Current developments and uses of cryosurgery in the

Current developments and uses of cryosurgery in the
treatment of keloids and hypertrophic scars
CHRISTOS C. ZOUBOULIS, DrMed; EFTICHIA ZOURIDAKI, DrMed; ALINA ROSENBERGER, DrMed;
ANNETTE DALKOWSKI, DrMed
Cryosurgery is currently regarded as the treatment of
choice for keloids and hypertrophic scars. Four techniques are established or currently under evaluation in
this area. The first is cryosurgery as monotherapy. Using
this regimen, 241 of 356 patients (68%) with keloids and
72 of 89 patients with hypertrophic scars (81%), showed
a greater than 50% improvement or complete regression
(five studies). Using the second technique, cryosurgery
with intralesional corticosteroids, significant regression
of keloids was found in 119 of 159 patients (75%; four
studies). Cryosurgery induces tissue edema and facilitates intralesional injections; however, the combined
therapy was not superior (90% greater than 50% reduction of lesional volume) to monotherapy (83.3%) in a
study of 40 patients with keloids. The third technique is
surgical debulkment prior to cryosurgery without corticosteroids. This regimen is unavoidable in large keloids;
however, it can result in recurrences despite its shortterm promising effects. Intralesional cryosurgery, the
fourth technique, was developed by modifying the
technique by Weshahy and is under evaluation in our
department. In addition, histological and immunohistological studies of keloids and keloidal fibroblasts in vitro
treated by cryosurgery have detected changes indicating
potential rejuvenation of the scars.
From the Department of Dermatology, University Medical Center Benjamin Franklin, The Free University
of Berlin, Berlin, Germany
Reprint requests: Prof. Dr. Christos C. Zouboulis, Department of Dermatology, University Medical Center
Benjamin Franklin, The Free University of Berlin,
Fabeckstrasse 60–62, 14195 Berlin, Germany.
Fax: + 49-30-84456908; Email: zouboulis@medizin.fu-berlin.de.
Copyright Ó 2002 by The Wound Healing Society.
ISSN: 1067-1927 $15.00 + 0
98
Cryosurgery—the well-aimed and controlled destruction of diseased tissue by application of cold—is an
effective and efficient method for treating various skin
diseases.1–3 The technique has several advantages2 and,
especially in the treatment of keloids and hypertrophic
scars, provides good therapeutic and cosmetic results
with few contraindications and a low incidence of
complications.4–7 The therapeutic properties of tissue
freezing have also been used successfully to treat
superficial atrophic acne scars.8,9
CRYOBIOLOGICAL BACKGROUND
The biological changes that occur in cryosurgery have
been studied in vitro and in vivo and are caused by a
reduction of tissue temperature and consequent freezing
(reviewed in4,10,11). Tissue injury is induced by direct
physical effects of cell freezing and by the vascular stasis
that develops in the tissue after thawing. The cryoreaction
is therefore characterized by the physical and vascular
phases. A postulated third phase of cryoreaction, the
immunologic phase, is still under investigation. Factors
affecting the effects of freezing on tissue and their optimal
parameters for the treatment of keloids and hypertrophic
scars are listed in Table 1.
Cryosurgical instrumentation
Currently, there are many commercially available, wellfunctioning cryosurgical units with variable design, function, and performance characteristics.4,12,13 Sufficient cold
for cryosugery can be produced by direct or indirect
application of a solid or liquid cryogen stored at low
temperatures, by lowering the pressure of a gas (JouleThompson effect), electromechanically, or simply by
refrigeration. The devices are mainly characterized
according to the cryogen applied and the manner of
cryogen application to the skin.
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VOL. 10, NO. 2
ZOUBOULIS, ET AL.
Table 1. Factors affecting the effects of freezing in tissue
Factor
Speed of tissue freezing
Speed of thawing
Intra-/extracellular osmotic
phenomena
Probe tip temperature
Tissue temperature
Duration of freezing
Repetition of freeze-thaw
cycles
Vascular reaction
Immunologic reaction
Optimum parameters*
Moderate speed (up to 100°C/min)
Slow speed (10°C/min, sponaneous
rewarming)
Heterogenous and homogenous
nucleation
)85°C to )190°C
)20°C to )25°C
30 seconds
No
Yes
Probable
*These parameters are optimized for treatment of keloids and hypertrophic scars.
Clinical development of cryoreaction
The physical clinical course of the cryoreaction starts with
the whitish frozen phase followed by a peripheral erythema, occurring immediately to 30 minutes after cryosurgery.4,10 The treated area becomes edematous between a
few minutes and a few hours after the procedure, and a
bulla is usually formed 1 to 3 days later. Consequently,
exudation lasts between a few days to 14 days after
cryosurgery followed by mumification of the lesion,
whereas a serum crust is built from the second to the
fourth post-treatment week. Finally, the healed area
presents a slightly atrophic, cosmetically acceptable,
initially erythematous scar. To minimize erythema and
edema occurring after cryosurgery, a mild, nonatrophogenic steroid cream (e.g., hydrocortisone acetate,
hydrocortisone buteprate, hydrocortisone-17-butyrate,
methylprednisolone acetate, prednicarbate) can be applied
to the lesion immediately after treatment, especially in
areas that usually react with strong edema (i.e., facial
area). The bulla serous content is aspirated with a sterile
99
fine needle 48 hours after treatment, whereas the bulla
roof is left on the lesion as a natural protective film. A
disinfectant-drying solution (e.g., Castellani colorless solution, merbromine 2%, povidone-iodine 10%) or lotion
(e.g., chlorhexidine 1% in lotio alba aquosa) is then
prescribed for use once daily.
CRYOSURGERY IN THE TREATMENT
OF KELOIDS AND HYPERTROPHIC SCARS
Cryosurgery is indicated for diverse benign and premalignant lesions and for selected malignant skin tumors.1–3,14
The method is considered the treatment of choice or a
valuable alternative treatment in several skin diseases. Any
area of the body can be treated, and there are no age
limitations. If the therapeutic result is not sufficient after
the first session, cryosurgical treatment can be repeated as
required every 20 to 30 days. Topical anesthesia is usually
not required.
Cryosurgery was found effective and safe in keloids
and hypertrophic scars in several studies performed over
the past few years (Table 2). Because of its major
advantage of rare recurrences, this technique, used either
as monotherapy or in combination, has been established as
the treatment of choice for keloids and hypertrophic
scars.2,4
Effects of freezing on the connective tissue
An advantage of cryosurgery often cited is that of minimal
scarring. The collagen fiber network of the dermis has been
shown to remain largely undamaged by the standard
cryosurgical procedures performed by clinicians.15 Using
the young domestic pig as a model and two 1-minute freezethaw cycles, no alteration in the periodicity of fibrillar
Table 2. Cryosurgery of keloids and hypertrophic scars: clinical results
Treatment
Lesion
Study
Number of
patients
Significant-tocomplete remission
%
Recurrences
Cryosurgery as
monotherapy
Keloids
Mende [24]
Zouboulis et al. [5]
Rusciani et al. [6]
Ernst & Hundeiker [7]
Zouridaki et al. [21]
Total
7
55
40
234
20
356
5
28
34
158
16
241
71
51
85
68
80
68
–
–
–
9
–
9 (2%)*
Hypertrophic
scar
Zouboulis et al. [5]
Ernst & Hundeiker [7]
Total
38
51
89
29
43
72
76
84
81
–
2
2 (2%)
Keloids
Hirshowitz et al. [28]
Ernst & Hundeiker [7]
Zouridaki et al. [21]
Banfalvi et al. [29]
Total
58
56
20
25
159
41
38
19
21
119
71
68
95
84
75
9
2
–
–
11 (7%)
Cryosurgery combined
with intralesional
corticosteroids
*Valves indicate recurrances as percent of total number of patients.
100
ZOUBOULIS, ET AL.
cross-banding and no fracturing or distortion of collagen
fibrils were found. In another study on rats, wound
contraction after freeze injury was minimal in contrast to
burn damage, in which contracture was the rule.16
Effects of freezing on keloid fibroblasts
Fibroblasts are rather resistant to freezing.15,17 Cryosurgery
was shown to increase their proliferation in vivo18 and, in
keloid fibroblast cultures from some but not all patients, in
vitro.17,19 Furthermore, cryosurgery induced synthesis of
collagen III and, consequently, an enhanced collagen III/
collagen I ratio in keloid fibroblasts, but not in normal
ones in vitro. In addition to these effects, alterations in
a-smooth muscle actin and tenascin C expression were
detected.20 Therefore, cryosurgery appears to affect differentiation of keloid fibroblasts toward normalization of
their phenotype.
Structural changes in keloids and hypertrophic
scars after cryosurgery
Significant skin thickening was found to occur 3 weeks
after cryosurgery of pig skin, which was consistent with an
increase in the number of fibroblasts followed by significant thinning at 6 months, probably due to the chronic
ischemia induced by cryosurgery.15,18 In humans, neovascularization, regular linear arrangement of collagen bundles, increased fibroblasts in stroma running parallel to the
skin surface, and mononuclear cells mostly arranged at the
perivascular area were found in clinically responding
lesions after cryosurgery.5 In a prospective, randomized
study of 40 patients with keloids that compared the clinical
and histological effects of cryosurgery as a single regimen
or combined with intralesional steroids, increased vessel
number and lumen dilatation in both groups and a
WOUND REPAIR AND REGENERATION
MARCH–APRIL 2002
reduction of the number and length of rete ridges in the
monotherapy group were the major structural changes
observed.21 Immunohistologically, enhancement and diffusion of tenascin C expression in the whole treated dermal
region and depletion of interferon-c expression, indicating
immune regulation, were found.22 These histological and
immunohistological studies indicate that cryosurgery can
induce changes in keloids that are compatible with
rejuvenation of the scars.
Cryosurgery as monotherapy
Cryosurgery as a monotherapy regimen was first used by
Shepherd and Dawber in 1982.23 They treated 17 patients
with keloids with a single cryosurgical session, achieving
80% improvement of the lesions; however, they observed a
high recurrence rate of 33%. With the exception of case or
technical reports, further monotherapy studies were probably postponed because of this rather disappointing
recurrence rate, until Mende,24 as well as Zouboulis and
Orfanos,25 showed that repeated cryosurgical sessions can
exhibit a beneficial effect on keloids and hypertrophic scars
and prevent relapses. In the meantime, 241 of 356 patients
with keloids (68%) and 72 of 89 patients with hypertrophic
scars (81%) in several studies have shown a greater than
50% improvement or complete regression after cryosurgery5–7,21,24 (Figure 1). Acne keloids also showed a 73%
improvement or complete regression in 16 patients treated.9
To achieve these results, 1 to more than 20 sessions lasting
an average of 30 seconds each applied once monthly, using
the contact method of treatment, were required. Progression or recurrence were rare (2%). The number of sessions
and the duration of lesions significantly correlated with the
result of the treatment, with more than three sessions and
lesions of less than 2 years’ duration providing the best
FIGURE 1. Hypertrophic scars after chemical burn with sulfuric acid and contraction of the right elbow joint. A 21-year-old male
patient as seen before (a) and 1 year after (b) nine sessions beginning with liquid nitrogen (four sessions) and ending with nitrous
oxide (five sessions), 30 seconds/lesion, contact technique. Elbow mobility is was completely attained.
WOUND REPAIR AND REGENERATION
VOL. 10, NO. 2
results. The age and sex of the patient, the size and location
of the lesions, and pretreatment with another method did
not influence the outcome of cryosurgical treatments.5
Cryosurgery was shown to exhibit significantly better
results than intralesional triamcinolone (5 mg/lesion) in a
randomized study of 11 patients with multiple acne keloids,
especially in early, vascular lesions.26
Cryosurgery with intralesional corticosteroids
Cryosurgery has been applied to the treatment of keloids
and hypertrophic scars using a weak cryotherapy regimen
prior to intralesional corticosteroids in order to induce
tissue edema and facilitate intralesional injections.27 This
procedure was advanced to a combination regimen by
Hirshowitz et al.28 with the impressive result of 71%
complete remission in 58 patients with keloids. In the
meantime, the regimen exhibited significant regression of
keloids in 119 of 159 patients (75%) treated in four
studies.7,21,28,29 However, the combined therapy with intralesional triamcinolone (2 mg/cm2) was not found to be
superior to cryosurgery alone in a randomized trial with 40
patients with keloids.21
Surgical debulkment prior to cryosurgery with or
without intralesional corticosteroids
Lesions refractory to cryosurgery, or cryosurgery combined with intralesional corticosteroids, can be surgically
removed and postsurgical cryoprevention, with or without
intralesional corticosteroids, can be applied to reduce
recurrences. This regimen is unavoidable in large
ZOUBOULIS, ET AL.
101
keloids30,31 (Figure 2). Intramarginal excision is advisable
because it is followed by a lower recurrence rate when
compared to extramarginal excision.32 Removal of the
lesion by surgery or CO2 laser presents similar recurrence
rates;33 however, CO2 laser provides a high degree of
hemostasis and avoidance of sutures.
Alternative cryosurgical approaches
A method of intralesional cryosurgery for keloids and
hypertrophic scars was developed by modification of the
technique by Weshahy34 and is under evaluation in our
department.4,11
The freezing peel (cryopeeling) is a full face, superficial cryosurgical treatment for atrophic acne scarring that
is especially useful in patients with mild-to-moderate
circinate scars. Results are similar to those obtained with
chemical peeling, but not as good as those obtained with
dermabrasion.35 If a mild regimen is chosen, repeated
sessions, sometimes over 2 to 3 years, are required to
obtain optimal results.36
COMPLICATIONS AND
CONTRAINDICATIONS
Cryosurgical treatment of keloids and hypertrophic scars is
generally well tolerated, and only minor complications
have been reported. Among the various temporary or
permanent complications described after cryosurgery,1,2,8,14
local pain during and/or shortly after treatment and lesional
hypopigmentation and/or peripheral hyperpigmentation
FIGURE 2. Huge keloids at the neck and the earlobe (arrow) before (a) and after (b) intramarginal excision with the carbon dioxide
laser under general anesthesia and intraoperative intralesional corticosteroid injections. This was followed by 12 sessions of cryoprevention (liquid nitrogen, 30 seconds per lesion, contact technique) and intralesional corticosteroids (triamcinolone, 2 mg/cm2
lesional surface).
102
ZOUBOULIS, ET AL.
are the major side effects that occur when treating keloids
and hypertrophic scars. About one-third of the patients
treated complained of mild local pain, which was easily
managed when necessary. Lesional hypopigmentation
developed in 12% to 100% of the subjects, and skin atrophy
in 1% to 8%. Single cases of large local edema, wound
infection, local hypoesthesia, local necrosis, and formation
of milia have been reported.5 Delayed wound healing is
an additional side effect that mostly occurs after the
combined regimen of cryosurgery with intralesional
corticosteroids.21 These complications are dependent on
the duration of freezing and the number of freeze-thaw
cycles applied.5,6,24
There are a few absolute contraindications, including
cold-inducible urticaria, cryoglobulinemia, cryofibrinogenemia, and Raynaud’s disease.1,2 Relative contraindications
are collagen diseases and lesions at the extremities of
elderly and black-skinned patients from long-term depigmentation attributable to melanocyte death.
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