British Journal of Dermatology 1999; 140, 1148–1152.

Squamous cell carcinoma complicating chronic venous leg

ulceration: a study of the histopathology, course and survival in
25 patients
B.T.BALDURSSON, M-A.HEDBLAD,* H.BEITNER* AND B.LINDELÖF†
Department of Dermatology, Gävle Hospital, 801 87 Gävle, Sweden
*Department of Dermatology, Karolinska Hospital, Stockholm, Sweden
†Department of Dermatology, Danderyd Hospital, Stockholm, Sweden
Accepted for publication 4 December 1998

Summary We have studied 25 cases of squamous cell carcinoma in chronic venous leg ulcers. Twenty-three of
the patients were dead and two were alive. The mean age at cancer diagnosis was 78·5 years. The
median survival was 1 year. Eleven tumours were well-differentiated, 10 moderately and four poorly.
All patients with a poorly differentiated tumour died within a year. Metastases were certain in eight
cases. The disease was lethal in 10 cases which included all poorly differentiated tumours. The
survival of the study group was significantly shortened compared with a control group of patients
with lower limb non-melanoma skin cancer (n ¼ 433) from the Swedish Cancer Registry
(P ¼ 0·0084). When diagnosed, squamous cell carcinoma in chronic leg ulcers merits a thorough
investigation of the degree of differentiation and spread. Assertive treatment is indicated as poorly
differentiated tumours and some moderately differentiated tumours may be fatal.

Key words: Cancer Registry, histopathology, squamous cell carcinoma, survival, venous leg ulceration

We have previously shown a significantly increased risk
of squamous cell carcinoma (SCC) in chronic leg
ulcers.1,2 but did not relate the course of the disease
to histology, spread at diagnosis or outcome. This dis-
ease is rare and, as the carcinomatous growth is prone
to be mistaken for a deterioration of the leg ulcer, it can
go undiagnosed for a long time or evade diagnosis
altogether. To improve our knowledge of this disease we
have retrospectively studied 25 cases of SCC in chronic
leg ulcers, and compared the outcome with a control
group of patients with SCC on the lower extremity from
the Swedish Cancer Registry.
Case reports
Patients who had SCC in venous leg ulcers were
extracted from 10,913 cases of venous leg ulceration
in the Swedish In-patient Registry by matching them
with reported cases of non-melanoma skin cancer
(NMSC) on the lower limb from the Swedish Cancer
Registry. The NMSC group is composed mostly of SCC;
Kaposi’s sarcoma and malignant tumours derived from
Correspondence: Baldur Baldursson.
E-mail: baldur.baldursson@lsgs.lg.se
skin appendices also fall into this category but not in situ
carcinoma nor basal cell carcinoma. A more detailed
description of these registries and patients can be found
in the literature.3–5 By this method 23 cases were
identified as SCC arising in a venous leg ulcer. Two
additional cases of SCC in a venous leg ulcer recently
diagnosed were added to the group. The SCC was
considered to arise from the ulcer when it appeared in
an open ulcer with a duration of 3 years or more (19
cases) or at the site of a remitting relapsing ulcer (six
cases). There were nine men and 16 women. The mean
age at ulcer diagnosis was 56·4 years. Every effort was
made to gather as much information about the patients
as possible from their hospital and general practice
records. Copies of death certificates from the Central
Statistical Bureau were used to ascertain date of death
and registered cause of death, which in five cases was
verified by autopsy. The clinical diagnosis of SCC was
made by dermatologists in 13 cases, surgeons in six
cases and other physicians in six cases.
Materials and methods
Histological slides from the lesions of 22 of the patients
were re-examined by one dermatohistopathologist

1148 q 1999 British Association of Dermatologists

 Table 1. Case reports of 25 patients with squamous cell carcinoma which developed in chronic venous leg ulcers

Age at cancer Ulcer

Patient Histological diagnosis duration Survival
no. differentiation (years) (years) (years) Clinical appearance Case history comments

1 Moderate 68 20 26 Superficial ulcer 3 × 10 Leg ulcers as a child, unknown diagnosis. Tumour

2 Good
3 Good
4 Good
5 Good
6 Moderate
7 Moderate
8 Good
9 Good
10 Good
cm, raised edges excised
82 32 0·2 Ulcer 20 cm in diameter Many biopsies because of non-healing and abnormal
with exophytic tumour appearance. SCC diagnosed in exophytic tumour.
5 × 5 cm Died of circulatory failure after amputation
78 21 3 Ulcer with exophytic Burn injury at 16-years-old. More than five
growth 4 × 4 cm biopsies taken from an ‘abnormal’ ulcer before diagnosis.
Amputated
71 14 15 Exophytic ulcer bed and Deformity of left ankle. A shift
raised margins in a 4 × 3 in ulcer location, ulcer appearance and raised margins
cm ulcer led to biopsy. Excision
81 40 1 A necrotic ulcer covering Two years of relentless ulcer growth and clinical
the whole left lower leg appearance led to biopsy. Amputated
78 7 5 A hyperkeratotic mass at Relapse 2 years after excision and transplantation.
the edge of an ulcer Cured by amputation
95 20 0·2 Non-healing ulcers Because of patient’s age and mental status conservative
covering the whole treatment was chosen. Died two months latera
lower legs bilaterally
67 11 15 Very irregular ulcer, Non-radical excision led to amputation. Died of lung
8 × 13 cm metastases of unknown origin
76 9 20 Ulcer 10 × 15 cm with an Six months before diagnosis an exophytic mass in an
exophytic mass proximal ulcer rapidly deteriorating for 1 year. Excised and re-exised,
metastatic inguinal lymph node removal
67 29 3 Ulcer 8 × 10 cm filled Many biopsies after an ulcer ‘healed’ with a verrucous surface.
with verrucous material Diagnosis after an excision of the ulcer. Radiation therapy of

q 1999 British Association of Dermatologists, British Journal of Dermatology, 140, 1148–1152

recurrence failed, and amputation was performed
11 Good 104 33 – Ulcer 10 × 3 cm with a A recalcitrant ulcer slowly growing larger. Suspicion of
central exophytic growth cancer but surgery refused by patient. Diagnosed at autopsy
12 Good 70 39 8 Ulcers 18 × 10 and Deterioration of the bilateral ulcers for 4 years.
5 × 3 cm with irregularities Radiation treatment, but widespread necroses led to
in the ulcer bed amputation. Non-healing ulcer on the remaining leg. Alive
1997
13 Poor 92 10 1 Ulcer 20 × 20 cm Treated with radiation. Amputation because of
with irregularities recurrence. Died of abdominal metastasesa
14 Poor 69 32 0·4 An exophytic growth 6 cm An ankle deformity and a recurring ulcer, biopsied because of
in diameter in a leg ulcer tumour. Amputated, died of pelvic and lung metastases.
Autopsy was performeda
15 Moderate 80 5 0·1 Voluminous ‘granulations’ Had a large inguinal metastasisa
SQUAMOUS CELL CARCINOMA AND LEG ULCERATION

in ulcer
16 Moderate 61 10 2 Ulcer 9 × 4 cm Burn injury in childhood. Treated with excision, amputation
and hip exarticulationa
1149
 Table 1. Continued
1150

Age at cancer Ulcer

Patient Histological diagnosis duration Survival
no. differentiation (years) (years) (years) Clinical appearance Case history comments

17 Moderate 60 4 21 Ulcers 9 × 4 cm with Treated with arsenic and ultraviolet irradiation in her thirties
verrucous margins for psoriasis. Radiation treatment left large life-long ulcers
18 Moderate 93 50 0·3 Voluminous growths in a The patient died before decision on treatment had been reacheda
very large ulcer
19 Moderate 93 23 0·9 Circumferential ulcer with Tumour growing in ulcer for half a year. Died 10 months
a 4-cm tumour later. Refused treatmenta
20 Good 77 40 6 A necrotic ulcer, 10 × 10 Repeated biopsies because of the ulcer ‘eating itself ’
cm, with raised margins through fibula. Amputated
B.T.BALDURSSON et al.

21 Moderate 82 10 3 Ulcer 12 × 12 cm Amputated. Died 2 years later due to carcinoma of the

with irregularities bladder
22 Poor 85 41 0·9 An exophytic tumour Excision. Inguinal metastases operated. Died of carcinosis
in ulcer 10 × 10 cm of the lungsa
23 Moderate 70 3 1 Ulcer 8 × 5 cm with Arsenic treatment for a dermatological condition
raised margins. Palpable 15 years earlier. Treated with excision, inguinal exploration
inguinal mass and radiation. Died of abdominal metastasesa
24 Good 78 40 2 Thickened edges in an Excised and re-excised after a recurrence. Second local
otherwise regular ulcer recurrence after 3 years follow-up
10 × 10 cm, recurrence
verrucous
25 Poor 86 76 0·3 Chronic ulcer with a Excision and transplantation. Necrotic inguinal metastases.
rapid central exophytic Rapid local recurrence. Refused further surgerya
growth

a
Lethal disease; SCC, squamous cell carcinoma.

q 1999 British Association of Dermatologists, British Journal of Dermatology, 140, 1148–1152

 SQUAMOUS CELL CARCINOMA AND LEG ULCERATION
(M-A.H), and classified as well, moderately or poorly
differentiated SCC in relation to the proportion of
mature, differentiated cells present in the tumour and
the degree of keratinization. In well-differentiated
tumours more than 75% of the cells were differentiated,
and in poorly differentiated, fewer than 25%. The
tumour was considered moderately differentiated if the
proportion was 25–75%. Classification on the basis of
depth, patterns of invasion or perineural invasion was
not possible because of the small size of many of the
biopsies.6
A survival control group was configured by obtaining
data on all patients diagnosed with NMSC of the lower
limb in the period 1970–78 from the Swedish Cancer
Registry. To get a similar age structure, only cases
diagnosed after 65 years of age were included, giving a
control group of 433 patients, 229 men and 204
women, with a mean age of 77·7 years at diagnosis of
NMSC vs. 78·5 years mean age of the study group. Of
the 433 controls, 18 were still alive at the end of 1995,
the last year on line. In the statistical calculations, 1996
was therefore used as their year of death. Non-
parametric tests were used on the material as it did
not appear to be normally distributed. The Mann–
Whitney test7 was used to estimate the significance of
difference in survival between the study and control
groups. Fisher’s exact test7 was used to test the differ-
ence in lethality between the different tumour groups. A
sample of 44 patients from the control group was taken
to compare the proportion of the different degrees of
differentiation by studying their histopathological
reports; the binomial hypothesis test was used.7
Results
A synopsis of the case reports is presented in Table 1.
Twenty-three patients were dead and two alive. The
mean age at cancer diagnosis was 78·5 years. The
median survival was 1·0 year. Of the tumours, 11
were well-differentiated, 10 moderately and four
poorly. Metastases were identified in eight cases, local
in one, in the inguinal nodes in four and distant in
three. Two patients had been treated with arsenic for
dermatological conditions (patients 17 and 23), and
two had suffered a burn injury in childhood (patients 3
and 16).
Survival of the study group (median 1 year) was
significantly shorter than that of the control group
(median 5 years) (P ¼ 0·0084). All patients with a
poorly differentiated tumour died within 1 year from
diagnosis. Ten patients probably died due to SCC
q 1999 British Association of Dermatologists, British Journal of Dermatology, 140, 1148–1152
1151
(marked ‘a’ in Table 1). In six cases (patients 13, 15,
16, 22, 23 and 25) it was an obvious chain of events
with spreading disease. In one case (patient 14) an
autopsy diagnosis was made, and in three cases
(patients 7, 18 and 19) death took place less than
year after diagnosis, with no other known cause of
death. All four patients with poorly differentiated SCC
died of their cancer; the remaining six in the group with
lethal disease had a moderately differentiated SCC. The
difference in lethality between poorly differentiated and
other degrees of differentiation was significant
(P ¼ 0·017). The difference between well-differentiated
and other degrees of differentiation was also significant
(P ¼ 0·0005). The proportions of the different degrees of
differentiation in the leg ulcer SCC cases were not
statistically different from those in a group of 44 non-
leg ulcer SCC cases: well-differentiated, 44% in the leg
ulcer group vs. 64% in the non-leg ulcer group; mod-
erately differentiated, 40% vs. 20%; poorly differen-
tiated, 16% vs. 16%.
Discussion
The worse prognosis of less well-differentiated tumours,
even though based on few cases, should prompt a
thorough evaluation of the histological differentiation
and the clinical aggressiveness of the tumour when a
diagnosis of SCC in a chronic ulcer is made. The
advanced stage of disease at which many of the patients
were diagnosed indicates that the cancer had been
present for a long time. This is a consequence of the
clinical appearance of this disease, hiding in an ulcer.
An increased level of suspicion is therefore justified and
the difficulty in distinguishing well-differentiated SCC
from pseudoepitheliomatous hyperplasia must be recog-
nized.8 The short survival of the study group further
underlines the significance of early diagnosis. The
theory of deterioration towards a lower grade of differ-
entiation because of delay in diagnosis was not sub-
stantiated by comparing the study group and the
histopathological reports of the control group from the
Cancer Registry. The proportion of poorly differentiated
tumours was similar in both groups. There seems to be
no correlation between clinical presentation and differ-
entiation. A ‘fungus like’ appearance described in the
records in most of the exophytic tumours might repre-
sent the keratin present in the tumour that, swelling
and whitening in the wet conditions of the ulcer, looks
similar to a vegetative growth.
Comparison of the different treatments with regard to
survival is not feasible as the stage of the disease is a
1152 B.T.BALDURSSON et al.
confounding factor. One would expect more radical
treatments in patients with extensive disease and a
worse prognosis. Therefore, no statistical analysis is
attempted. However, the experience from this material
indicates that in well-differentiated tumours, excision
seems to be an appropriate treatment. Considering the
high rates of recurrence and re-excision, either a large
margin is necessary or the operation should be done
with Mohs’ surgery. Whether or not the wound is
covered by skin grafting, careful controls for local and
nodal recurrences are important. As all the patients
with poorly differentiated tumours and some with mod-
erately differentiated tumours had a very aggressive
disease, an attempt should be made to judge the clinical
and histological aggressiveness. As the risk for metas-
tases and death seems increased, assertive treatment
such as amputation might be indicated.
Radiation treatment should probably not be consid-
ered, not even as a palliative treatment. In this group of
patients it left a chronic wound and did not effectively
eradicate the tumour growth. Black came to the same
conclusion. Of four patients treated with radiation in his
series, three had to have amputation.9 Many SCCs in
chronic ulcers probably go undiagnosed for a length of
time and might conceivably be lethal without a diag-
nosis being made. Biopsies to exclude cancer should be
considered in non-healing, deteriorating or atypical
ulcers. Careful evaluation of the histological and clinical
aggressiveness of an SCC when diagnosed is a prerequi-
site for successful treatment where surgical measures,
excision or amputation should be used. Radiological
treatment is seldom indicated. The role of previous
q 1999 British Association of Dermatologists, British Journal of Dermatology, 140, 1148–1152
topical or systemic carcinogens is uncertain in this
series of cases but awareness of the cancer risk in
chronic ulcers suggests caution when trying as reme-
dies substances with uncertain potential, such as the
different growth factors.
Acknowledgments
This work has been supported by grants from The
Research and Development Forum, Gävle Hospital and
The Finsen-Welander Foundation, Stockholm. Mrs
Carol Scinto helped with the English language.
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