our patient’s paronychial warts
could be due to HPV 5 or yet another viral type. In this
regard it is significant that the warts on the dorsum on
her hand, as well as the sole, which were readily eradi-
10970142, 1981, 3, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(19810801)48:3<820::AID-CNCR2820480325>3.0.CO;2-H, Wiley Online Library on [21/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
. Shelley and Wood
823
cable, did not show malignant change. Only those per-
sisting in the anogenital region and in the paronychial
sites became malignant. This draws attention to an-
other factor, that of time. The induction of malignant
change may require years of stimulus by the virus.
Although slow-growing and insidious, these squa-
mous cell epitheliomas were not simple histologic
aberrations such as is seen after the application of
podophyllin.2 They were true invasive malignancies
with the potential of metastasis. Whatever their pre-
cise pathogenesis, they suggest that the common wart
may well be one of the antecedents of the squamous
cell carcinomas of many non-actinically damaged
areas such as the nail and the sole (epithelioma
cuniculatum pedis).12

824 CANCERAugust 1 1981
FIG.4. Higher magnification of tissue from nail bed. Note vacuolated cells and variation in size and staining quality of cells and their nuclei
typical of intraepidermal squamous cell cancer of the bowenoid type (H & E , x 130).
Our encounter with this patient has enlarged our
perception of the oncogenic potential of human papil-
loma virus from the special cases of disseminate flat
warts of epidermodysplasia verruciformis and anogen-
ital warts to that of the common wart. To further docu-
ment this role of the HPV, there is need for histologic
monitoring of all unusually persistent and treatment-
resistant warts of adults, as well as those appearing in
immunosuppressed patients, to determine how fre-
quently and under what circumstances the remarkable
malignant conversion we have observed occurs.
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