ARTICLE
Auteur(s) : Laura
Eibenschutz, Samantha Marenda, PierLuigi Buccini, Paola De
Simone, Angela Ferrari, Giustino Mariani, Vitaliano Silipo,
Caterina Catricalà
Department of Dermatology-Oncology, S Gallicano Dermatological
Institute, Via Elio Chianesi, Rome, Italy
accepté le 18 Juillet 2008
Basal cell carcinoma is the most common malignancy in the
Caucasian population, frequently appearing as a small lesion
(< 1 cm in diameter), located on the trunk in 10% and
on the head and on the neck in 80-85% of cases. In a small subset
of patients (< 1%) large manifestations may cause extensive
local invasion and disfigurement representing a therapeutic
challenge [1]. In most cases, the size of the tumour is consistent
with the duration of the growth, and the time of onset of larger
BCC lesions is usually earlier than that of smaller ones. The
criteria for the definition of giant BCC vary, but according to the
International Union Against Cancer Classification (UICC) [2], it is
considered if the greatest dimension is 5 cm or more (T3),
whereas T2 are classified tumours with a dimension > 2 <
5 cm. Characteristics commonly found in giant BCC are the
duration of neglect by the patient, the recurrence after previous
treatments and the history of radiation exposure [3].
In addition, large or giant BCC, which may be located in
high-risk areas or develop in patients with a poor general
condition, require an alternative treatment to surgery. In the
past, according to the literature, giant BCC were treated only with
radiotherapy, although the growth of the neoplasm, when relapsing
after radiation therapy, tends to be larger and more invasive than
other recurrent BCC lesions [4].
In 26 European countries, Australia and New Zealand, the use of
photodynamic therapy with methyl aminiolevulinate (MAL-PDT) is
currently approved in actinic keratosis and non melanoma skin
cancer (superficial BCC, small nodular BCC and Bowen’s disease)
[5].
Due to the efficacy, tolerability, cosmetic outcome and patient
satisfaction, topical PDT is considered a first-line treatment
(rating AI) in actinic keratosis, Bowen disease and superficial
BCC, even for large and multiple lesions [6-8], however, despite
such evidence, only a few reports on large BCC treated with topical
PDT exist.
In this paper we present a retrospective non-comparative
follow-up study to evaluate the response of giant and large BCC
treated with MAL-PDT.
Materials and methods
Patients and lesions
From February 2003 to February 2007 we treated 17 patients, 10 men
and 7 women, with an average age of 71 years, ranging from 56 to
92, with 19 BCCs with a diameter over 4 cm which had been
developing in most cases since 7 years. The inclusion criteria were
that only patients who had not received treatment in the last 6
months were included, patients with Gorlin’s syndrome, xeroderma
pigmentosum or porphyria, or patients who had received
immunosuppressive treatment before or after MAL-PDT were excluded.
During the treatment and follow-up period the use of concomitant
topical medication was not allowed. Seventy per cent of the
patients were in poor general condition (bleeding abnormalities,
anticoagulant therapy, cardiac risk factors, pacemaker carriers and
lymphoproliferative diseases), where surgery would have been a
risk.
The clinical characteristic of the lesions were: 17 (89%)
superficial BCC, 1 (5%) nodular BCC and 1 (5%) mixed BCC; five of
them (26%) were on the scalp, 8 (42%) were located on the face, 4
(21%) on the trunk and 2 (11%) on the extremities. In particular,
13 lesions (68%) were located in “difficult-to-treat” areas (i.e.
the central part of the face, the ear and severely sun-damaged
areas), and 3 patients (15.7%) had recurrent lesions, which had
developed after other previous treatments: one patient underwent
previous surgery, whereas two patients underwent many cryotherapy
sessions.
The histological evaluation of the lesions, made before
treatment, did not show an aggressive pattern, with no perineural
involvement in any case. Fourteen lesions were T3 and 5 were T2
according to the UICC classification [2] and the average level of
invasion was 0.6 mm (ranging from 0.2 to 4 mm).
Photographic documentation was taken for every lesion, before and
after the treatment, and during the follow-up.
Treatment procedure
Before treatment, every lesion was prepared to facilitate the
penetration of the cream into the tissue by removing any crusts,
and by a debulking procedure, using a surgical curette for the
nodular lesion, taking care not to cause possible bleeding. MAL
160 mg cream (Metvix®) was applied to the prepared
lesions and to a 5 mm-wide surrounding area to capture any
subclinical extension, and the whole area was then covered with an
adhesive occlusive dressing. After 3 hours the dressing was removed
and the lesion area exposed to Wood light to perform fluorescence
diagnosis (PDD), and then to a non-coherent red light with an
emission spectrum of 630 nm, light dose
75 J cm–2 (Aktilite®); the
illumination time was automatically calculated, according to the
light intensity and the light dose. The patients were treated with
a PDT cycle, comprising 4 sessions of PDT every two weeks and, in
case of clinical evidence of the disease, a second cycle was
repeated 3 months later, as previously reported for
“difficult-to-treat” BCC [9, 10].
Follow-up, clinical and cosmetic evaluation
The initial cure rate was evaluated six months after the last
MAL-PDT session, stating CR (complete disappearance of the tumour),
PR (partial remission of the tumour) or NR (no response), and the
follow-up was performed at 12 and 36 months after the end of the
treatment, taking into account the percentage of CR or recurrence
and the cosmetic outcome only. To evaluate the presence, the
localisation and the extension of either persistent or recurrent
tumoral tissue, PDD was repeated on all the lesions at 6, 12 and 36
months after the last treatment, showing whether neoplastic tissue
was still present, sharply demarcated, red fluorescent areas on a
weakly fluorescent background.
Either a biopsy or a cytological examination was performed when
the clinical clearance was difficult to evaluate, or in case of a
suspected recurrence. However, due to the size of the lesions, and
the poor condition of the patients, in some cases a biopsy could
not be performed.
The cosmetic outcome was assessed according to scar development,
atrophy, depigmentation and redness, by both the examiner and the
patients, at 6 and 36 months and was rated “excellent” when the
lesion area was not visible and “good” when a slightly visible
scarring, redness or depigmentation were present.
Results
Response to the treatment
Altogether, 19 lesions were treated with MAL-PDT; eleven with 1
cycle and 8 with 2 cycles and in 16 out of 17 patients the follow
up was at least at 36 months. A complete response (CR) was observed
in 18 lesions (95%) at 6 months in 13 (68.4%) at 12 months and in
10 (52.6%) at 36 months, with an overall long-term cure rate of
66%, ranging from 39% for giant BCC to 100% for lesions sized
4-5 cm. Due to the difficulty in evaluating the clinical
response, in five lesions biopsies were performed at 6 months, all
resulting negative. A partial response (PR), confirmed by PDD
evaluation, was observed at six months in a patient with a mixed
BCC (6 × 4 cm in size) localized in the retro-auricular area
with the resolution of the lesion in the superficial part and
persistence in the nodular area thicker than 3 mm, which was
surgically excised.
In total, 8 out of 18 successfully treated lesions recurred
after MAL-PDT, 5 of which (28%) at 12 months and 3 (23%) at 36
months, all giant BCC (table 1, figure 1); the
punch-biopsy performed before the treatment revealed a thickness in
these lesions ranging between 0.6 and 0.8 mm. Two of the
recurrent BCC had been previously treated with several cryotherapy
applications during which the lesions had enlarged, whereas after
PDT the recurrences were always localized within the original area,
appearing as small foci, and none of them had spread out (figures 2A, B, C).
All the recurrences were confirmed by PDD.
The degree of pain and discomfort referred by the patients
during the treatment was mild in 45% and severe in 55% of the
cases, consistent with the extension of the lesion and located in
the treated area; in just a few cases, the pain persisted on the
following day. However, no patients discontinued the treatment, nor
asked for anaesthesia as, after cooling the lesions with a water
spray or by pausing the light for few minutes, the pain could be
sufficiently soothed. No systemic adverse effects were noted and
most of the reactions observed, such as erythema, oedema and
crusting, were mild in severity and ended within 2 weeks after the
session.
Table 1 Patient details, characteristics of lesions and
recurrences
|
Patient
|
Sex
|
Age
|
Lesion
|
Location
|
Size of BCC
|
Time of recurrence
|
|
1
|
C.L.
|
M
|
82
|
sBCC
|
Trunk
|
6.5 × 5
|
|
|
2
|
R.M.
|
F
|
79
|
sBCC
|
Leg
|
5.5 × 2
|
|
|
3
|
B.S.
|
M
|
62
|
sBCC
|
Arm
|
5.5 × 4.5
|
|
|
4
|
C.L.
|
M
|
82
|
sBCC
|
Zygoma
|
5 × 4
|
12 months
|
|
5
|
L.L.
|
M
|
70
|
sBCC
|
Temple
|
6 × 8
|
36 months
|
|
sBCC
|
Scalp
|
7 × 12
|
12 months
|
|
sBCC
|
Scalp
|
6 × 7
|
12 months
|
|
6
|
M.A.
|
F
|
74
|
sBCC
|
Zygoma + nose
|
6 × 7
|
36 months
|
|
7
|
P.F.
|
F
|
72
|
mBCC
|
Trunk
|
5 × 4
|
12 months
|
|
8
|
T.A.
|
M
|
76
|
sBCC
|
Scalp
|
6 × 8
|
|
|
9
|
S.V.
|
F
|
82
|
sBCC
|
Trunk
|
6 × 9
|
|
|
10
|
Z.F.
|
M
|
48
|
sBCC
|
Trunk
|
6 × 9
|
12 months
|
|
11
|
B.L.
|
M
|
81
|
sBCC
|
Forehead
|
5 × 3
|
36 months
|
|
12
|
C.M.
|
M
|
74
|
sBCC
|
Auricular
|
4 × 3
|
|
|
13
|
M.C.
|
F
|
55
|
sBCC
|
Zygoma
|
4 × 3.5
|
|
|
14
|
L.S.
|
M
|
46
|
sBCC
|
Scalp
|
4 × 4
|
|
|
15
|
T.B
|
M
|
76
|
sBCC
|
Forehead
|
3 × 4
|
|
|
16
|
M.A.
|
F
|
92
|
nBCC
|
Forehead
|
4 × 3
|
|
Cosmetic outcome
The investigators considered the cosmetic outcome excellent in 5
cases (27%) and good in 13 cases (73%) at 6 months, and excellent
in 35% and good in 65% at 36 months; cosmesis was considered
excellent by 50% of patients at 6 months and by 65% at 36 months.
Discussion
Treatment of giant BCC poses a great challenge even because only a
few reports have been published [11, 12]. Our results demonstrate
that MAL-PDT can be used for the treatment of giant and large BCC,
with a significant percentage of resolution, a low rate of
complications and the additional advantage of a good cosmesis. With
regard to the treatment procedure, we decided to repeat more than
two sessions of PDT in the same cycle because of the large
dimension of the lesions; for the same reason we chose an interval
of 2 weeks between the sessions to ensure a good healing.
The overall long-term cure rate of our study was 66% with a rate
of 100% for lesions measuring 4 to 5 cm, when the percentage
reported in the literature, regardless of size and localisation, is
about 79% at 24-48 months [13].
All the recurrent cases, previously giant BCC, with an average
size of 6.8 cm, appeared as small foci within the context of
the original lesions, and never developed beyond their boundaries.
None of these recurrencies showed an aggressive course and
treatments less invasive than radiotherapy were performed. Four out
of eight of our patients underwent other MAL-PDT sessions, 2 out of
8 underwent surgical excision of the recurrent foci, while 2 out of
8 received topical therapy with imiquimod. Also, concerning the
mixed BCC showing a partial response, the treatment with PDT
induced a significant decrease of the tumour size, allowing less
invasive surgery. In the past, according to the literature, the
only treatment for giant BCC was radiotherapy, despite the trend of
the relapsing neoplasm’s growth to be larger and more invasive than
other recurrent BCC lesions [4].
Vinciullo et al. demonstrated that MAL-PDT is a promising
alternative for difficult-to-treat BCC, with a CR of 89% at 3
months, 84% at 12 months and 78% at 24 months [9]. Horn et al.
showed similar results for BCC at risk of complication due to the
tumour’s size, its location or the poor condition of the patient
[10].
In our study all the lesions treated represented a great
therapeutic challenge, due to the size of the lesions, the age and
the general condition of the patients and the risk of
complications, disfigurement and recurrences. Even if several
therapeutical options can be considered, including excision,
cryotherapy, curettage or radiotherapy [14, 15], all these may be
less satisfactory, particularly when the tumour is located on the
face and on the scalp [16, 17].
One of the main problems related to the treatment of large BCC
is the persistence of focal lesions with the risk of recurrence,
which increases according to the diameter of the tumour together
with the poor cosmetic outcome. The 5 year recurrence rate after
excision of primary BCC of the head is reported to be 3.2% for
lesions smaller than 0.5 cm, 8% for lesions 0.6 cm to
1 cm and 9% for lesions larger than 1 cm. BCC larger than
2 cm treated by electrodessication and curettage had a 5 year
recurrence rate higher than 26% [18]. Moreover, when adopting
either a surgical approach or radiation therapy, the treatment
cannot be repeated, due to the scarring and fibrosis developed in
the tissues and to the risk of cancerogenesis entailed by the
exposition to a high dose of radiation.
Our series of giant BCC clinical evaluation and PDD analysis
showed a recurrence rate of 28%, mostly appearing at twelve months.
A biopsy was not perfomed in all cases because of the small size of
the recurrence and its multifocality, compared to the large size of
the original lesions. Conversely, PDD represented a useful
diagnostic procedure for evaluating recurrences even if the depth
of PDD penetration can be considered the threshold of this tool. In
most of our cases, both the investigator and the patients graded
the cosmetic results as good or excellent, similar to those
reported by Horn et al. [10].
In our experience, MAL-PDT has proved to be an effective and
selective treatment, able to achieve good results with low risks,
fast healing and good patient tolerability. Considering the size
and the location of the lesions, this technique can be an effective
tool for the treatment of giant BCC, particularly in patients with
a high risk of surgical complications.
Acknowledgements
Financial support: none. Conflict of interest: none.
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