Efficacy and Safety of Carbon Dioxide Laser Ablation Combined with Manual Dermabrasion and Intralesional 5-Fluorouracil Injection in Bowen’s Disease

Abstract

Background:

Bowen’s disease (BD) is a precancerous in-situ squamous cell carcinoma and has a high recurrence rate with any single treatment modality, necessitating combination therapy for a successful outcome.

Aim:

This study aimed to the efficacy and safety of carbon dioxide (CO₂) laser ablation followed by manual dermabrasion and intralesional 5-fluorouracil (IL 5-FU) injection as combination therapy for BD.

Materials and Methods:

This was a retrospective, observational study comprising 29 clinically and histopathologically diagnosed BD patients with no history of prior treatment. Demographic characteristics and clinical examination of the lesions and regional lymph nodes were retrieved. All patients were subjected to CO₂ laser ablation followed by manual dermabrasion and IL 5-FU injection.

Results:

Mean age was 61.93 ± 9.31 years with male preponderance (62.1%). Trunk (48.3%) was the most frequently involved site. Mean tumor size was 40.8 ± 16.4 mm (range: 15–86 mm). All lesions healed with a cure rate of 96.6%. Complications seen in patients included atrophic scarring with persistent post-inflammatory hyperpigmentation in three patients (10.3%), secondary infection in two cases (6.9%), and hypertrophic scar with early keloid in one patient (3.4%). Recurrence was reported in one patient (3.4%).

Limitation:

The study was limited by retrospective study design, small sample size, and no comparison with standard therapy.

Conclusion:

Combination approach using carbon dioxide laser ablation followed by manual dermabrasion and IL 5-FU injection has been proved to be effective, efficient and safe with good functional, oncological and aesthetic outcomes in treating BD.

Introduction

Bowen’s disease (BD) is an intraepithelial in-situ squamous cell carcinoma (SCC) of the skin and mucous membranes.[1] Clinically, it appears as an asymptomatic, slow-growing, persistent, erythematous, reddish-brown, dry scaly or crusted patch or plaque with an irregular well-demarcated border. It can be pigmented, verrucous or fissured and is usually single but can be multiple.[2,3] BD is commonly located in white skin people on sun-exposed areas but can also affect various covered areas such as lower legs, subungual, periungual, genitals and the perianal area.[3,4] Histologically, it affects full thickness of the epidermis with cells lying in complete disorder described as a “windblown appearance”, with the presence of abnormal dyskeratotic keratinocytes with atypical nuclei which can extend deep into pilosebaceous unit up to the insertion of sebaceous duct and may replace infundibulum, external root sheath and the sebaceous gland.[4,5] Its extragenital (3–5%) and genital or perianal lesions (10–11%) can progress into invasive SCC, metastasize and even cause death when untreated.[2,6,7] The exact etiological factors are not known; however, various factors such as chronic sun exposure, arsenic ingestion, human papillomavirus, radiotherapy, chronic trauma, and immunosuppression are thought to be responsible.[6,8,9,10] Various treatment modalities include topical [5-fluorouracil (5-FU), imiquimod cream], photodynamic therapy, cryotherapy, radiotherapy, curettage with cautery, surgical excision [standard/Moh’s micrographic surgery (MMS)] and laser therapy [carbon dioxide (CO₂), argon, neodymium-doped yttrium aluminium garnet (Nd:YAG)].[6,11,12] Among these, the CO₂ laser is found to be effective and reliable, which is usually restricted to the epithelium in the vaporizing mode used to destroy neoplastic lesions.[12,13,14,15] Nevertheless, few studies have shown 20% recurrence rate with CO₂ laser ablation and one study has reported malignant transformation to invasive SCC.[16,17] Treatment failure may be related to the extension of BD either from lateral margins or deeper follicular extensions.[6,12,13] In this study, two passes of CO₂ laser ablation of lesions along with 5 mm of normal peripheral skin/mucosa have been combined with manual dermabrasion followed by intralesional (IL) 5-FU injection to address the lateral and deep components of BD at one sitting to achieve optimum outcomes. This study investigated the efficacy, safety, recurrence, oncological, functional and aesthetic outcomes of the stated combination in the treatment of BD. To the best of our knowledge, this combination has not been used earlier.

Materials and Methods

Study design

This was a retrospective, observational study carried out at outpatient department at a tertiary health center of Mumbai from July 2015 to September 2020. Patients who were diagnosed with BD based on clinical examination and biopsy and no history of prior treatment were included. Patients with active malignancy and pregnancy were excluded. This study conformed to the principles outlined in the Declaration of Helsinki and approved by local Institutional Ethics Committee. A written informed consent was obtained from each patient.

Data collection

Demographic, clinical characteristics of lesion and regional lymph nodes, disease duration, biopsy (histopathological) findings, procedural characteristics and treatment outcomes were collected as per the predefined proforma. Complications and recurrence rates were reported.

Preoperative workup

The duration, type, size and anatomical location of the lesions along with status of regional lymph nodes were recorded. All cases were biopsied to rule out malignant changes and to confirm the diagnosis of BD. All patients were started on broad-spectrum antibiotics, analgesics and anti-inflammatory drugs before treating them on an outpatient basis.

Procedure

The area was surgically prepared and local anesthesia (1% lignocaine with or without adrenaline) was administered. Protective eye pads were used and marking was done on the normal perilesional cutaneous/mucosal surface, 5 mm away from the border of lesion all along its periphery. The focusing lens of 10,600 nm CO₂ laser (LaserbioOptotechl., Mumbai, India) hand piece was removed and parameters were adjusted (power mucosal: 6–8 W, cutaneous: 8–12 W, spot size: 6 mm, mode: continuous wave—vaporizing). The first pass was taken in horizontal plain (X-axis), and entire marked area was ablated with an overlap of 10–15% to bubble it out using freehand technique, moving from one pole to other in rapid to and fro sweeping movements. The bubbled out ablated debris was wiped off to leave behind pinkish dermis/mucosa. The second pass in vaporizing mode was taken perpendicular to the first pass in vertical plain (Y-axis) to entirely cover the treated area, causing intensified blanching due to further destruction of superficial papillary dermis/submucosa. The debris was wiped away to leave behind a pinkish red papillary dermis/submucosa. Dermabrasion was carried out with a manual dermabrader in a crisscross manner through the papillary dermis to the desired level (maximum: junction of upper and mid-reticular dermis); with end points being rapid excessive bleeding with fraying or appearance of breaks in the pink white to gray colored parallel lines and ridges with a feeling of resistance. The base was injected intralesionally with1 ml of 5-FU (50 mg/ml) diluted with 3 ml of distilled water, to a total of 4 ml of solution (concentration of 5-FU being 12.5 mg/ml). The entire ablated area was injected with 0.05 to 0.1 ml of solution at equidistant points. Antibiotic ointment was applied and the wounds were dressed, except genitals wounds that were left open and allowed to heal by secondary intention.

Postoperative

Pain, edema and discomfort experienced by all patients following surgery were well controlled with anti-inflammatory drugs and analgesics. Oral antibiotics were continued for 8–10 days. Topical antibiotic ointment was continued for genital wounds until healed. Other wounds were redressed every week till they healed (4–6 weeks). All lesions healed by secondary intention with or without transient pigmentation and superficial atrophic scarring, which settled down over 6–9 months in most of the cases. Recurrence was observed in one patient; he was retreated and followed up at weekly intervals for 1 month, monthly interval for 3 months, three monthly intervals for 1 year and six-monthly intervals for the total period of 5 years.

Data analysis

Descriptive statistics were presented as mean ± SD for continuous variables and as frequency (%) for categorical variables. Statistical analyses were done using the Statistical Package for Social Sciences (SPSS) version 18.0 software (SPSS Inc., Chicago, IL, USA).

Results

A total of 29 BD patients with a mean duration of 11.3 ± 7.5 years were analyzed. Mean age was 61.93 ± 9.31 (range 45–80) years. Male [18 (62.1%)] patients were predominantly afflicted with BD than females [11 (37.9%)] with ratio of 1.63:1. Mean tumor size was 40.8 ± 16.4 mm (range: 15–86 mm). Anatomical sites involved were trunk in 14 (48.3%), lower limb in 5 (17.2%), scalp in 4 (13.8%), genital in 4 (13.8%), palm in 1 (3.4%) and subungual in 1 (3.4%). A cure rate of 96.6% was achieved after the procedure. Sun exposure was a risk factor in all patients. All the lesions healed with superficial scarring and transient post-inflammatory hypo/hyperpigmentation, which settled over a period of 6–9 months [Figures 1 and 2].

Figure 1.

Bowen’s disease combo technique on lateral aspect of back (a) before, following (b) CO₂ laser ablation, (c) manual dermabrasion, (d) intralesional injection of 5-fluorouracil, and (e) complete healing with postinflammatory hyperpigmentation after 1 month

Figure 2.

Bowen’s disease combo technique on scrotum (a) before, following (b) CO₂ ablation, (c) manual dermabrasion, (d) intralesional injection of 5-fluorouracil, and (e) complete healing with postinflammatory hyperpigmentation after 1 month

Complications seen were atrophic scarring with persistent post-inflammatory hyperpigmentation (PIH) in 3 (10.3%), secondary infection in 2 (6.9%) and hypertrophic scar with early keloid in 1 (3.4%). Recurrence was reported in one patient (3.4%) who after treatment with second session of similar combination healed with atrophic scarring and PIH with no recurrence or transformation to invasive SCC, achieving cure rate of 100% at the end of 5 years. Summary of BD cases is presented in Table 1. Disease-free survival period was 5 years for all patients.

Table 1.

Summary of 29 cases with Bowen’s disease

Case	Sex	Age on diagnosis	Duration of disease (months)	Size (mm × mm)	Site	Recurrence	Complication
1	Male	53	6	23×31	Scalp	No	–
2	Female	80	8	44×61	Trunk	No	–
3	Male	45	12	38×44	Lower limb	No	–
4	Male	61	12	29×27	Scalp	No	–
5	Female	47	11	52×43	Trunk	Yes*	Atrophic scarring with persistent PIH†
6	Female	59	3	12×18	Scalp	No	–
7	Male	56	18	39×55	Trunk	No	–
8	Female	55	9	42×33	Lower limb	No	–
9	Male	68	16	51×39	Trunk	No	Secondary infection
10	Male	75	24	21×30	Scalp	No	–
11	Female	69	7	48×56	Trunk	No	–
12	Female	73	36	47×41	Trunk	No	Hypertrophic scar with early keloid
13	Male	52	14	89×83	Lower limb	No	–
14	Female	49	6	42×45	Trunk	No	–
15	Female	59	3	31×27	Genital	No	–
16	Male	71	6	44×38	Lower limb	No	–
17	Female	62	9	58×43	Trunk	No	–
18	Male	64	18	64×57	Lower limb	No	Atrophic scarring with persistent PIH†
19	Male	68	5	29×22	Genital	No	–
20	Male	73	6	47×41	Trunk^	No	Atrophic scarring with persistent PIH†
21	Male	62	5	25×20	Genital	No	–
22	Male	71	18	43×45	Trunk	No	–
23	Male	58	3	39×46	Trunk	No	–
24	Male	52	12	32×29	Palm	No	–
25	Male	51	24	79×63	Trunk	No	–
26	Male	56	12	19×14	Subungual	No	–
27	Female	69	6	24×23	Genital	No	–
28	Male	66	9	46×67	Trunk	No	Secondary infection
29	Female	72	9	62×57	Trunk	No	–

^†PIH, Post inflammatory hyperpigmentation. ^Lesion on the back near scapula treated with complete response to two injections of intralesional triamcinolone acetonide. *Recurrence: Patient was retreated with similar treatment with no further recurrence or transformation to invasive squamous cell carcinoma

Discussion

BD has a superficial intraepithelial component and may have a deeper follicular and lateral marginal extensions, and hence, there can be chances of recurrence or transformation to invasive SCC.[2,6,11,12,13] However, a proper clinical and histopathological evaluation followed by active and prompt treatment can be beneficial in treating BD. In this study, sequential combination was used to address these factors. The CO₂ laser ablation is easily accessible, simple, safe and rapid with a bloodless operative field. It achieves precise de-ephitheliazation with minimal collateral thermal damage.[15] In this study, using freehand technique, the epidermal-dermal/epithelial-submucosal split with bubbling effect was achieved with completely defocused beam of uniform intensity and a high tissue temperature was reached (100°C boiling point) to cause ablation of the lesion and the peripheral marked area. The two criss-cross passes ensure destruction of lateral and deeper components of superficial papillary dermis/submucosa.[15] Most of the studies have included a lateral margin of perilesional normal area from 2 to 4 mm during CO₂ laser ablation to take care of the lateral extension of the atypical cells with varied success rate.[12,13] In this study, a margin of 5 mm of perilesional normal area was vaporized, which may have further helped in vaporizing the lateral extensions of the remaining atypical cells. The residual components left behind if any were further taken care of by well-visualized sequential planning to reach the junction of upper and mid-reticular dermis, thus combining safety with efficacy through manual dermabrasion. Premalignant conditions such as BD and actinic cheilitis have been effectively treated by dermabrasion alone or combining it with intralesional injection of 5-FU.[18] 5-FU has an antimetabolite action, which inhibits proliferation and differentiation of the atypical cells (intra-epithelial/deep follicular or lateral extensions) through its cytotoxic action and has been used topically and intralesionally alone or in combination with other therapies to successfully treat BD with reduced recurrence rate.[6,11,12,18,19,20] In this study, the well-spaced out injection of 5-FU at multiple places may have further helped in the destruction of lateral and deeper follicular/submucosal extensions of remnant of atypical cells.[18,19] Treatment modality and outcomes of previous and present study are outlined in Table 2.

Table 2.

Treatment modality and outcomes of previous study and present study

Author	Key findings
Present study	IL (5-FU) injection was combined with CO2 laser ablation and manual dermabrasion to achieve primary success rate of 96.6% which improved to 100% when same combination was repeated for the single recurred case
Gordan et al.[16]	20% recurrence rate with carbon dioxide laser vaporization in BD
Tantikun N et al.[21]	Complete response with no recurrence to CO2 laser therapy for BD with a follow up of 7.7 years with good functional and cosmetic outcome
RK et al.[22]	Poor response to only laser therapy while discussing various treatment options in patients with perianal BD
Fader and Lower et al.[23]	Three patients of BD treated with combination of CO2 laser with long-pulsed diode laser with no recurrence at 4 months
Dave et al.[17]	Sixteen patients with 25 lower leg BD lesions treated with CO2 laser reported 100% healing at 2 months, with no recurrence at 6 months; nevertheless, there was progression to invasive SCC in 12% within 1 year
Covadonga Martínez-González et al.[12]	Clearance of 86.3% (38 out of 44) cases of BD after first sitting and 11.3% (five out of 38) after more than one treatment of CO2 laser ablation. In 2.2%, that is, in one patient, topical 5-FU cream had to be added to achieve complete clearance as there was no response, thus bringing out the importance of combination therapy
Covadonga Martínez González et al.,[12] Savant SS et al.,[18] Wang et al.,[24] and Welch et al.[25]	Combination of 5-FU with other modalities such as occlusion, iontophoresis, dermabrasion, cryotherapy, CO2 laser ablation, and erbium: YAG laser, imiquimod, acitretin, and so on, increases their effectivity in treatment of BD with response rate up to 96.2%

The combination of three different modalities adopted in this study has multiple advantages such as being office-based and can be performed under local anesthesia even on large lesions in one session. Postoperative mobility and functional ability of treated tissue are retained. There are minimal side effects and complications, and the procedure can be repeated in case of recurrence. However, there are certain disadvantages such as lesions take longer time to heal than primary surgical excision or MMS.[6] The main disadvantage is that the vaporized tissue is not available for histopathology.[6,15,18]

Complications seen in this study were atrophic scarring with persistent PIH in three cases; this could have been because during CO₂ laser ablation and dermabrasion, the depth may have gone beyond the reticular dermis.[15,18] Also, laser wounds are known to heal with minimal superficial atrophic scarring due to reduction in the number of myofibroblast.[26] Secondary infection occurred in two cases, which was well controlled by extending the oral antibiotic coverage. Hypertrophic scar with early keloid formation (0.5 in. diameter) occurred in one case where there was delayed wound healing as the lesion was large and located over the back near the scapula, it being a tension prone area with regional tendency to form keloid due to delayed wound-healing response.[27,28] This was successfully controlled with two sequential intralesional injections of triamcinolone acetonide (10 mg/ml) given at 6 week intervals and proper follow-up. Early keloids are known to respond well to repeated intralesional injections of TCA.[29] Recurrence was observed in one case after 4 months, which responded well to similar line of treatment with complete clearance and no further recurrence or transformation to invasive SCC. This could have been due to residual atypical cells left behind either at the deep or lateral margins after first sitting. They got completely destroyed in the second sitting; hence, there was 96.6% initial and 100% final success rate with no recurrence or transformation into invasive SCC on follow-up of 5 years.

Thus, this study confirms the efficacy, safety and usefulness of the combination of CO₂ laser ablation with manual dermabrasion followed by intralesional injection of 5-FU to achieve successful aesthetic, oncological and functional outcomes in treating lesions of BD.

Limitations

This study is limited by its retrospective nature and small sample size. Additionally there is no comparative arm as a simple double cauterization followed by 5-FU injection/ointment, curettage with cautery (electrodessication/RF ablation), dermabrasion followed by injection of 5 FU, liquid nitrogen cryo followed by 5-FU injection, and so on.

Conclusion

BD is a potentially premalignant condition that can transform into SCC; hence, prompt treatment following clinical evaluation and histopathological confirmation is important. From this retrospective study, one can conclude that CO₂ laser ablation followed by manual dermabrasion and intralesional 5-FU injection is an innovative combination to treat BD. It is effective in achieving excellent oncological result and offers ease in surgery, minimal blood loss and recurrence as well as no aesthetic disfigurement with preserved function than other more aggressive or more expensive treatment modalities; hence, it is a better treatment option for BD.

Ethics: Ethical approval has been obtained from local institutional committee (Registration No: ISBEC/NR-22/KM-KM/2022).

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

No source of funding.

Conflicts of interest

There are no conflicts of interest.