Annals of Burns and Fire Disasters - vol. X - n. 2 - June 1997

POST-BURN PATHOLOGICAL SCAR: CLINICAL ASPECTS AND THERAPEUTIC APPROACH

Magliacani G.,(1) Stella M.,(1) Castagnoli C.,(1) Trombotto (2) Ondei S.(2) Calcagni M.(1)

(1) Department of Plastic Surgery and Burn Unit, Trauma Centre, Turin, Italy
(2) Centre for Immunogenetics and Experimental Oncology, National Research Council, Italy

SUMMARY. Pathological scarring continues to represents a major challenge for reconstructive surgeons. its anatomopathological classification is poorly defined and the relative epidemiological data are controversial. Our research group has therefore drawn up a classification chart on the basis of the morphological aspects of pathological scars. Hypertrophic scarring, the burn sequela most frequently observed in our case records, is characterized by the onset of typical clinical features which after a variable time course of activation undergo a phase of remission. The factors that produce this progressive radical change in the scars are not clear. It has recently been suggested that immunological factors may play a major role in the pathogenesis of hypertrophic scars. In order to have a better understanding of the pathophysiological factors involved, we studied active hypertrophic scars by means of immunohistochemistry. Among the wide range of cytokines, only interferon y was highly expressed in active hypertrophic scars on lymphocytes; it was less expressed in the remission phase and in control samples. The management of abnormal wound response can be considered appropriate only if it aims at the prevention or minimization of pathological scarring, and the results can be considered satisfactory only if the therapy is successful in specific anomalies related to particular lesions and in strict correlation with the scarring evolution phase. It is therefore indispensable to adopt a common clinical classification as this will provide better correlation between the clinical and the biological situation and a better interpretation of the mechanisms responsible for hypertrophic scarring.

Introduction

Pathological scarring still represents a major challenge for reconstructive surgeons. This is due to many factors: poor knowledge of aetiopathogenesis, the lack of a rational clinical classification, the absence of a scientific basis of noninvasive therapy, and the limited results of treatment.
The importance of the management of pathological scars must not however be underestimated, as they represent one of the most important limited factors for the complete recovery of patients.
Even today, the diagnosis is based mainly on clinical judgement, since no laboratory test is yet capable of evaluating the current state of a skin scar or of predicting its evolution, healing time, and final outcome. Also, owing to the subjective nature of the evaluation of lesions and to the lack of correlation between clinical status and biological evolution, this type of diagnosis is not very reliable.
During its evolution, the scar structure undergoes continuous changes, particularly with regard to its immunogenetic and histomorphological aspects, and even if a number of histological, immunological, and biochemical studies have provided an abundance of new evidence about the different aspects of pathological scarring, the real difficulty lies in interrelating all the single elements to each other and to clinical findings.
The biological phase of the scar cannot be evaluated by any standard classification criteria, as it is not correlated to the real evolutive state. This lack of classification makes it impossible to conduct an accurate investigation of the various everchanging aspects of pathological scarring. Scars have a poorly defined anatomopathological classification, the epidemiological data are controversial, and the risk factors are unknown.
Our experience has led us to believe that the first step towards a correct analysis and understanding of this phenomenon is the collection of epidemiological data, and it is therefore necessary to adopt a common clinical classification in order to permit, first of all, a comparison of case reports.
On the basis of these considerations, we elaborated a classification chart according to the morphological aspects of pathological scars, thus obtaining a better and more homogeneous patient grouping. This takes into account: hypertrophy, hypertrophy and contracture, contracture, and atrophy (Table 1).

Hypertrophy is the most frequently encountered pathology, either alone or in combination with other pathologies, especially contracture, at the same time in the same patient. Some biological aspects of hypertrophy are well known, such as continuous collagen production, extracellular matrix abnormalities, in particular chondroitin sulphate distribution, neovascularity, and increased cell turnover.
Clinically, the hypertrophic scar is a fibrous elevated skin lesion that normally does not exceed the limits of the original injury, subsiding spontaneously after an initial activation phase followed by a phase of regression. Initially it is erythematous, elevated, painful, and pruritic, suggesting an inflammatory phenomenon. This phase may persist for long periods of time and varies considerably from individual to individual.
The end of the activation phase is marked by a progressive decrease of the inflammatory symptoms.
After months or even years, the scar flattens, softens, and blanches and there is a reduction in dysaesthesia. These phases correspond to the various important modifications in the tissues, particularly with regard to immunocompetent cell and cytokine production.
In active hypertrophic scars activated T cells represent 70% of leukocyte infiltrates, compared with a maximum of 30% in normotrophic scars, where infiltrates are less abundant (Fig. 1). This suggests that immunocompetent cells play a pivotal role in the mechanisms that lead to hypertrophy.
CD3, CD4, and CD8 T cells differ significantly in active hypertrophic scars when compared with those observed in regressive hypertrophic scars and normotrophic scars (p > 0.0001) (Fig. 2). Lymphocytes infiltrate the deep and superficial dermis and are also observed in the epidermis.

Fig. I - Percentage of activated T lymphocytes in post-burn scar tissues. Fig. 2 - CD3, CN, CD8 lymphocytes per 0,25 MM2 in scar tissues.

After activation, the T cells release several cytokines, intercellular signals that show major changes as they pass from the active to the regressive phase. With regard to the tumour necrosis factor B (TNF B), the transforming growth factor 8 (TGF B), and interleukin6 (IL-6) positive samples, there are no significant differences in the active and regressive phase of hypertrophic scars or in controls (Fig. 3).
The number of positive specimens for interleukin-IB (ILAB) is significantly higher in all hypertrophic scars than in normotrophic scars, while the percentage of positive samples for turnout necrosis factor a (TNF (x) is significantly lower in active and regressive hypertrophic scars than in controls.
Interferon 7 (IFNy) positivity is higher in active hipertrophic scars when compared with the regressive phase and control (Fig. 4).

Fig. 3 - TGFP, TNFP, IL-6 detection in scar tissues Fig. 4 - IFN7, TNFu., IL- 10 detection in scar tissues

It is evident that there are significant differences between the active and the regressive phases of hypertrophic scars, while there are no differences between the regressive phase of hypertrophy and normotrophic scars. The only changed cytokine in the regressive phase is IFN y - which might well be considered a regression marker - and this correlates well with the clinical evolution.
The onset time for the remission phase and the total duration of hypertrophy regression are still controversial. According to the classification proposed by Muir in 1990,9 we can consider three groups of scars: short-term evolution, when they are active for a maximum period of six months and then remain static for some months, after which remission begins and normally becomes complete in one year after healing; long-term evolution, when the activity continues for years and the scar often spreads to the surrounding normal skin; and an intermediate group, when they normalize within two years.
As to distribution, scars can he generalized (when they involve all areas of spontaneous healing, grafting surfaces, or donor sites) or localized (when limited to some portions of these areas (Table I).
In burn patients, the importance of the anatomical region remains to be clarified: hypertrophic scarring in fact seems to be only partially associated with areas traditionally considered more liable to hypertrophy than others.
When both hypertrophy and contracture are present, there is not only hypertrophy but also skin coarctation, with a reduction in the surface area determined by centripetal forces of variable strength, tending to evolve into atrophy and/or chronic ulceration and to transform into neoplastic lesions.
On the basis of this classification, 293 patients were analysed: 21% were normotrophic, 34% were hypertrophic, 4% had contractures, 29% were hypertrophic with contractures, and 12% were not yet classifiable.
These data indicate that some kind of abnormal wound healing process was present in 67% of burn patients: thus, even if pathological scarring is extremely frequent, it is not an inevitable sequela.
The data also confirm our conviction that hypertrophy and contracture should be classified separately if we are to have a better understanding of the pathophysiology of pathological scarring.
With regard to distribution, 3 1 % of scars were generalized and 69% localized. Regarding the time of evolution, the data show that 21.5% were short-term, 32.5% intermediate, and 46.0% long-term evolution scars.
As for the question of treatment, we shall limit our observations to noninvasive management. There are - and always have been - many therapeutic trends but, to quote Linares,' "with the same degree of confusion and controversy as their morphological and etiopathogenic descriptions, owing to the fact that there is not enough scientific demonstration of their effectiveness.
Several therapies have been proposed for hypertrophic scars, and this diversity reflects the clinical heterogeneity of such lesions. They can be treated with physical methods, such as Pressure devices, cryotherapy, and laser therapy, or with pharmacological methods, such as topical therapy with retinoic acid and intralesional corticosteroid injection, while recent preliminary reports have suggested that human recombinant interferon y exerts a successful action.
Pressure by means of elastic garments and silicon gel sheeting or ordinary tapes are a much~used and very easy method to obtain a thinning effect. The mechanism of this effect is unknown: many hypotheses have been put forward but there is no general agreement.
A number of researchers have claimed varying degrees of success, often only slight, with cryotherapy and laser therapy, which induce cell disruption. However, the subsequent reshaping within the tissues has not been fully investigated. Good cosmetic results and relief of symptoms have been obtained with radiation therapy. There are however in the literature reports of neoplasms and radiation effects in body structures, even if recent research has demonstrated that appropriate dosimetry and shielding can limit these adverse effects.Topical retinoids have been reported to decrease fibroblast proliferation and to reduce collagen synthesis in vitro, but their true action is unclear. No studies have yet been performed in vivo. The intralesional corticosteroid response rate is extremely variable and dosage and administration times are arbitrary. Also, steroid deposition may lead to hypopigmentation, atrophy, telangectasis, and/or necrosis. Steroids have been shown to produce a systemic response and cannot therefore be used safely in generalized hypertrophy.
Our experience includes interesting observations of intralesional human interferon, which shows different behaviours in the various scar evolution phases.
Our studies demonstrate that interferon y and its receptor are highly expressed in active hypertrophic scars and start to decrease at the beginning of the regression phase (Fig. 3).
No trials reported in the literature explain the evolutive status and we must consider whether the promising results are to be imputed to the drug used in the regressive phase, when the interferon y rate is low, or to a dose-related effect, when the drug is used during the active phase.
At present we are unable to answer this question, and further studies are needed to establish interferon y's efficacy and to justify its cost compared with that of other therapies.
It must also be considered that interferon, like steroids, has systemic effects and can be used only in restricted scars and not in extensive scarring pathologies. In conclusion, it is essential in our opinion to adopt a common clinical classification, as it has been demonstrated that the morphology of each scar not only differs from patient to patient but also in the same patient, in areas Of the same scar, and in the different evolutive phases.
The purpose of the classification is to enable the clinician to make an accurate identification of the kind and stage of the scar and to predict the clinical course of abnormal healing. Current clinical classification criteria are unsatisfactory, as there is no relationship between the clinical and the biological situation. This gives rise to an excessive variety of aetiopathogenic interpretations of the mechanism responsible for hypertrophic scarring. When every aspect of the pathogenesis of hypertrophy is better understood, it will be possible to have a sound biological basis on which to plan more effective prevention and treatment of pathological healing, with minimal complications.
The management of abnormal wound response can be considered appropriate only if it aims at the prevention or minimization of pathological scarring, and the results can be considered satisfactory only if the therapy is successful in specific anomalies related to particular lesions and in strict correlation with the scarring evolution phase. Failing these conditions, every attempt to formulate a rational treatment will be inadequate and even if there may be numerous therapeutic proposals, the net result in most cases will be frustration.

RESUME. La cicatrisation pathologique continue à constituer un gros problème pour les chirurgiens reconstructifs, qui doivent se fier à une classification anatomopathologique très approximative et à des données épidémiologiques controverses. Pour ces raisons notre groupe de recherche a préparé un tableau de classification basé sur les aspects morphologiques des cicatrices pathologiques. La cicatrice hypertrophique, la séquelle des brûlures la plus commune dans notre casuistique, est caracterisée par la manifestation de certaines particularités cliniques typiques suivie, après une période variable d'activation, par une phase de rémission. Les facteurs qui provoquent cette transformation radicale des cicatrices ne sont pas bien compris. Récemment l'hypothèsé a été formulée que certains facteurs immunologiques puissent jouer un rôle majeur dans la pathogenèse des cicatrices hypertrophiques. Pour étudier plus en profondeur ces aspects pathophysiologiques, nous avons sommes servis de l'immunohistochimie pour étudier les cicatrices hypertrophiques actives. Nous avons examiné une large gamine de cytokines, dont seulement l'interférony est hautement exprimé sur les lymphocytes des cicatrices hypertrophiques actives; il est moins exprimé dans la phase de rémission et dans les témoins. La gestion du développement anormal des lésions peut être définie appropriée si elle mire à la prévention ou à la réduction de la cicatrisation pathologique, et les résultats peuvent se considérer satisfaisants seulement si la thérapie réussit dans le cas de certaines anomalies spécifiques liées à des lésions particulières et en rigoureuse corrélation avec la phase de l'évolution de la cicatrisation. Il est donc essentiel d'adopter une classification clinique commune parce qu'elle pourra nous donner une corrélation meilleure entre la situation clinique et la situation biologique et une interprétation meilleure des mécanismes responsables de la cicatrisation hypertrophique.

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