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May 2021 Volume 5 Issue 3

IN-DEPTH REVIEW

Verrucous Carcinoma Arising Secondary to Diabetic Foot Lesions:
A Systematic Review of the Literature

Kayla Neville, MS1, Aleksandar Obradovic, MPhil2,3

1New York College of Podiatric Medicine, New York, NY
2Department of Systems Biology, Columbia University Irving Medical Center, New York, NY
3Columbia University Center for Translational Immunology, New York, NY

Diabetic foot ulcers are a common
complication of chronic uncontrolled
diabetes, and the lifetime incidence of foot
ulcers is estimated to affect 19% to 34% of
people with diabetes.1 Diabetic foot
ulceration is often complicated by other
diabetic symptoms, including severe
peripheral neuropathy, peripheral arterial
disease, and systemic immunosuppression.2
Foot ulcers place patients at significant risk
of infection, as more than half of ulcers
become infected,3 potentially leading to
sepsis or lower limb amputation in
approximately 20% of moderate or severe
diabetic foot infections.1,4,5 Therefore,

management of chronic diabetic foot ulcers
comprises represents a significant area of
concern in primary care of diabetic patients.

A rare and often unappreciated sequelae of
diabetic foot ulceration is malignant
transformation resulting in verrucous
carcinoma. Verrucous carcinoma is
classically considered a variant of squamous
cell carcinoma, which forms painful lesions
marked by an exophytic appearance, with
deep invasion into local underlying
structures.6,7 Ackerman first described
verrucous carcinoma in the oral cavity,
associated with chewing tobacco,7 and
verrucous carcinoma of the oral cavity has
been so closely associated with the use of
snuff and chewing tobacco that is has been

ABSTRACT

Verrucous carcinoma is classically considered a variant of squamous cell carcinoma, most commonly
occurring in the oral cavity in association with snuff and chewed tobacco. However, the association
between verrucous carcinoma of the foot and diabetes is less well known. This study presents a
systematic review of all articles containing the search term “verrucous carcinoma” and “diabetic foot
ulcer” in the abstract or title that have been published in PubMed before September 2020. The
requirement for inclusion in our report were that the patient data had been documented in a case‐
related manner and the patient diagnosed with verrucous carcinoma secondary to diabetic foot lesion.
Seven descriptions of verrucous carcinoma presenting in patients with diabetic foot ulcers were
presented across six case reports, and clinical case descriptions are collected here along with
treatment outcomes, where available, and discussion of common mimics of verrucous carcinoma of
the foot. Due to treatability and potential for extensive invasion of local structures requiring resection
with wide margins, verrucous carcinoma should be carefully considered in the differential diagnosis of
a warty foot lesion in the setting of the diabetic foot.

INTRODUCTION

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called the “snuff dipper’s cancer”.8 However,
verrucous carcinoma has been reported to
arise outside of the oral cavity in the larynx,
the genitalia, and the foot.9 The association
between verrucous carcinoma of the foot
and diabetes is less well known.

Here we have conducted a systematic
review of literature describing verrucous
carcinoma developing secondary to a
diabetic foot ulcer. This is an important item
on differential diagnosis of dermatologic
deformity secondary to diabetic foot
ulceration, particularly as the warty
appearance of these carcinomas may mimic
more common foot pathology. Verrucous
carcinoma, when diagnosed early, is
treatable, but any delay in treatment may
increase the degree of local invasion, and it
therefore should not be overlooked as a
diagnosis. This article represents the most
comprehensive review to date of published
cases describing verrucous carcinoma
arising secondary to diabetic foot ulcers, and
provides important insights into the
presentation and management of this rare
complication of diabetes.

We retrieved all articles containing the
search term “verrucous carcinoma” and
“diabetic foot ulcer” in the abstract or title
that had been published in PubMed
(www.pubmed.com) before September
2020. Until that time, there had been no
systematic reviews or meta-analyses
analyzed following PRISMA guidelines.10
Sixteen publications were analyzed in more
detail, of which six met the requirements to
be included in our review. The selection was
made by two authors (KN and AO). There
were no discrepancies in the lists of articles
selected by the two authors. The
requirement for inclusion in our report were

that the patient data had been documented
in a case‐related manner and the patient
diagnosed with verrucous carcinoma
secondary to diabetic foot lesion. One case
of carcinoma cuniculatum11 and one case of
Ackerman carcinoma12 were included in our
analysis, as these are classified as alternate
names for verrucous carcinoma.6 One case
report13 included two separate cases of
verrucous carcinoma secondary to diabetic
ulcer in the same patient, for a total of seven
such cases across six case reports. Finally,
we did not include articles that described
patients with different disorders such as
verrucous skin lesions, verrucous
hyperplasia, etc. that were not verrucous
carcinoma. Data collected included gender,
age at the time of diagnosis, comorbidities,
lesion location and size, lesion duration prior
to verrucous carcinoma diagnosis,
histological and gross pathological features,
treatment approach, and recurrence status.
A quantitative meta‐analysis of outcomes to
treatment was not possible based on the
limited number of total reported cases in the
literature and variations in longitudinal
follow-up.

Diabetes History
Patients included both men11,14,15,16 and
women,12,13 with ages ranging from 44 to 72
years old (Table 1). Across the six reported
cases, all patients had a past history of
diabetic foot ulcers followed by
histopathological confirmed diagnosis of
verrucous carcinoma arising in the region of
the ulcer. Only two of six studies reported
HbA1c as an objective metric of diabetes
control (Case 1 HbA1c = 5.9%12, Case 3
HbA1c=7.7%14). Cases did not uniformly
describe the severity of diabetes, though 5/6
cases specify that the patient’s diabetes was
poorly controlled with several diabetic

METHODS RESULTS

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Table 1. Summary of Patient Characteristics.

Demographics Diabetes History Lesion
location

Lesion
duration

Treatment
Approach

Recurrence

Case 1:
Dörr et al.

72 y/o female peripheral artery
disease, neuropathy,
stage G3bA2
nephropathy, previous
partial amputations and
revascularizations of the
foot

R Medial
foot

8 years -Primary tumor
excision
-Second resection
with tumor free
margins
-Split-skin graft
and negative
pressure wound
therapy

No long-term
follow-up

Case 2:
Di Palma
et al.

44 y/o female uncontrolled type 2
diabetes with severe
peripheral neuropathy in
both feet

R Plantar
1st MTP

L Plantar
5th MTP

~1 year

~5
months

-Primary wide
excision

-Secondary Mohs
resection

-Mohs resection

Recurrence at
14 months,
no longer-
term follow-up

No long-term
follow-up

Case 3:
Priesand
et al.

62 y/o male type 1 diabetes,
neuropathy with renal
insufficiency,
hypertension,
hyperlipidemia, diabetic
retinopathy, multiple
digital amputations

L Plantar
1st MTP

1 month -Wide excision
with tumor-free
margins
-Partial first ray
and hallux
amputation

No long-term
follow-up

Case 4:
Nakamura
et al.

66 y/o male insulin-dependent
diabetes, neuropathy

R sole 6 years -Excision with 1
cm margin

No
recurrence at
12 months

Case 5:
Penera et
al.

44 y/o male uncontrolled type 2
diabetes

R Dorsal
1st MTP

1 year -Wide excision
-Full thickness skin
graft

No
recurrence at
12 months

Case 6:
Lozzi et
al.

72 y/o male 15-year history of
diabetes mellitus

R sole

6 years -Tumor Excision No
recurrence at
36 months

complications including: diabetic neuropathy
(n=4), kidney manifestations (n=2), and
previous partial amputations (n=2). Table 1
lists the complications detailed in each case.
No patients were described as having a
history of cutaneous malignant tumors or
other predisposing risk factors, with the
exception of Case 1 who admitted to
smoking, nor were they described as taking
any immunosuppressive medications (i.e.
steroids, chemotherapy, etc).

Presentation and Timeline
Carcinomatous lesions arose from foot
ulcers ranging in size from 1 to 7cm in width,

all occurring in the forefoot. Patient ulcers
had a peripheral hyperkeratotic border with
subsequent wart or cauliflower-like
transformation. Malodorous secretions were
described in several cases,12,13,16 although
one case specifically noted a lack of
malodor or drainage.14 Verrucous carcinoma
was diagnosed over a very short or long
period following initial ulcer development,
presenting in a range from 1 month14 to 8
years.12 Only a single patient13 reported pain
in the lesion, with the rest reporting painless
presentation throughout the disease course,
a finding which may be explained by
concurrent peripheral neuropathy. Case 3

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illustrates that it is possible for verrucous
carcinoma to develop even after a
previously active ulcer is considered healed
and closed, as carcinomatous
transformation in this patient was noted at
the 1 month follow up appointment post
wound closure.14 Presentation was primarily
unilateral, with the exception of a single
patient who developed carcinomatous
transformation in an ulcer of the left foot
after previous transformation and treatment
of a verrucous carcinoma arising from an
ulcer of the right foot.13

Diagnosis and Treatment
Verrucous carcinoma significantly overlaps
in presentation with common foot
dermatopathology, and was misdiagnosed
as a straightforward diabetic foot ulcer
(Cases 1, 2, 3, 5), verrucous skin lesions on
the feet in the setting of diabetic neuropathy
(Case 4), and plantar wart (Case 6).
However, wound debridement and
cryotherapy were ineffective in treatment of
verrucous carcinoma. Lesions were
diagnosed following biopsy, and definitive
surgical treatment included excision of the
lesion with tumor-free margins, curative in
five of the six clinical cases, with varying
length of follow-up. However, Case 2
experienced recurrence of the lesion 14
months after primary excision, and thus a
Mohs surgery was performed on the
recurrent lesion and as primary treatment for
the subsequent verrucous carcinoma
observed on the contralateral foot in that
patient.

This article presents a comprehensive
review of the literature to date describing
malignant transformation of diabetic foot
ulcers into verrucous carcinoma, and
provides important insights into the

presentation and treatment of this rare
diabetic complication. To date, descriptions
of verrucous carcinoma in the literature have
been sparse and potentially misleading in
the context of diabetes, describing a classic
clinical presentation of painful ulcers most
often localized in the throat.6,7,8 Cases of
chronic diabetic foot ulcers resulting in
verrucous carcinoma of the foot are
comparatively under-appreciated. Further
study of this transformation is needed to
determine molecular drivers and predictors
of cancer development among patients, and
we have collected here the clinical
information on these cases available to date.
Critically, we find that among 6 described
cases of diabetic foot ulcer resulting in
verrucous carcinoma, only a single patient
reported pain in the area of the lesion.
Therefore, concurrent diabetic neuropathy
effectively disguises the typical presentation
of this carcinoma. Instead, reported cases
describe warty or cauliflower like lesions
arising over months to years following
development of diabetic foot ulcers with no
associated pain. This presentation mimics a
range of more common dermatological
diagnoses including plantar warts. However,
it is unresponsive to the first-line treatments
for these more benign diagnoses including
cryotherapy and wound debridement.

Clinically, patients presenting with warty
lesions in the setting of chronic diabetic foot
ulcers and refractory to repeated first-line
plantar wart treatment should be promptly
biopsied for pathological assessment of
verrucous carcinoma as a “do-not-miss”
diagnosis. Reports suggest effectiveness of
surgical intervention in such cases, with 5
out of 6 patients cured by total excision of
the lesion with tumor-free margins. A single
patient required Mohs surgery for curative
treatment, which was subsequently applied
in the first line on a recurrent tumor in the
contralateral foot, but the relative rarity of

DISCUSSION

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this presentation is difficult to assess from
the extent of current literature.

Increased awareness of verrucous
carcinoma as a consequence of diabetic
ulceration will result in larger cohorts of
reported patients and their response to
varying treatment approaches, enabling
more comprehensive assessment of
excision vs. Mohs surgery as a first line
surgical approach. Most importantly,
physicians should strongly consider the
possibility of malignant transformation in
chronic diabetic foot ulcers as a mimic of
more benign foot pathology in any
treatment-refractory cases, since surgical
therapy appears effective, and early
intervention in these cases may greatly
reduce the degree of local tissue invasion
and subsequent post-surgical morbidity.

Conflict of Interest Disclosures: None

Funding: None

Corresponding Author:
Kayla Neville, MS
New York College of Podiatric Medicine
53 E 124th St, New York, NY 10035
Phone: 631-456-9961
Email: kneville2023@nycpm.edu

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