Eur J Plast Surg (2016) 39:201–206 DOI 10.1007/s00238-015-1170-6

ORIGINAL PAPER

Cryotreatment of keloids: a single Italian institution experience Marco Fraccalvieri 1 & Paolo Bogetti 1 & Marco Salomone 1 & Claudia Di Santo 1 & Erind Ruka 1 & Stefano Bruschi 1

Received: 9 September 2014 / Accepted: 29 October 2015 / Published online: 27 November 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Background Keloids are pathologic scars that can cause significant aesthetic disfiguration and symptoms. There are no specific causing factors, and a common consensus on their management has not been reached. This study provides an evaluation of the efficacy of cryotherapy and cryosurgery in their treatment. Methods Patients with keloids who were hospitalized at the Plastic Surgery Unit, University of Turin, were submitted to cryotreatment. A significant sample of 153 patients with 192 lesions, treated between 2009 and 2013, was considered for the purpose of this study. The protocols chosen were outpatient cryotherapy sessions and cryosurgery (surgical shaving combined with cryotherapy). Reductions of the scar volume and thickness, together with the reduction of clinical symptoms, were assessed. Results On average, the follow-up was 12–72 months. In 83 % of patients who received outpatient cryotherapy, there was a diminishment of 75–82 % in the size of the lesions, with an average of 5–10 applications needed. In 94 % of those submitted to cryosurgery, one session was enough to achieve an almost complete smoothing (reduction in lesions sizes higher than 80 %). However, 13 % of the patients submitted to cryosurgery also needed sessions of outpatient cryotherapy to achieve effective results. For both approaches, the main adverse effects included dyschromia with healthy skin and dystrophic scars. No recurrence was observed.

* Marco Fraccalvieri [email protected] 1

Department of Reconstructive and Aesthetic Plastic Surgery, Città della Salute e della Scienza Hospital, University of Turin, Via Cherasco, 23, 10100 Turin, Italy

Conclusions Our experience confirms the cryotreatment among first-line monotherapies against keloids, in terms of therapeutic effectiveness, safeness, costs, and ease of application. A careful selection of the protocol treatment on the base of the lesion characteristics (age and the morphology) and a good compliance of patients are necessary to reach optimal results. Level of Evidence: Level IV, therapeutic study.

Keywords Keloid . Scar . Cryotherapy . Cryosurgery . Cryotreatment

Introduction Keloid scars usually develop as a result of an abnormal and pathologic proliferative response of the cutaneous connective tissues after a skin injury [1]. They clinically present as hard, raised, reddish-brown plaques or nodules. They can cause significant aesthetic disfiguration and symptoms like itching, pain, or limitations in the mobility of the affected area [2]. Compared to hypertrophic scars (HTS), they expand beyond the margins of the primary wound, they do not reduce in size, and they tend to recur after excision [3]. Keloid scars develop most commonly in the sternal region and on shoulders, upper back, back of the neck, earlobes and ear tents, face, limbs, and inguinal region and rarely on mucous membranes, palms, or soles [4]. The etiology of keloids is still not clear: keloids are probably associated with an abnormal wound-healing process, in predisposed individuals, as a result of skin lesions such as burning, surgery, abrasions, tattoos, insect bites, piercings, or processes causing skin inflammation (acne, folliculitis, herpes zoster) [5]. In the medical literature, there have been also

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reported cases of spontaneous lesions (Bspontaneous keloids^), probably caused by overlooked micro-traumas, unnoticed by the patient [6, 7]. Histopathologically, keloids present an increased collagen synthesis in comparison to healthy skin and non-pathologic scars: they show larger, thicker, and wavier fibers organized in a random orientation [8]. The treatment of keloids is challenging since no single treatment is equally effective in all patients; therefore, multiple strategy options may be needed for a single patient. Moreover, following treatment, a larger lesion may develop. Currently, therapies used to treat keloid scars include cryosurgery (alone or associated with shaving excision), steroids, radiation, laser, silicone sheets, and/or gel. However, a common consensus for the treatment of keloids has not yet been achieved. Experimental therapies such as interferon, 5-FU, and retinoic acid are also being used [6]. The treatment with exposure to very low temperatures alone, or associated with surgical excision, was firstly described in 1980s and 1990s [9]. It seems to cause keloid tissue destruction with direct cellular and vascular injury [10–12]. This study provides an efficacy evaluation of cryosurgery alone and of cryosurgery combined with surgical shaving in the treatment of keloids. The evaluation takes into account the scar reduction in terms of volume and thickness as well as the reduction of the subjective and objective clinical symptoms (pain, itching, functional limitation).

Each patient signed a written informed consent. Alternative treatments were explained before the procedure. This study protocol is conformed to the ethical guidelines of the 1964 Declaration of Helsinki and subsequent amendments. Photographs and measurements of the lesions were taken during each visit. A millimeter ruler was used to measure size and thickness of the keloids (three measurements for each dimension): the highest values of the three measurements were considered and noted (the thickest and the largest part of the keloid). We also recorded the objective properties of the lesions (such as the hardness, elevation, and color) and the subjective symptoms referred by the patients (pain, itching, sense of tension, limitations in the mobility). For almost all these properties, we used an evaluation scale in which B0^ was Bno^ or minimum complain of the patient and B3^ was the maximum [13]. Pain and thickness were instead respectively recorded with Visual Analog Scale (VAS) [14] and evaluated according to the Vancouver Scar Scale (VSS) [15]. In addition, we also recorded whether the patient treatment procedure was cryosurgery only or cryosurgery with excision too. Patients were treated with the handheld unit Criotom (ASMOT S.r.l., Turin, Italy), which consists of a cylinder full of liquid nitrogen at a temperature of −89 °C which cools an iron ferrule (chosen in function of the size of the scar). After an accurate disinfection, the iron ferrule was directly applied on the lesion, causing a burn to cold. Special care was taken to avoid freezing of the healthy tissue, in order to prevent additional risk of dystrophic scarring. One of the two treatment protocols described below were applied, depending on the characteristics of the lesion:

Patients and Methods & The study was conducted at the Plastic Surgery Unit, University of Turin, Hospital BCittà della Salute e della Scienza^ of Turin. The institute introduced this technique from 1970s, but, because of the loss of some files and incomplete data collection, it was chosen to not consider the years earlier than 2009. A number of 153 patients, for a total of 192 keloid scars, treated from 2009 to 2013 have been analyzed. We excluded HTS as they have different clinical behaviors: attitude to answer to the therapies and different recurrence rates. A possible bias in the effectiveness assessment of the treatment would have been created with HTS inclusion. The collected data of each patient included: – – – – – –

The cause of the lesion The anatomical site of the lesion The size and thickness of the lesion The time the lesion appeared Whether the subject tried other therapies before Whether the subject had other kind of pathologic scares (hypertrophic, atrophic…)

&

Cryosurgery. In lesions characterized by small or mediumlarge width, large base, and thickness below 4 mm, two freezing applications per session were performed: the first lasting 3 min and the second lasting 2 min, with a 3–5-min break between the two applications. The applications caused the freezing halo to cross several millimeters beyond the scar borders. The application time should be reduced in the following sessions, depending on the lesion improvements, up to a minimum of 1 min. Besides, if esthetical sites, the time should be decreased already from the first session (2 or 1 min); in the same way, it should be longer if the scar is particularly thick and/or old (rarely more than 4 min). Only 8 % of people requested the application of topic anesthetic (lidocaine cream) before the procedure. At the end of the procedure, the patient was treated with local antibiotic and steroid cream, and a nonadhesive gauze was applied. Shaving, followed by cryosurgery. In bigger scars, with narrow, long peduncles and/or greater thickness (above 4 mm), the following procedure was followed: 1. Local anesthesia (with carbocaine 1 % or 2 %);

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2. Shaving with a scalpel no. 15 or 24; 3. Cryotherapy session as described for the protocol above. A comparison was not possible between the two groups due to local characteristic of the lesion, which leaded to different treatments. For this reason, no statistical or endpoint comparison was performed. A 1000-mg tablet of acetaminophen every 8 h was administered to the patient, if the pain was higher than level 3 in the VAS scale. To evaluate the primary outcome, the aspects mainly considered were the scar’s thickness and volume reduction, the total number of required sessions, and the improvements of the clinical symptoms. For every group of results, a summarizing chart is provided to help the evaluation of the overall effectiveness of the treatment. If pain was not tolerated, we reduced the time of application and/or interrupted and postponed the session. In both protocols, every patient was instructed to continue the dressing at home with antibiotic and steroid cream and non-adhesive gauze, once a day until the healing of the wound. The average interval between outpatient cryosurgery sessions was between 3 and 5 weeks. The complete re-epithelialization of the wounds was the mandatory condition to proceed with the next session.

Fig. 2 Preoperative posterior view of the same patient

consequences of surgical operations (24 %), cutaneous inflammations (19 %), traumas and burns (13 %), and Bspontaneous keloids^ (7 %). The median range of follow-up of each patient was 12–72 months. Eighty-seven percent of the patients received cryotherapy as their first treatment, while in the remaining 13 %, the cryotreatment was anticipated by intralesional injections of steroids, surgery excision, or silicon sheets. For the patients treated with steroid injections, it was not always possible to track the drug and the dosage. No recurrence of keloids was observed in both groups.

Results

Cryosurgery

A total of 153 patients were recruited in this study, 82 females and 71 males, aged between 11 and 45 years (only 5 % of patients were under 10 years old). Keloids were localized in the earlobe and tent (38 %, Figs. 1 and 2), sternal region (26 %), back (19 %), and face and limbs (10 and 7 %). Scars were present from 6 months to 10 years (maximum of 18 years). Pre-treatment dimensions ranged from 0.5 to more than 15 cm2. The most reported etiologies included earlobe and/or ear tent piercings (37 %), surgical excision of skin lesions (tumors, cysts, nevi…) and

In this group, 76 patients (41 females, 35 males) received cryosurgery alone. The treatment lasted between 12 and 36 months. There was an overall significant reduction in the volume of the lesions, with differences in rates compared with the number of sessions needed. Eighty-three percent of the patients obtained a keloid size reduction between 75 and 82 %, with an almost complete smoothing (i.e., 0.8 mm maximum resulting thickness). They required between 5 and 10 sessions. Good results were also achieved in 20 % of the patients of this group, with a keloid scar size reduction between 35 and 60 % and thicknesses above 3 mm; in these cases, the treatment required less than seven sessions. In 5 % of the people, the response was not completely satisfactory, with size reduction lower than 30 % and thickness rarely inferior than 3 mm; the number of required session varied notably from <5 to 15, with an average around 5–7 (Table 1). Shaving with cryosurgery

Fig. 1 Preoperative lateral view of a 30 year-old male patient with keloid of the ear tent due to piercing

In this group, 77 patients (38 females) received surgical keloid excision followed by cryosurgery.

204 Table 1

Eur J Plast Surg (2016) 39:201–206 Clinical assessment after the cryosurgery Range

Mean

Volume reduction (%)

30–82

73

Hardness (score 0–3)

0–2

0.7

Dyschromia (score 0–3) Itching (score 0–3)

0–2 0

0.8 0

Tenderness (score 0–3) Functional limitation (score 0–3)

0–2 0–1.5

0.8 0.8

Pain (VAS)

0–4

2.5

Thickness (mm according to VSS)

0.8–3.5

2.2

Ninety-four percent of the patients achieved in one session an almost complete smoothing of the lesions, with high reduction in size and thickness. Six percent of the patients, in spite of the good results obtained after the first session, needed further cryosurgery sessions to achieve smoothing. In these cases, the average number of sessions needed to reach a good result was five, in a follow-up period of 12–18 months. One of the main adverse effects of both protocols was hypopigmentation that affected 75 % of cases. Among these, in 84 % of cases, hypopigmentation was temporary (3–6 months). Sixty-seven percent of the patients showed normal re-pigmentation, the remaining hyperpigmentation. No infections, neither necrosis nor bleeding were reported; 1.6 % resulted in atrophic depressed scars. Recurrences arose after a few cryosurgeries, but in the other cases, no recurrences were observed during the follow-up period. The best responses were observed for keloids located on earlobes, ear tents (Figs. 3, 4, and 5) and face; among the most resistant and easily recurring keloids were the ones located in the sternal and parasternal regions and in the high back (Table 2).

Fig. 3 Postoperative view at 1st day after surgical excision and cryosurgery

Fig. 4 Postoperative lateral view at 12 months

Discussion The management of keloid scar is evolving. With better understanding of pathophysiology of such scars newer possibilities of treatment are emerging [16]. Cryosurgery was first introduced as monotherapy for these scars by Shepherd and Dawber in 1982: they achieved 80 % improvement with only one session in their 17 patients, but the recurrence rate was high [17]. Mende and Zouboulis in 1987 and 1990 noticed that more cryotreatment sessions could prevent relapses [9–23]. Studies evaluating the cellular events that follow cryotreatment were made to explain the rationale of its choice [8]. The treatment caused changes in the general histology of

Fig. 5 Postoperative posterior view at 12 months

Eur J Plast Surg (2016) 39:201–206 Table 2

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Clinical assessment after the shaving with cryosurgery Range

Mean

Volume reduction (%)

80–100

87

Hardness (score 0–3)

0–1.5

0.55

Dyschromia (score 0–3) Itching (score 0–3)

0–2 0

0.8 0

Tenderness (score 0–3) Functional limitation (score 0–3)

0–1.5 0–1.5

0.65 0.75

Pain (VAS)

0–3

1.2

Thickness (mm according to VSS)

1–4

2.4

the skin and in particular in the structure of the collagen bundles of fibers that lose their swirl aspect and are denser; the thickness of this layer reduces without spaces between the chains Bbecause of the presence of fewer septal bands^ [8]. The proliferation rate of the fibroblast cells also decreases, as demonstrated by the research carried out on the expression of nuclear antigen markers [8]. On the other hand, if the low temperature cannot alter the number of blood vessels that remains in the pathologic scar, it determines an anoxic injury on an already damaged and inadequate microcirculation, activating a cascading cellular response to hypoxia. This leads to blood stasis, with the formation of platelets thrombi and final necrosis, which macroscopically translates in keloid reduction [8–12]. Among the most recent studies on cryotherapy effectiveness, Rusciani et al., in their 14 years’ experience, obtained very good results in 79.5 % of the lesions treated with cryotherapy [24]. Fikrle and Pizinger’s experience reports a complete flattening of scars in five of their seven young patients and no recurrence within 1 to 4.5 years of follow-up [25]. Among the factors that led to unsatisfying therapy responses, we must firstly consider the compliance of the patients: usually more than one session was needed, lasting also more than 30–60 min. Other times, the patient did not respect both the frequency of the procedure and the lasting time of the application of therapy procedure required by the protocol. We also lost 8 % of the cases, because the patients prematurely decided to stop the treatment after the resolution of the painful and/or itchy symptomatology alone or the improvement of the functional limitations; this percentage includes also those who stopped the cryosurgery, after only a few sessions. In agreement with Rusciani et al. [25], the most influencing factors that seem to produce a minimal effectiveness of the therapy are age and morphology of the treated lesions. The most recent lesions had unstable behaviors in the short-term period, but showed better responses than the older ones. Regarding the keloid size, scars thicker, bigger than 15 cm and with a wider base were more resistant and required more therapy sessions and larger metallic ferrule, with higher risk of no

uniformity of the result or even of dyschromic/dystrophic outcomes. On the other hand, these characteristics rather leaded to the choice of shaving associated with cryosurgery. We suggest cryosurgery alone as the best option for keloids with small or medium-large wideness, large base, and thickness below 4 mm. Bigger scars, with narrow, long peduncles and/ or thickness above 4 mm, allow an easy surgical shaving, followed by cryosurgery. No recurrence was observed. Sometimes, the poor response could be caused by the insufficient freezing time of the application considering the characteristics of the original lesion. The surgical excision of keloid creates a tissue damage that stimulates the reparation process. It is supposed that, if the subsequent cryosurgery is not enough, according to the protocol proposed, it is unable to hinder the tissue healing [8–12], resulting in a stimulation of the keloid’s growth instead of its destruction. Rusciani et al. [26] analyzed the recurrence of keloids in 65 patients with cryotreatment: no recurrence was observed during follow-ups ranging from 17 to 42 months. On the other hand, Park et al. [27] showed great variability of the recurrence in children (42–10.5 %) according to anatomic location (higher in lower extremity) and by treatment modality (higher with surgical excision, full-thickness skin grafts, and corticosteroids), but cryosurgery was not taken into account. Limitations of our study include that the cryotreatment is an operator-dependent procedure, difficult to standardize, and it requests a certain degree of practice and experience. For this reason, in our department, periodic courses are organized by technicians showing the correct use of the Criotom. Another bias of the study is the high turnover of the operators: not always the same staff performs the procedure, and sometimes, especially in the case of outpatient cryosurgery, a single patient might be treated by different operators. As further evidence, we considered other therapies reported as first-line strategies during the last 10 years, highlighting their rates of effectiveness and their major side effects. The intralesional corticosteroid injection requires multiple and painful injections and may cause discomfort, skin atrophy, and telangiectasia; the results show flattening among 73 % of the lesions, with recurrence rate of 2–8 % [3, 6, 18]. These values depend also on the kind of molecule used (triamcinolone acetonide suspension, betamethasone sodium, betamethasone acetate) and on the concentration of the active principle (10–40 mg/mL) [4–16, 18]. Randomized controlled trials have shown the efficacy of silicon sheets and/or gel [19, 20], and this is one of the evidence-based treatments recommended by the International Advisory Panel on keloid management [21]. However, because of the very variable responsiveness rate (50 to 100 %), it does not always answer to an ideal cost-effectiveness [6–16, 18].

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Currently, we are conducting a preliminary study with the usage of vacuum therapy made of silicone layer (with which an 80-mmHg negative pressure) distributed on the keloid scar region. The rationale of this alternative, noninvasive treatment is the resultant compression of the keloid and the application of the silicone. Preliminary results show an average thickness reduction of 43.8 %, and the treatment seems to be well tolerated by patients, with improvements in the symptomatology, but prospective studies are necessary to investigate whether these preliminary observations are confirmed [22].

5. 6. 7.

8.

9. 10. 11.

Conclusion Our experience confirms that the use of cryotherapy with liquid azote can be considered among the first-line monotherapy against keloid scars, in terms of therapeutic effectiveness, safeness, costs, and easiness of application. A small percentage of patients results in a not satisfying response, but a specific cause cannot be identified. Further researches and comparative prospective studies are necessary. Compliance with ethical standards Conflict of interest Marco Fraccalvieri, Paolo Bogetti, Marco Salomone, Claudia Di Santo, Erind Ruka, and Stefano Bruschi declare that they have no conflict of interest.

12.

13.

14.

15. 16.

17. 18.

Ethical Standards This study protocol has been approved by the local ethics committee and is conformed to the ethical guidelines of the 1964 Declaration of Helsinki and its subsequent amendments.

19.

Patient consent Each patient signed a written informed consent prior to their inclusion in the study, and alternative treatments were explained before the procedure. Addtional consent was obtained for the use of their images.

20.

Funding None.

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22.

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