Abstract
Dermal substitutes offer alternative approaches for wounds of all thicknesses where sufficient donation sites are not available for self‐grafts. Several dermal substitutes are described in literature. This study included 20 patients treated with a dermal induction template after the removal of malignant skin cancers situated in various parts of the body. The participants were especially aged patients with multiple skin cancers, and complex clinical conditions, often affected by pathologies such as cardiopathy, diabetes mellitus, and hypercholesterolaemia, and receiving pharmacological multi‐therapies, particularly antiplatelets and anticoagulants. In many of these patients, the general complex clinical picture provided significant contraindication for complex reconstructive surgery because of the high risk involved. All patients achieved complete healing about 8 weeks after the first surgery. By using a dermal induction template, it was possible to cover substantial loss of substances without the need of autologous tissue, with smoother and less apparent scar, minor occurrence of hypertrophic and retracted scars, better flexibility of healed skin and therefore a better result from an aesthetic point of view.
Keywords: Basal cell carcinoma, Dermal induction template, Hyalomatrix PA, Skin cancers, Squamous cell carcinoma
Introduction
Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are among the most common cancers worldwide 1, 2. SCC and melanoma may be extremely aggressive cancers with high morbidity and mortality 2. Reconstruction of defects after excision of malignant skin cancers still remains a substantial challenge to the surgeon, requiring experience and reliable evaluation capacities. Excision of the cancer and direct confrontation of the margins still remains the most common method in treating small defects. If the loss of substance is large, skin self‐graft, flaps, free flaps or other techniques of reconstructive plastic surgery are the best treatment 3, 4. Alternative approaches for all thickness wounds without sufficient donation sites available for self‐grafts include the use of dermal substitutes 3. Several dermal substitutes are described in literature; this article presents our experience in 20 selected patients, where the covering of cutaneous defects after the removal of malignant skin cancers in various parts of the body was obtained using a dermal substitute, Hyalomatrix PA® (Fidia Advanced Biopolymers, Abano Terme, Italy) 5, 6.
Methods
In the period from March 2010 to June 2011, 20 patients were enrolled at the Department of Reconstructive and Aesthetic Plastic Surgery in the Policlinico Umberto I in Rome: 14 males and 6 females ages 20–90 years, average age of 73·35 years. All patients were affected by cutaneous cancers. Of the 20 patients considered, 6 (30%) had SCC, 4 (20%) BCC, 3 (15%) metatypical carcinoma, 5 (25%) melanoma, 1 (5%) had malignant histiocytoma and 1 (5%) sarcoma (Table 1). The locations were: scalp (40%), face (30%), foot (20%) and ankle region (10%). As regards the general pathological conditions of the 20 patients, 19 showed comorbidity (95%): 10 patients (50%) had hypertension, 3 (15%) had diabetes mellitus, 4 (20%) hypercholesterolaemia, 2 (10%) chronic cardiac insufficiency, 2 (10%) had atrial fibrillation due to chronic treatment with anticoagulants, 2 (10%) had cerebrovascular insufficiency with previous episodes of transient ischaemic attack, 1 (5%) had glaucoma, 1 (5%) had hepatitis, 3 (15%) benign prostate hypertrophy, and 1 (5%) had anaemia; 11 (55%) patients had a past history of malignant tumours of which 8 (40%) were cutaneous cancers. All patients were treated with removal of the tumour and application of the dermal substitute.
Table 1.
Patients recruited in the protocol, and localisation and diameter of the skin loss
| Patient | Age | Sex | Type of skin cancer | Localisation | Size | Treatment | Comorbidities |
|---|---|---|---|---|---|---|---|
| 1 | 20 | M | Sarcoma | Left foot | 5 × 3.5 | Application of Hyalomatrix | None |
| 2 | 77 | M | Metatypic carcinoma | Forehead | 5 × 4 | Application of Hyalomatrix | Diabetes mellitus, dyslipidemia, hypertension, other epitheliomas |
| 3 | 81 | M | Squamous cell carcinoma | Scalp | 10 × 7 | Application of Hyalomatrix + graft | Epitheliomas, cardiomyopathy, chronic lymphocytic leukaemia |
| 4 | 88 | M | Squamous cell carcinoma | Scalp | 10 × 12 | Application of Hyalomatrix + graft | FAP, PMK, hypertension, other epitheliomas |
| 5 | 72 | M | Metatypic carcinoma | Nose | 2 × 1.5 | Application of Hyalomatrix | Lung cancer, other epitheliomas |
| 6 | 88 | M | Squamous cell carcinoma | Scalp | 15 × 10 | Two applications of Hyalomatrix + graft | TIA |
| 7 | 85 | M | Squamous cell carcinoma | Scalp | 10 × 8 | Application of Hyalomatrix + graft | Hypertension, dyslipidemia, renal cancer |
| 8 | 85 | F | Melanoma | Right foot | 5 × 4 | Two applications of Hyalomatrix + graft | Diabetes mellitus, breast cancer |
| 9 | 70 | M | Squamous cell carcinoma | Left leg | 6 × 4 | Application of Hyalomatrix | Hypertension, dyslipidemia, oral cancer |
| 10 | 73 | M | Basal cell carcinoma | Forehead | 5 × 4.5 | Application of Hyalomatrix | Hypertension, dyslipidemia. |
| 11 | 68 | F | Melanoma | Right leg | 5 × 4.5 | Application of Hyalomatrix + graft | Hypertension |
| 12 | 90 | F | Melanoma | Right foot | 5 × 5 | Application of Hyalomatrix | Breast cancer, uterus cancer, renal cyst |
| 13 | 56 | F | Basal cell carcinoma | Forehead | 10 × 17 | Application of Hyalomatrix + graft | Hypertension, thyroidectomy, appendectomy, other epitheliomas |
| 14 | 77 | F | Melanoma | Right foot | 3 × 1.5 | Application of Hyalomatrix | Hypertension |
| 15 | 81 | M | Basal cell carcinoma | Scalp | 10 × 7 | Application of Hyalomatrix | Hypertension |
| 16 | 59 | M | Basal cell carcinoma | Medial canthus of left eye | 1 × 2 | Application of Hyalomatrix + graft | Diabetes mellitus, dyslipidemia |
| 17 | 81 | M | Squamous cell carcinoma | Scalp | 8 × 7 | Application of Hyalomatrix | Chronic cardiac insufficiency, TIA, aortic atherosclerosis |
| 18 | 66 | M | Metatypic carcinoma | Left cheekbone | 3 × 2 | Application of Hyalomatrix + graft | Chronic atrial fibrillation, anaemia |
| 19 | 87 | M | Malignant histiocytoma | Scalp | 5 × 5 | Application of Hyalomatrix + graft | Hypertension, dyslipidemia, other epitheliomas |
| 20 | 63 | F | Melanoma | Scalp | 5 × 4 | Application of Hyalomatrix + graft | Hypertension, glaucoma, grade 2 melanomas, hepatitis, uterus cancer |
FAP, paroxysmal atrial fibrillation; PMK, pace‐maker; TIA, transient ischemic attack.
According to the therapeutic protocol, the cancer was removed respecting the margin of oncological security. In two cases, the locoregional tributary lymph nodes affected by the neoplastic process were removed. After a careful haemostasis, the dermal substitute was applied to the wound bed with stitches and covered with a non‐adherent dressing composed of 0·2% hyaluronic acid and sterile gauze. A non‐adherent secondary medication was applied along with a moderately compressive bandage.
Clinical dressing check was performed every 3–5 days. While applying the dressing, the wound margins were disinfected with sodium hypochlorite 0·05% (Amuchina S.p.A., Genova, Italy), iodopovidone 0·5% (Betadine®; Meda Pharma S.p.A., Milano, Italy) and rinsed off with saline solution. Visual control through the transparent membrane showed that the process of regeneration of the derma was continuing and there was no infection. The wound appeared first white, later yellow and at last pink, when it was covered with vital granulation tissue and the borders showed a reepithelialisation fringe.
Three weeks after the application of the dermal substitute, after the removal of silicon layer, we considered three patient groups for epidermal reconstruction: the first group included the patients who showed a significant reduction of the wound size and continued dressings until wound healing; the second group included the patients with a good wound bed, who underwent surgery; finally, the third group included the patients who had no sufficient dermal regeneration after dermal substitute removal, and who received a second application of the dermal substitute.
After complete reconstruction, the patients underwent control visits at 3, 6 and 12 months for final evaluation and photographic documentation. The results have been documented by comparative photography, Visual Analogue Scale (VAS) for patient satisfaction with a scale from 0 to 10, and Vancouver Scar Scale (VSS). It assesses four variables: vascularity, height/thickness, pliability and pigmentation and assigns each of them a score; higher is the score, worse the scar features 7, 8. Patients were also included for long‐term follow‐up to check for any relapses typical of some malignant skin cancers.
Results
The 20 patients included in the protocol and treated by removing the skin cancer and application of Hyalomatrix were healed. No adverse reactions were registered in the follow‐up period. Loss of substance was common for all the patients because of the removal of skin cancer. The mean diameter of the loss of substance was 6·5 × 6·4 cm2, and on average a sheet of Hyalomatrix with a diameter of 10 × 10 cm2 was applied (Table 1).
The two‐step surgical procedure lasted an average of 40 minutes. All patients were discharged the same day or the day after surgery. At the first dressing change, 1 week after surgery, partial integration of the model was evident with the formation of granulation tissue and neodermis. Significant differences between young and old patients or the thickness of the loss of substance were observed.
At 21 days (mean) after surgery, the patients were evaluated by considering three options. Nine patients (45%) were included in the first group, with small size wound and received continued dressings until complete wound closure for a second inspection; second group comprised of 11 patients (55%) with larger defects and a good wound bed after dermal substitute removal and received a dermo‐epidermal partial‐thickness grafting; 2 patients (10%) included in the third group had no sufficient dermal regeneration and received a second application of the matrix.
All patients underwent check‐ups twice a week. Those in the first group achieved complete healing 4 weeks after the first surgery, the second group patients healed 6 weeks after surgery and the third group after about 8 weeks. One month after healing, the VSS showed no significant difference between the various groups of patients considering age and thickness of the loss of substance with an average result of 6·5. Furthermore, there were no significant differences in the VSS score among patients who received dermo‐epidermic graft after application of Hyalomatrix and patients who did not, and who had slightly superior values. A year after surgery all the patients were present at the control visit. The VSS score compared with that of the second evaluation showed an improvement in the mean values, from 6·5 to 4. Patients who had not received dermo‐epidermic graft had a higher reading, probably due to the localisation of the loss of substance, subject to more traumas and traction force on the scar. Patients were also included for further 3 months follow‐up visits to locate and treat any relapses.
The images in Figures 1, 2, 3, 4 show some of the patients recruited in the protocol before, during and at the end of treatment.
Figure 1.
(A) Patient no. 6, male ages 88 years with squamous cell carcinoma of the scalp. The tumour appeared round with irregular margins with a maximum diameter of about 3 × 4 cm2, it was ulcerated with necrotic base and eschar. In the posterior part near the vertex, there was another cutaneous neoformation with nodules and ulcers and indefinite margins. Around these two neoformations, there were several discheratosic and hypercheratosic lesions. The patient was hospitalised for the asportation of the cutaneous neoformations and two applications of Hyalomatrix (8 × 10 cm2). (B) Intraoperative view after asportation of the epithelioma. (C) Application of Hyalomatrix (on the left). Appearance 2 weeks after application of Hyalomatrix (on the right). (D) Three weeks after application of Hyalomatrix. (E) Second application of Hyalomatrix. (F) Two months after dermo‐epidermic graft.
Figure 2.
(A) Patient no. 16, male ages 55 years with basocellular carcinoma in inner left eye. The neoformation appeared oval in shape, in relief with defined margins and a maximum diameter of 0·5 × 0·5 cm2, and no pigmentation. (B) Three weeks after application of Hyalomatrix. (C) Dermo‐epidermic graft. (D) After 1 year.
Figure 3.
(A) Patient no. 2, male ages 77 years with basocellular carcinoma in the left frontal region. The neoformation appeared irregular in shape, indefinite margins, ulcerated and a maximum diameter of 4 × 5 cm2. The dermal substitute was applied after cancer excision. Dressings were continued until complete wound healing. (B) After 1 year.
Figure 4.
(A) Preoperative aspect. Three quarters left side, frontal, three quarters right side views. (B) After 1 year.
Discussion
Reconstruction after oncological demolition has always been a challenging task. With progress in plastic and reconstructive surgery, new problems have arisen regarding the complete morphofunctional restoration of the area affected by cancer and the possibility of reducing the complexity and number of surgeries and the scars, making these as far as possible acceptable and invisible 9.
All this has encouraged research on skin substitutes, which has seen a boom in production during the last 30 years, and which have become a key point of interest for the reconstruction of loss of substance due to various aetiologies. Dermal substitutes can be divided into cellular (cultures of fibroblasts) and acellular. Most dermal substitutes are acellular and made up of allogeneic material (Alloderm), xenogeneic (Integra e Matriderm) or synthetic (Hyalomatrix) material.
Hyalomatrix PA®, is a ‘bio‐inductor’ containing phase‐specific factors that optimise the biological mechanisms that heal the wound (growth factors, cells and hyaluronic acid). It is a bilayer of an esterified hyaluronan scaffold, made up of a biodegradable absorbent sheet beneath a silicone membrane. The external layer is made up of a flexible, transparent silicon layer, which acts as a semipermeable barrier protecting the wound from external agents and impeding loss of fluids. It consists of a biological matrix that acts by modifying the physical–chemical characteristics of hyaluronic acid, a natural polysaccharide present in the extracellular matrix and has a primary role in the regeneration process of tissues and undergoes esterification with benzylic alcohol for the formation of hyaluronic acid ester (HYAFF®; Anika Therapeutics, Inc., Bedford, MA) 10, 11, 12.
This matrix moves when in contact with the wound, gradually releasing hyaluronic acid that interacts with cell functions that stimulate the process of dermal regeneration. Furthermore, the three‐dimensional matrix undergoing biodegradation, provides a scaffolding for cellular colonisation and neoangiogenesis 13. It adapts well to the margins of the lost substance and can be cut to emulate the shape of the wound. It is indicated for an immediate covering of the lesion or as surgical preparation of the wound bed for the successive apposition of autologous graft. The non‐integrated fibres can partially become gel by taking on a yellow‐orange colour that may later become brown. Sometimes there may also be a characteristic smell. This must not alarm the inexpert user in the absence of clinical signs of local infection (oedema, perilesional red colour, pain and temperature) and the matrix must not be removed. It can be left in situ for a maximum period of 21 days after which it has to be substituted by a new medication or by an autologous graft. From a practical point of view, Hyalomatrix is ready‐to‐use and easy to apply so as to give complete cover to the wound in question, protecting it from contamination, from penetration by foreign agents and limits the loss of fluids. These properties render it very useful for all other loss of substance where it can also be used as a ‘bridge’ for the temporary cover while waiting for the permanent one (i.e. graft or culture of autologous keratinocytes) 13.
In our clinical cases, the application of a three‐dimensional matrix of HYAFF to cover significant cutaneous defects gave satisfactory results from an aesthetic and functional point of view. The artificial derma is biocompatible, ready for clinical use and as confirmed by our experience, easy to use and convenient associated with rapid recovery and minimum morbility 14, 15.
A significant contribution has been provided by dermal substitutes in the management of defects that follow the removal of skin cancers. Recent studies show the advantages obtained by the use of dermal substitutes, in particular Hyalomatrix and Integra, in the treatment of defects caused by tumour removal of the scalp. Compared with Integra, however, Hyalomatrix has the advantage of being less expensive giving the same, if not better, results in the quality of the scar. In Italy, the cost of treatment for each patient is €226·67 for a model of 10 × 10 cm2 of Hyalomatrix® compared with the €1350·00 for a model of 10 × 10 cm2 of Integra® 16.
With dermal substitute discovery, the choice of more complex reconstructive procedures (such as borders, pedunculates or free) becomes less challenging. The possibility of covering exposed bone with a dermal matrix makes the reconstructive procedure simpler and less invasive for the patient, reducing hospital stay and costs. Artificial derma provides an immediate covering for the skull and a barrier against microbe contamination. Many authors have confirmed the possibility of using the dermal matrix to cover a loss of substance with exposure of the bone 17, 18. These types of wounds, in particular if they have bone or tendons exposed, have an insufficient blood flow for the graft to grow and survive requiring the use of flaps. At the same time, the flaps constitute rather complex reconstructive procedures, such as reconstructive surgery with pedunculated flap that lasts on average 1 hour, and with free flap up to 6 hours, whereas the application of a dermal substitute can be performed in about 30 minutes and the patient can be discharged on the same day, drastically reducing costs.
Local and regional pedunculated flaps provide a more stable covering of the wound compared with grafts, but among the factors that limit use is the dimension of the defect. Defects with dimensions of 12 × 13 cm2 have been successfully treated with fronto‐occipital bipedunculated flaps. This technique has limitations where the area concerned by the defect has been compressed by previous reconstructions or radiations. In a study conducted by S. Gupta et al., three patients in whom all the above mentioned reconstructive techniques had failed were successfully treated with dermal substitutes 11, 12.
Another negative aspect not to be ignored in flap reconstruction is the difficulty in reconstructing an eventual cancer relapse with respect to the use of skin graft or dermal substitutes, which apart from providing a limitless and immediate cover of the loss of substance, conserves the original surgical borders of resection. We must also point out that compared with grafts, covering the surgical wound with dermal substitutes makes possible, in the case of histological results of cancer not completely removed, a radicalisation of removal without having to reopen the wound and so compromising the previous graft 12.
Furthermore, comparing covered areas using dermal substitutes with those rebuilt with only partial‐thickness skin grafts we could see a smoother and less apparent scar, minor occurrence of hypertrophic and retracted scars, better flexibility of healed skin and therefore a better result from an aesthetic point of view.
Conclusions
In this study, 20 patients treated with a dermal induction template after the removal of malignant skin cancers situated in various parts of the body were included. Most of them are aged patients, average age of 73, with multiple, relapsed skin tumours with a complex pathological picture and often affected by interior pathologies such as cardiopathy, diabetes mellitus, and hypercholesterolaemia. In many of these patients, age, the general complex clinical picture and the use of pharmacological multi‐therapies, in particular antiplatelets and anticoagulants, provided significant contraindications for complex reconstructive surgery because of the high risk involved. With the use of a dermal substitute, the duration and the difficulty of the surgical operation is drastically reduced. Dermal substitutes may be applied under local anaesthesia. Compared with autologous grafting, this matrix provides an immediate and unlimited coverage of the cutaneous defect without creating another wound in the donation site. It has also been demonstrated that the scars of patients treated only with Hyalomatrix and those of patients treated with the dermal substitute and grafts were similar. This means that it is possible to avoid another graft surgical operation for the patient and therefore the cost involved where it is not absolutely necessary. The conservation of the excision surgical margins, after histological examinations in the case of a carcinoma not completely removed, has allowed the radicalisation of the operation without having to reopen the wound. With this reconstruction method, it has in fact been possible to limit the hygienic costs, reduce the surgery risks and improve the quality of life of the patient.
Acknowledgement
The authors would like to thank Dr. Franco Bartolomei for his help in preparing this article.
References
- 1. American Cancer Society . Cancer facts & figures 2009. Atlanta: American Cancer Society. http://www.cancer.org/Research/CancerFactsFigures/cancer‐facts‐figures‐2009. [accessed on 24 August 2011]
- 2. Ashfaq A, Marghoob MD. Skin cancers and their etiologies. Semin Cutan Med Surg 2011;30:S1–5. [DOI] [PubMed] [Google Scholar]
- 3. Boyce ST, Kagan RJ, Greenhalgh DG, Warner P, Yakuboff KP, Palmieri T, Warden GD. Cultured skin substitutes reduce requirements for harvesting of skin autograft for closure of excised, full‐thickness burns. J Trauma 2006;60:821–9. DOI: 10.1097/01.ta.0000196802.91829.cc. [DOI] [PubMed] [Google Scholar]
- 4. Andreassi A, Bilenchi R, Biagioli M, D'Aniello C. Classification and pathophysiology of skin grafts. Clin Dermatol 2005;23:332–7. DOI: 10.1016/j.clindermatol.2004.07.024. [DOI] [PubMed] [Google Scholar]
- 5. Price RD, Das‐Gupta V, Leigh IM, Navsaria HA. A comparison of tissue‐engineered hyaluronic acid dermal matrices in a human wound model. Tissue Eng 2006;12:2985–95. [DOI] [PubMed] [Google Scholar]
- 6. Stark HJ, Willhauck MJ, Mirancea N, Boehnke K, Nord I, Breitkreutz D, Pavesio A, Boukamp P, Fusenig NE. Authentic fibroblast matrix in dermal equivalents normalises epidermal histogenesis and dermoepidermal junction in organotypic co‐culture. Eur J Cell Biol 2004;83:631–45. [DOI] [PubMed] [Google Scholar]
- 7. Duncan JAL, Bond JS, Mason T, Ludlow A, Cridland P, O'Kane S, Ferguson MW. Visual Analogue Scale scoring and ranking: a suitable and sensitive method for assessing scar quality? Plast Reconstr Surg 2006;118:909–18. [DOI] [PubMed] [Google Scholar]
- 8. Durani P, McGrouther DA, Ferguson MWJ. Current scales for assessing human scarring: a review. J Plast Reconstr Aesthet Surg 2009;62:713–20. [DOI] [PubMed] [Google Scholar]
- 9. Shevchenko RV, James SL, Elizabeth James S. A review of tissue‐engineered skin bioconstructs available for skin reconstruction. J R Soc Interface 2010;7:229–58 first published online 28 October 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Chen WYJ, Abatangelo G. Functions of hyaluronan in wound repair. Wound Repair Regen 1999;7:79–89. [DOI] [PubMed] [Google Scholar]
- 11. Fosang AJ, Hardingham TE. Matrix proteoglycans. In: Comper WD, editor. Extracellular matrix. Molecular components and interactions. Vol. 2. The Netherlands: Harwood Academic Publishers, 1996:200–29. [Google Scholar]
- 12. Toole BP. Proteoglycans and hyaluronan in morphogenesis and differentiation. In: ED H, editor. Cell biology of extracellular matrix, 2nd edn. New York: Plenum Press, 1991:305–41. [Google Scholar]
- 13. Violas P, Abid A, Darodes P, Galinier P, de Gauzy JS, Cahuzac JP. Integra artificial skin in the management of severe tissue defects, including bone exposure, in injured children. J Pediatr Orthop B 2005;14:381–4. [DOI] [PubMed] [Google Scholar]
- 14. Lorenz C, Petracic A, Hohl HP, Wessel L, Waah KL. Early wound closure and early reconstruction: experience with a dermal substitute in a child with 0 percent surface area burn. Burns 1997;23:505. [DOI] [PubMed] [Google Scholar]
- 15. Onesti MG, Marcasciano F, Staccioli S. Utilizzo di matrice biologica rigenerante (Hyalomatrix®) nel trattamento di una perdita di sostanza traumatica a tutto spessore in età pediatrica. Derm Clin 2004;22:95–8. [Google Scholar]
- 16. Chou TD, Chen SL, Lee TW, Chen SG, Cheng TY, Lee CH, Chen TM, Wang HJ. Reconstruction of burn scar of the upper extremities with artificial skin. Plast Reconstr Surg 2001;108:38. [DOI] [PubMed] [Google Scholar]
- 17. Leffler M, Horch RE, Dragu A, Bach AD. The use of the artificial dermis (Integra) in combination with vacuum assisted closure for reconstruction of an extensive burn scar. A case report. J Plast Reconstr Aesthet Surg 2010;63:e32–5. [DOI] [PubMed] [Google Scholar]
- 18. Lee‐Pu LQ. An alternative approach for soft‐tissue coverage of a complex wound in the foot and ankle with vacuum‐assisted closure over artificial dermis and subsequent skin graft. J Plast Reconstr Aesthet Surg 2009;62:e682–4. [DOI] [PubMed] [Google Scholar]