Efficacy of Bleomycin Intralesional Injection for Treating Digital Mucous Cysts: A Comparative Study of Corticosteroid Intralesional Injection and Surgical Excision

Abstract

Background

Sclerotherapy has shown superior efficacy among the nonsurgical options for managing digital mucous cysts (DMC). Notably, previous research has indicated that bleomycin offers a more favorable side-effect profile and similar efficacy to conventional sclerosing agents.

Objective

This study aimed to assess the efficacy and safety of bleomycin intralesional injection (ILI) for treating DMC through a comparative analysis of corticosteroid ILI and surgical excision.

Methods

We retrospectively reviewed electronic medical records and clinical photographs. Telephone interviews were conducted to further investigate long-term treatment efficacy, safety, and overall treatment satisfaction.

Results

Ten patients underwent surgical excision, and 13 and 15 patients received bleomycin and corticosteroid ILI, respectively. Both surgical excision and bleomycin ILI demonstrated superior treatment efficacy compared to corticosteroid ILI. No statistically significant difference in the treatment effectiveness between surgical excision and bleomycin ILI was observed. No significant adverse effects were observed. In the survey, the level of satisfaction was the highest for bleomycin ILI, followed by surgical excision and corticosteroid ILI.

Conclusion

This study revealed that bleomycin ILI exhibits a treatment efficacy higher than that of corticosteroid ILI and slightly lower than that of surgical excision, without any side effects. Therefore, bleomycin ILI is a safe and effective therapeutic option for the treatment of DMC.

INTRODUCTION

Digital mucous cysts (DMC) are benign, highly recurrent tumors that typically involve the proximal nail fold and distal interphalangeal (DIP) joints of the fingers. The precise epidemiologic characteristics of the disease remain unknown; however, females are estimated to be affected twice as often as males¹. DMC usually presents as an asymptomatic solitary skin-colored nodule with clear, thick, and gelatinous content². However, it occasionally induces joint stiffness, nail deformities, and pain, which can vary depending on its anatomical location. de Berker et al.²,³ classified DMC into three subtypes based on their location within the nail apparatus The most prevalent subtype, type A, is located between the nail fold and DIP joint. Type B DMCs are found within the proximal nail fold and can exert pressure on the underlying nail matrix, leading to the longitudinal grooving of the nail plate. In rare cases, DMC may extend beneath the nail plate, which is classified as type C.

Although the pathogenesis of DMC remains unclear, it is believed to be associated with degenerative changes in adjacent joints. Kleinert et al.⁴ reported a pedicle connecting the cyst and degenerative joint, and a radiological study further revealed that approximately 80% of DMCs communicate with the adjacent DIP joint³.

To date, no standard therapeutic approach for DMC has been established. Recently, a systematic review proposed a treatment algorithm based on cure rates⁵. According to the review, surgery yields the highest cure rate (95%), followed by sclerotherapy (77%), cryotherapy (72%), corticosteroid intralesional injection (ILI; 61%), and simple aspiration (39%). Therefore, surgical excision is recommended as the primary treatment option. However, it has limitations such as variability in recurrence rates and potential side effects, which are influenced by the surgeon's expertise and the surgical techniques used⁶,⁷,⁸,⁹,¹⁰,¹¹. Among the nonsurgical treatment options, sclerotherapy has demonstrated the highest cure rate; however, side effects, such as joint stiffness and skin necrosis, have raised concerns¹²,¹³.

Bleomycin is an antitumor agent with a sclerosing effect and is primarily used in dermatology for treating vascular tumors and viral warts¹⁴. In prior studies on vascular tumors, bleomycin ILI demonstrated a similar effect with lower incidence of skin and systemic side effects compared to conventional sclerosing agents¹⁵,¹⁶. Additionally, in a preliminary study using an animal model of rheumatoid arthritis, Maralcan et al.¹⁷ proposed that intra-articular administration of bleomycin may attenuate synovial inflammation and fibrosis. Based on the aforementioned evidence, we propose that bleomycin can be considered a safe alternative to conventional sclerosing agents. Reportedly, there have been limited studies on the use of bleomycin ILI to treat ganglion cyst, including DMC¹⁸. Therefore, this study aimed to evaluate the therapeutic efficacy and safety of bleomycin ILI for treating DMC by comparing it with surgical excision and corticosteroid ILI.

MATERIALS AND METHODS

Patients

Data of all patients who visited the Korea University Medical Center (KUMC) Anam, Ansan, and Guro hospitals between January 2012 and May 2023 for DMC treatment were retrospectively analyzed. Patients with insufficient medical records that prevented the accurate assessment of treatment responses were excluded. This study was approved by the Institutional Review Board (IRB) of KUMC (IRB No.2023AN0462). The requirement for informed consent was waived due to the retrospective nature of the study.

Treatment procedure

1) Intralesional injection

The DMC was punctured with a 24-gauge needle and the content was manually expressed by applying pressure to the surrounding area. Subsequently, we injected bleomycin or corticosteroid through the puncture site until blanching appears and applied a compressive dressing. The volume of injection was different depends on the size of tumor.

Bleomycin and corticosteroids were diluted in normal saline and lidocaine, respectively (bleomycin: 0.25 mg/mL, triamcinolone: 4–10 mg/mL).

The patients were followed up every month and re-treatment was done upon suspicion of lesion reappearance. In the absence of any signs of reappearance, we kept observation. The treatment was concluded as remitted if there was an absence of palpable nodule for three consecutive months. Throughout the follow up period, patients had the option to discontinue the treatment through consultations with their physician.

2) Surgical excision

A longitudinal linear incision was made between the nodule and adjacent interphalangeal joint. After identifying the cyst, thorough dissection was performed to locate the pedicle (Fig. 1). The pedicle was ligated using an absorbable suture and the surrounding stroma was electrocoagulated. In cases in which the pedicle could not be identified, this step was excluded. Finally, the cyst was excised, and the skin incision was closed.

Fig. 1. Intraoperative photographs of surgical excision. Linear incision was made between DIPJ and nail fold. (A) After identifying the cyst, surrounding stroma was thoroughly dissected toward DIPJ to locate pedicle (arrow) (B).

DIPJ: distal interphalangeal joint.

Assessment

1) Clinical characteristics

The clinical characteristics of patients were collected from the hospital’s medical information system and clinical photographs. The collected information included sex, age, anatomical location of the lesion, lesion subtype based on the de Berker classification, number of treatment sessions, treatment response, and duration of follow-up.

2) Treatment efficacy

The treatment efficacy was assessed by a board-certified dermatologist in terms of size reduction and tumor flattening. The treatment response was categorized according to the timing of lesion reappearance following treatment. In the ILI group, response was evaluated based on the last treatment session, whereas in the surgery group, response was evaluated based on the date of surgery. A complete response (CR) was defined as the absence of palpable nodules for at least 3 months after treatment. Partial response (PR) was defined as reappearance of the lesion within 3 months, and recurrence was designated when the tumor recurred 3 months after achieving CR.

In September 2023, a telephonic interview was conducted to investigate long-term treatment efficacy, adverse events, and overall treatment satisfaction. During the interview, investigators inquired the patients about the following aspects: 1) reappearance of the lesion; 2) side effects, including joint stiffness, pain, and post-procedural scarring; and 3) overall treatment satisfaction (using a five point-Likert scale).

Statistical analysis

Multivariable logistic regression with the backward Wald selection algorithm was used to identify the predictors of achieving CR. Statistical differences in the level of satisfaction between the treatment options were analyzed using the Kruskal–Wallis test. All analyses were performed with IBM SPSS (version 23.0; IBM Corp., Armonk, NY, USA), and p-values<0.05 were considered statistically significant.

RESULTS

A total of 38 lesions in 36 patients were included in the study (Table 1). The patients had an average age of 62.8±9.9 years. The lesions were more frequently observed on the fingers than on the toes (6.6:1 ratio). In contrast to previous studies, the proportion of males (1.12:1) and patients classified as type B (1.53:1) was slightly higher. In the bleomycin ILI group, there were two patients (1 male and 1 female), each with two lesions on different digits. Ten lesions were surgically excised, 13 were treated with bleomycin ILI, and 15 were treated with corticosteroid ILI. There were no significant differences in sex, age, anatomical location, or clinical subtype among the groups.

Table 1. Summary of the patient characteristics and treatment outcomes.

Procedure	CR	PR	Recurrence	# of lesions	Duration of follow-up (wks)		Age	Sex		Finger		Toe
					Median	IQR		M	F	A	B	A	B
Surgery	9/10	1/10	2/10	10	209.5	259.25	57.1±13.1	4	6	5	3	2	0
Bleo ILI	11/13	2/13	3/13	13	49	44.5	63.7±6.6	7	6	4	7	0	2
Steroid ILI	6/15	9/15	1/15	15	193	148	63.3±9.5	9	6	4	10	0	1
Total	-	-	-	38	-	-	62.8±9.9	20	18	13	20	3	2

Values are presented as mean±standard deviation.

CR: complete response, PR: partial response, IQR: interquartile range, M: male, F: female, A: de Berker classification type A, B: de Berker classification type B.

The treatment outcomes are presented in Table 1. In the surgery group, 90% (9/10) of the lesions showed CR, but two lesions recurred after achieving CR. In the bleomycin ILI group, 84.6% (11/13) of lesions achieved CR, and three cases of recurrence were reported. In the corticosteroid ILI group, 40% (6/15) of the lesions showed CR, but one lesion recurred. One to seven treatment sessions (mean of 3.1 sessions) were required to achieve CR in the bleomycin ILI group and one to four treatment sessions (mean of 2.8 sessions) in the corticosteroid ILI group. Of the three recurrent cases in the bleomycin ILI group, two were retreated, and both achieved CR again after two and three sessions of intralesional bleomycin, respectively. Similarly, the patient who experienced recurrence after corticosteroid ILI achieved CR after two sessions of corticosteroid ILI retreatment. The proportion of patients classified as PR was observed to be 15.4% (2/13), 60% (9/15), and 10% (1/10) in the bleomycin ILI, corticosteroid ILI, and surgery groups, respectively.

Table 2 summarizes the adverse events reported by the patients. No side effects were reported in the ILI group except for post-procedural pain. However, in the surgical excision group, one patient reported joint stiffness, three reported scarring, and one reported mild, transient pain.

Table 2. Patient reported adverse events.

Treatment	Adverse event
Surgical excision	Pain (1/10, 10%)
	Joint stiffness (1/10, 10%)
	Scar (3/10, 30%)
Bleomycin ILI	Pain (3/13, 23%)
Corticosteroid ILI	Pain (1/15, 6.7%)

ILI: intralesional injection.

In a multivariable logistic regression model (Table 3), the bleomycin ILI and surgical excision groups showed 8.3-fold and 13.5-fold higher probabilities of achieving CR, respectively, than the corticosteroid ILI group. No significant differences were observed between the bleomycin ILI and the surgical excision groups. None of the other variables significantly affected the treatment success rate.

Table 3. Univariable and multivariable logistic regression model assessing associations of patient characteristics and treatment modalities with treatment success.

Patient		Univariate		Multivariate
		OR (95% CI)	p-value	OR (95% CI)	p-value
Sex
	Male	0.429 (0.103–1.785)	0.244	NA	NA
	Female	1.00	NA	NA	NA
Age		0.980 (0.913–1.053)	0.581	NA	NA
Treatment
	Bleomycin	8.250 (1.328–51.263)	0.024	8.250 (1.328–51.263)	0.024*
	Surgery	13.5 (1.340–135.983)	0.027	13.5 (1.340–135.983)	0.027*
	Corticosteroid	1.00	NA	1.00	NA
Location
	Finger	1.533 (0.221–10.639)	0.665	NA	NA
	Toe	1.00	NA	NA	NA
Subtype
	Type A	1.00	NA	NA	NA
	Type B	1.143 (0.284–4.604)	0.851	NA	NA

OR: odds ratio, CI: confidence interval, NA: not available.

^*Significant in statistics.

The results of the treatment satisfaction survey are summarized in Table 4. In the bleomycin ILI group, the patients reported a relatively high level of satisfaction (median, 5; interquartile range [IQR], 1) than those who underwent surgical excision (median, 4; IQR, 1.25) or corticosteroid ILI treatment (median, 4; IQR, 2).

Table 4. Results of overall treatment satisfaction survey using a five-point Likert scale.

Treatment	No.	Median	IQR	Mean±SD
Surgery	10	4	1.25	4.20±0.789
Bleomycin ILI	13	5	1	4.31±0.947
Corticosteroid ILI	15	4	2	3.93±1.100
Total	38	4	1.25	4.13±0.963

The five-point Likert scale consists of the below points: 1, very dissatisfied; 2, dissatisfied; 3, neutral; 4, satisfied; 5, very satisfied.

IQR: interquartile range, SD: standard deviation, ILI: intralesional injection.

DISCUSSION

DMC is associated with degenerative changes in the joint and tends to recur frequently even after appropriate treatment. Although surgical excision has been revealed to have the highest cure rate (95%)⁵, alternative treatments are still needed for various reasons. First, a surgical excision requires considerable time and resources. Second, the outcomes of surgery largely depend on the surgeon’s skill and surgical techniques used⁶,⁷,⁸,⁹,¹⁰,¹¹. Lastly, it is anticipated to result in more side effects such as joint stiffness, bleeding, infection, nail deformities, persistent swelling, and pain than other treatment options⁶. In this study, surgical excision achieved a cure rate of 90%, albeit with the highest incidence of side effects, which is consistent with the results of previous studies. All side effects reported in our study were mild to moderate in severity and did not substantially affect daily living.

Intralesional steroid injections are among the most frequently used treatments owing to their high accessibility and minimal side effects. Previous studies that evaluated the efficacy of the intralesional steroid injection reported high recurrence rates, ranging from 40%–100%¹⁹,²⁰,²¹. In this study, 40% exhibited CR, whereas 60% showed PR and 10% showed recurrence after receiving corticosteroid ILI treatment. Notably, the corticosteroid ILI group demonstrated the highest PR and lowest recurrence rates among the three treatment groups. These results may be attributable to the definitions of PR and recurrence used in this study. In the corticosteroid ILI group, lesions often reappeared within 3 months of the last treatment session, leading to the classification of these cases as PR rather than recurrent cases. The majority of these patients have opted to either discontinue the treatment or switch to alternative methods, such as surgical removal. This finding is consistent with that of a previous study that reported relatively short-term recurrence following steroid ILI²¹.

Sclerotherapy is employed as an alternative approach to surgical excision in DMC treatment, as it demonstrated the highest cure rate (77%) among the nonsurgical treatment options⁵. Currently available sclerosing agents usually fall into three major categories: hyperosmolar, detergent, and chemical sclerosants²². Detergents such as sodium tetradecyl sulfate and polidocanol have been predominantly used to treat DMC¹²,¹³,²³,²⁴, and the main disadvantages of these compounds include skin necrosis and ulceration²². Additionally, given that DMC is often connected to adjacent joints, detergents entering the joint space can induce synovial fibrosis. Joint stiffness and skin necrosis have been reported in patients with DMC who have undergone sclerotherapy¹²,¹³.

Bleomycin is a cytotoxic antineoplastic agent first isolated by Umezawa et al.²⁵ in 1962. In addition to its cytotoxic effects, bleomycin has been found to have a sclerosing effect on the vascular endothelium²⁶. Although there are no current FDA-approved indications for treating DMC, several studies have provided evidence that bleomycin ILI can be a safe treatment option for DMC¹⁵,¹⁶,¹⁷. A major concern associated with the use of bleomycin is the risk of pulmonary fibrosis. However, these side effects occur when high cumulative doses are used systemically²⁷,²⁸. In the case of low-dose ILIs, only transient and localized reactions at the injection site have been reported²⁹.

In this study, bleomycin ILI exhibited higher treatment efficacy than corticosteroid ILI and similar treatment efficacy as surgical excision. The recurrence rate in the bleomycin ILI group (23.1%) was comparable to that in the surgical excision group (20.0%), and there were no significant adverse events, except for mild transient pain. Furthermore, patients who experienced recurrence after bleomycin ILI responded favorably to retreatment with bleomycin injections, achieving CR in relatively few treatment sessions. These results highlight the rationale for the retreatment of patients who experience recurrence after bleomycin ILI. The overall treatment satisfaction level was higher in the bleomycin ILI group than that in the other groups. This heightened satisfaction with bleomycin ILI can be attributed to its convenience compared to surgical interventions and its superior treatment efficacy compared to steroid injections.

When considering the anatomical locations, Jung et al.³⁰ reported better treatment responses for type B DMCs. However, in this study, there were no statistically significant differences in treatment response based on anatomical locations. Considering our limited sample size, additional studies are required to validate these results.

One of the most robust aspects of this study is that it was the first to use bleomycin ILI for the treatment of DMC. Because bleomycin is a commonly used treatment option for viral warts, it is a relatively familiar and easily accessible medication for dermatologists. Furthermore, we conducted a comparative study between bleomycin ILI and other commonly used treatment options. In addition, a straightforward survey was conducted to assess patient-perceived satisfaction. Our findings provide valuable guidance for managing DMC in the real-world clinical practice.

This study had some limitations. First, as this was a retrospective study, the extent and quality of clinical information were limited. Second, the study included a relatively small number of patients. Further studies with larger sample sizes and longer follow-up periods are required to confirm our results. Finally, we hypothesized that bleomycin acts as a sclerosing agent; however, the precise mechanism of action remains unclear. In addition, apart from one preliminary study, there are no reported data on the effects of bleomycin on the synovium.

In conclusion, bleomycin ILI demonstrated superior therapeutic efficacy compared with corticosteroid ILI, and no significant side effects were reported. Furthermore, they showed a higher level of satisfaction than those with surgical excision and corticosteroid ILI. Therefore, intralesional bleomycin can be considered a relatively safe and effective nonsurgical treatment option for DMC.