INTRODUCTION

Keloids are exuberant forms of scar formation due to abnormal wound healing in responses to trauma and inflammation, or occasionally occur spontaneously in predisposed individuals, resulting in benign fibrous growth with excessive formation of connective tissue (collagen and glycosaminoglycans). They are raised/flat/pedunculated, firm, painful, pruritic tumors with borders extending beyond original wound and can cause contractile functional problems.[12] Various factors, such as immunological, genetic, fibroblast activity, hypoxia, hormonal, tension, trauma, and inflammation, are thought to be responsible for the development of keloid scars. Various treatment modalities include radiation,[1,2,3,4,5] corticosteroid injection,[1,2,3,4,5] surgical excision,[1,2,3,4,5,6,7] cryotherapy,[1,2,3,4,5,68,9] laser,[2,3,4,58] compression therapy,[2,3,4,5,6] silicone gel sheet (SGS),[2,3,4,5,6] 5-fluorouracil injection,[2,3,4,5,610] and botulinum toxin.[3,4,5] Many of these modalities have been associated with a high recurrence rate. None single effective treatment modality yields satisfactory results; hence, the combination therapies have become popular.[2,3,4,5,611] We have selected surgical excision or cryotherapy in combination with intralesional corticosteroids along with 5-fluorouracil [IL (S + 5-FU)] injection, followed by SGS under compression therapy in the treatment of keloids. With extralesional or intralesional surgical excision, nearly total debulking can be achieved.[1,2,3,4,5,6,7] LN₂ cryotherapy (intralesional or surface) achieves debulking through tissue necrosis by cellular destruction and vascular stasis.[13,4,5,6,812] Decreased production and increased breakdown of collagen can be achieved by regulating fibroblasts through other modalities, such as corticosteroids (growth factors),[1,2,3,4,5,610,13] 5-fluorouracil (antimetabolite action),[1,2,3,4,5,610,1113,14] SGS (hydration of keratinocytes),[24,611,13] and compression therapy (decreases blood supply, hypoxia).[2,3,4,5,611,13] This study was carried out to investigate efficacy, safety, recurrence, and aesthetic outcome of combination therapy—surgical excision or cryotherapy and IL (S + 5-FU) injection, followed by SGS under compression therapy in the treatment of keloids. To the best of our knowledge, such an individualized multimodal approach has not been used earlier.

MATERIALS AND METHODS

RESULTS

Of total 21 (11 males and 10 females) keloids patients, 11 (52.4%) were treated with LN₂ cryotherapy and 10 (47.6%) with surgical excision. The mean age was 30.8 ± 7.6 years with a range of 14−44 years. A mean surface area/volume of keloid lesion was 96.8 ± 170.5 cm³. The most common shape of keloid lesion was bulky (eight patients [38.1%]). Anatomical sites of keloid were as follows: auricle (8 [38.1%]), anterior chest wall (4 [19.0%]), shoulder (2 [9.5%]), bilateral elbow joint (1 [4.8%]), abdomen (1 [4.8%]), nape of neck (1 [4.8%]), left elbow joint (1 [4.8%]), bilateral mandibular margin of face (1 [4.8%]), planter aspect of lower limb (1 [4.8%]), and suprapubic (1 [4.8%]). Patients received the following treatment: intralesional LN₂ cryotherapy (6 [28.6%]), intralesional excisional surgery (6 [28.6%]), surface LN₂ cryotherapy (5 [23.8%]), and extralesional excisional surgery (4 [19.0%]). Keloids scars were completely healed after receiving the mentioned treatment [Figures 1–5]. Complications of recurrence (2 [9.5%]), secondary infections (2 [9.5%]), persistent postinflammatory hypopigmentation (1 [4.8%]), and atrophic scarring with postinflammatory hyperpigmentation (1 [4.8%)] were noted. After a study period of 2.5 years, 100% cure rate was achieved. A summary of 21 cases with keloid is presented in Table 1.

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Figure 1

(A) Multiple bulky keloids on bilateral elbow joint, (B) multiple bulky keloids on bulky keloids right forearm, (C) multiple bulky keloids on left forearm, (D) multiple bulky keloids treated with intralesional cryotherapy, (E) immediate postoperative, (F) complete flattening after six sessions, (G) complete flattening after six sessions, and (H) complete flattening after six sessions

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Figure 2

(A) Flat keloid left forearm, (B) surface ln2 cryo roller, (C) intralesional injection (S + 5-FU), and (D) after four sessions

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Figure 3

(A) Bulky keloid on face, (B) debulking with radiofrequency, (C) after complete debulking—suturing, (D) after complete suturing, (E) compression with SGS, and (F) after complete healing

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Figure 4

(A) Nodular keloid over left auricle rim, (B) surgical excision, (C) complete debulking, (D) suturing the auto flap, (E) sutured flap immediate postoperative, and (F) complete healing

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Figure 5

(A) Bulky keloid on plantar aspect of foot, (B) debulking with scalpel, (C) complete debulking with scalpel, (D) intralesional (S + 5-FU), and (E) complete healing

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DISCUSSION

Keloids pose a challenge as they have high recurrence rate and do not respond completely to any single treatment modality. Hence, surgical key for successful outcome is the sequential combination of multiple modalities after maximum debulking either by cryotherapy or surgical excision.[2,3,4,5,6,7,8,911,12,13] However, after extralesional surgical excision, most of the studies have reported a high recurrence rate of 80%–100%.[13] Lee et al.[7] devised intralesional autoflap surgery and reported no recurrence in 20 of 24 patients (90%). Various advantages have been proposed for reducing recurrence in support of intralesional as against extralesional surgical excision are: (a) it avoids injury to neighboring skin[15] and the deep dermal layers with subcutaneous fat,[16] (b) reduces the most proliferative central fibroblastic group,[17] (c) facilitates injecting intralesional corticosteroid,[15] and (d) provides protective action by retaining the keloidal rim.[18] By contrast, many studies are not in support of this as some amount of keloidal tissue (rim) is left behind, which can proliferate, so also keloid can arise from the extralesional peripheral areas and, thus, has reported high recurrence rate (45%).[1920] Hence, various adjuvant therapies have been suggested along with surgical excision. Auricular compression devices and intralesional TCA have been combined with surgical excision to successfully treat auricular keloids with reduced recurrence rate and improved scar quality.[21] There are other studies that have combined intralesional excision with multiple sessions of intralesional TCA (10–40 mg per session) and a recurrence rate of 0%–25% over a follow-up of 9–36 months.[1113,18,19,20] In this study, after surgical excision, IL (S + 5-FU) was given intra- and postoperatively, followed by the use of SGS under compression to achieve complete regression in 9 of 10 patients (90%).

Standard LN₂ cryotherapy either intralesional or surface (spray/probe) achieves rapid debulking of large bulky/flat keloids.[1,2,3,4,5,68,911,12] However, following both these techniques, there are tissue necrosis, ulceration with surface destruction, delayed wound healing, pigmentary changes (hypo/hyper/depigmentation), atrophy, scarring, and recurrence.[1,2,3,4,5,68,911,1222] As against standard intralesional cryotherapy,[89,22] where the LN₂ is used to freeze the lesion completely from inside (core) out to destroy it along with surface skin, in this study, two freeze-thaw cycles were carried out to achieve debulking with minimal damage to the overlying surface skin at the entry and exit points of the needle only. Similarly, as against standard surface cryotherapy,[1,2,3,4,5,611,12] where the LN₂ is used to freeze the lesion from outside either by spray or probe to destroy it along with surface skin, in this study, metallic rollers were used to cause shallow cryoinjury to achieve debulking without damaging the surface skin. The results of the most of the intralesional cryotherapy studies reported mean volume reduction ranging from 51.4% to 63% (range: 16%–100%).[89] Stromps et al.[23] reported volume reduction of 89% for facial and 47% for presternal scars. Gupta and Kumar[22] reported more than 75% scar volume reduction in 7 of 12 patients. van Leeuwen et al.[8] in addition reported 58.5% mean scar surface area reduction. Most of this reduction occurred after single treatment in 3–4 months. Most studies evaluated the results after single cryo session, whereas some used up to 10 sessions.[89] In this study, more than 75–100 scar volume reduction was achieved in 11 patients with one or both methods of cryotherapy in 4–6 sessions. Cryotherapy, when used alone, has shown variable recurrence rate; hence, it has been combined with TCA with or without 5-fluorouracil, SGS, compression therapy, etc. to successfully reduce the recurrence rate by many authors.[1,2,3,4,5,610,1113,14,15,1820,2123,24] Boutli-Kasapidou et al.[25] reported complete recovery in 87% using cryosurgery and intralesional corticosteroids. Weshahy and Abdel Hay[26] used the combination of intralesional cryotherapy and intralesional corticosteroid injections in 22 of 25 cases with 93% mean volume reduction after 4 months (P < 0.001). Stromp et al.[23] as mentioned earlier used SGS as an adjuvant to intralesional cryotherapy and achieved good results in 21 of 32 (89%) cases. In this study, after cryotherapy, ILS + 5-FU injection was given intra- and postoperatively followed by SGS under compression to achieve complete regression in 10 of 11 patients (90.9%).

Response of keloids to corticosteroid injection alone is reported to be variable with 70%–90% regression rate and with 33%–50% recurrence rate after 1 and 5 years.[14] The combination of TCA with 5-FU has been reported to be more effective with less side effects and better patient satisfaction.[2,3,4,5,6] Darougheh et al.[10] in a double-blind study of 40 patients reported more than 50% improvement in 55% of cases treated with TCA and 5-FU as against only 20% of cases treated with TCA alone. Khan et al.[27] compared the use of intralesional TCA alone and its combination with 5-fluorouracil and found that the combination was superior to TCA alone in achieving faster response with fewer side effects. The intralesional 5-fluorouracil (50 mg/mL 2–3 times a week) shrinks keloid safely while avoiding the side effects of repeated corticosteroid injections such as tissue atrophy and telangiectasia.[28] Corticosteroids and fluorouracil when combined, complement each other by diminishing the adverse effect of each other such as menstrual irregularity (corticosteroids), ulceration (5-fluorouracil) as fewer treatment sessions are required to achieve favorable outcome, thus increasing the patient compliance.[2728] In this study, the combination of intralesional injection of short-acting (hydrocortisone) and long-acting (TCA) corticosteroids along with injection 5-fluorouracil was used intra- and postoperatively, which gave immediate symptomatic (pain and itching) relief with volume/surface reduction that was sustained over next 4–6 weeks. In this study, no adverse effects of corticosteroids or 5-fluorouracil were observed in any of the patients, fewer numbers of sessions were required to achieve volume reduction with flattening, and there was good patient compliance with recurrence in only 2 of 21 cases (9.1%).

Most of the standard (intralesional/superficial), cryotherapy studies reported mild-to-moderate postoperative pain with local edema and superficial necrosis in the first few weeks followed by postoperative pigmentation (de/hypo/hyper) in majority of the cases; which improves over a period in most of them.[1,2,3,4,5,68,912,1322] Two meta-analysis studies on intralesional cryotherapy reported that hypopigmentation persisted permanently in 30%–35% of patients.[89] One study reported wound infection in 7.5% of cases, which improved after conservative treatment.[8] In this study, minimal postoperative pain and edema occurred in all the patients who were successfully treated with anti-inflammatory and analgesic drugs. Secondary infection was reported in two patients, which was successfully controlled with additional course of antibiotics. There were transient postoperative pigmentary (de/hypo/hyper) changes, which gradually subsided and disappeared over the next 6–9 months in all 10 of 11 patients (90.9%) treated with cryotherapy. However, postinflammatory hypopigmentation persisted in one patient even after a follow-up of 2.5 years. The recurrence rate in most of the studies ranged from 0% to 24% with a mean of 7.6%% ± 10.1%.[8] One study reported recurrence at the periphery (0.5–1 cm³) in 12% of cases, which flattened after repeated intralesional steroid injections.[21] In this study, recurrence was noted in 2 of 21 patients (9.1%) in spite of combination treatment. One patient with large multifocal keloid on the plantar aspect (extralesional surgical excision) had recurrence 2 months after undergoing three sessions of extralesional excision at monthly interval and another with large bulky circumferential keloid near the elbow (intralesional and surface cryotherapy) had recurrence 1.5 months after six sessions of intralesional surface cryotherapy. This could have been due to incomplete removal or destruction of the active part of the keloidal lesion; both these patients were further subjected to similar sessions of treatment as mentioned above, and SGS under compression was continued for prolonged time even after flattening of the keloid (4–6 months) to achieve complete clearance without any further recurrence on follow-up of 2½ years. Patients with multifocal keloids healed with atrophic scarring and postinflammatory hyperpigmentation due to multiple sessions of extralesional surgical excision. Thus, this study brings out the importance of individualized multimodal approach for successfully treating keloids. However, the study is limited by a single-center study design with a relatively small sample size.

All in all, this study concludes that a long-term multimodal approach comprising of IL (S + 5-FU) injection followed by SGS under compression after the initial debulking by either surgical excision or LN₂ cryotherapy as per the individual lesions was found to be highly effective and safe in treating small nodular/pedunculated to large bulky/flat keloids of variable size, number, or anatomical location. There was also a reduction in volume and recurrence rate with less complications and complete regression with flattening effect. The modified cryotherapy adopted in this study minimized surface damage, thus achieving favorable aesthetic and functional outcomes.