Povidone Iodine Sclerotherapy for the Treatment of Persistent Seromas after Breast Cancer Surgery

Abstract

Persistent seroma following breast cancer surgery causes morbidity and delays adjuvant treatment. Sclerotherapy helps in managing recalcitrant seromas. We evaluated efficacy of 10% povidone iodine sclerotherapy treatment for persistent seromas after breast cancer surgery. Persistent drainage of > 100 mL/day 15 days following surgery, and seromas that required aspiration > 100 mL/week 2 weeks after drain removal, was considered for 10% povidone sclerotherapy in a non-randomized observational study. Resolution (drain output < 20 mL/day), treatment days, recurrence, and complications were assessed as measures of efficacy. Descriptive measures of central tendency and dispersion were reported. The relationship of the seroma quantity with risk factors (age, body mass index, levels and number of axillary lymph nodes dissected, neoadjuvant chemotherapy) and efficacy was analysed. We examined the correlation using Pearson and Spearman’ signed rank, Student’s t, and Mann–Whitney U-tests, to compare the means. Of 14/312 (4.5%) patients with persistent seroma, 13 (92.8%) had complete resolution after sclerotherapy within 6.71 days (range: 6–8). AC (p = 0.04), neoadjuvant chemotherapy (NACT) (p = 0.005), and number of nodes harvested without NACT (p = 0.025) were significantly associated with the quantity of discharge, while age (p = 0.072), body mass index (p = 0.432), type of surgery (breast conservation surgery vs. modified radical mastectomy) (p = 0.28), and total number of axillary lymph nodes (p = 0.679) were not. When used in this unique innovative manner, 10% povidone iodine sclerotherapy was found to be very effective (93%), minimally invasive, and safe in our study, and therefore appears to be an ideal sclerosing agent.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13193-022-01629-0.

Introduction

Seromas are collections of serous fluid under skin flaps or in the dead space following modified radical mastectomy (MRM), breast conservation surgery (BCS), or axillary lymph node dissection (ALND). Actually, it is an exudate from the raw surgically created wound cavity, arising from cut end of blood capillaries and lymph from the catchment area of axilla, i.e., upper limb, upper torso and breast (after breast cancer surgery). Seroma development is a common complication with an incidence of 3–85% after breast cancer surgery (ALND, BCS, or MRM) [1]. It causes morbidity in the form of discomfort, pain, esthetic deformity, chronicity, need for repeated aspiration, possible introduction of infection, and most importantly, delay in adjuvant therapy.

Most persistent seromas and serous discharge can be managed conservatively. Some may respond to repeated aspiration. Various types of sclerotherapy (ethanol, doxycycline, and 0.2%, 1%, and 10% povidone iodine solution etc.) help with the management of recalcitrant seroma and serous discharge [2].

Recognizing that sclerotherapy can be an effective therapy for persistent seroma and serous discharge, we aimed to evaluate the use of 10% povidone iodine solution (our current practice) as a sclerosant in the treatment of persistent seromas and serous discharge; to evaluate its efficacy.

Aims and Objectives

To retrospectively evaluate the use and efficacy of 10% povidone iodine sclerotherapy for the treatment of persistent seromas and serous discharge after breast cancer surgery over a period of 3 years in a tertiary cancer care hospital (Health Care Global Cancer Hospital, Bangalore, India).

Methods

This was a non-randomized observational study. All the patients who underwent ALND in BCS or MRM without reconstruction, under cover of prophylactic preoperative dose of antibiotic by a single surgeon, in a tertiary cancer center (Health Care Global Cancer Hospital, Bangalore, India) over a period of 3 years (April 1, 2018, to March 31, 2021) were included in the study. Institutional review board (IRB) approval was obtained.

Patients with drains with a persistent drainage of > 100 mL/day, 15 days after surgery, and patients who had seromas requiring aspiration of > 100 mL/week, 2 weeks after the removal of the drain, were identified and considered for 10% povidone sclerotherapy, which was instilled in a manner described below with an aim to resolving seromas.

Patients, who were allergic to iodine compounds were tested by means of patch test were excluded from the study.

Procedure of Instillation of Sclerosant

Ten percent povidone iodine sclerosant was instilled through percutaneous drain after the complete removal of residual seroma collection. Informed written consent was obtained from all patients before the procedure. If 14 Fr percutaneous drain was removed previously, it was inserted under local anesthesia, sedation, ultrasound guidance, and antibiotic prophylaxis. Patient was made to lie supine during the drainage, with the dwell time for the drain being 60 min. Twice daily, 20 mL of 10% povidone iodine solution was instilled, initially under supervision in the hospital clinic for the first 2 days and later, on domiciliary basis by the hospital home care team (after appropriate counseling). Drains were removed when output was reduced to < 20 mL/day.

Patients were seen every 3 days until removal of the drain and weekly after the removal of the drain up to 1 month, and monthly thereafter until 6 months.

The following parameters were assessed with regards to the efficacy of 10% povidone iodine sclerosant:

• Resolution when drain output was < 20 mL/day, following which the drain was removed

• Number of treatment days from the day of sclerosant instillation until seroma resolution and removal of the drain were noted

• Recurrence: Reappearance of seroma after the removal of the drain

• Local and systemic complications like erythema, infection, upper limb/axillary lymphedema, and allergic reactions

Statistical Analysis

The statistical analysis was conducted using SPSS statistical software version 23.0 for Windows (SPSS, Chicago, IL, USA). Descriptive statistics for measures of central tendency and dispersion (mean, median, standard deviation and confidence interval) were reported. The objective of the analysis was to determine the efficacy of povidone sclerotherapy and relationship of the quantity of serous discharge with possible risk factors like age, body mass index (BMI), neoadjuvant chemotherapy (NACT), number of axillary lymph nodes harvested with or without NACT, and levels of ALND. This was achieved by determining the correlation using Pearson and Spearman’ signed rank test or by comparing means using Students’ t and Mann–Whitney U-tests. All the tests were 2-tailed with 0.05 as the threshold of statistical significance.

Results

The total number of patients with ALND with BCS or MRM over the 3 years (2016–2019), was 312. Mean age was 54 (SD 3.41, range 24–60) years; 309 of 312 (99.03%) patients were females while 3/312 (0.07%) were males.

Histopathological diagnosis of 259 (83%) patients showed ductal carcinoma, 15 (5%) were lobular carcinoma, 16 (5%) were medullary carcinoma, and the remaining 22 (7%) comprised of mucinous (9; 3%), tubular (6; 2%), invasive papillary (4; 1%), and metaplastic (3; 1%). Of 312 patients, 309 (99%) had unilateral disease and 3 (1%) had bilateral disease. Furthermore, 99 (32%) patients had diabetes mellitus and 78 (25%) had hypertension. Overall, 112 (36%) patients received NACT.

The total number of patients with persistent seromas and serous discharge was 14 (4.5%) (Table 1). Patients with persistent drainage of > 100 mL/day after 15 days of surgery were 3/312 (0.96%). Seromas, which required aspiration of > 100 mL/week after removal of the drain were 11/312 (3.52%). The successful completion of 10% povidone sclerotherapy treatment occurred over a mean 6.71 (range: 6–8, SD – 0.825) treatment days (Tables 2 and 3). Complete resolution of seroma and serous discharge at the time of completion of sclerotherapy occurred in 13 (92.8%) patients with no recurrence. However, in 1 patient, recurrence of seroma occurred (60 mL) 7 days after the removal of the drain, which resolved after 2 consecutive aspirations over a period of 14 days.

Table 1.

Patients characteristics with persistent seroma and serous discharge

Total number of patients with seromas and persistent serous discharge	14/312	4.5%
Persistent serous discharge Seroma	3/312 11/312	0.96% 3.52%
Age (years)	24–65	Mean — 45.21 SD — 10.01 CI (39.44–50.99)
Sex (female:male)	14:0
BMI (kg/m2)	19–30	Mean — 22.21 SD — 2.547 CI (20.07–23.69)
Diabetes mellitus	2/14	14.28%
Hypertension	3/14	21.42%
Stage
1	0	0%
2	6/14	42.85%
3	8/14	57.14%
4	0	0%
NACT	8/14	57.14%
Surgery
BCS/ALND	9/14	64.28%
MRM	5/14	35.71%
Levels of axillary dissection
1–2	5/14	35.71%
1–3	9/14	64.28%
Number of lymph nodes harvested	8–32	Mean — 17.43 SD — 6.297 CI (11.35–18.51)
Drain output (mL/day)	120–250	Mean — 181.43 SD — 39.973 CI (168.85–209.73)
Treatment days	6–8	Mean — 6.71 SD — 0.825 CI (6.45–7.41)

SD, standard deviation; CI, confidence interval; BMI, body mass index; NACT, neoadjuvant chemotherapy; BCS/ALND, breast conservation surgery/axillary lymph node dissection; MRM, modified radical mastectomy

Table 2.

Overview of the results

Patients with persistent serous discharge Seroma	3/312 11/312	0.96% 3.52%
Treatment days	6–8	Mean — 6.71, SD — 0.825 days
Efficacy (resolution)	13/14	92.8%
Recurrence	1/14	6.2% (7 days after the removal of the drain)
Complications	None	0%

SD, standard deviation

Table 3.

Details of povidone iodine sclerotherapy patients

Type of collection	QTY (mL)	Surgery	Age (yrs)	BMI	AX LN levels	LNNO	HPR	NACT	Treatment Duration (days)	Outcome
Seroma	190	AXLN/BCS	46	20	1–3	8	IDC	NACT	7	Resolved
Seroma	150	AXLN/BCS	35	24	1–2	16	LOB	-	7	Resolved
Seroma	190	MRM	40	19	1–3	14	MED	NACT	7	Resolved
Seroma	140	AXLN/BCS	50	24	1–2	14	IDC	-	6	Resolved
Seroma	220	MRM	65	25	1–3	10	IDC	NACT	8	Recurrencea
Serious discharge	180	AXLN/BCS	42	28	1–3	12	IDC	NACT	6	Resolved
Seroma	190	MRM	42	22	1–3	32	IDC	-	6	Resolved
Seroma	250	AXLN/BCS	50	21	1–3	14	IDC	NACT	8	Resolved
Seroma	180	AXLN/BCS	56	19	1–2	19	MET	-	6	Resolved
Seroma	230	AXLN/BCS	38	20	1–2	10	IDC	NACT	8	Resolved
Serious discharge	190	MRM	53	22	1–3	22	IDC	-	7	Resolved
Seroma	200	AXLN/BCS	42	24	1–3	12	IDC	NACT	8	Resolved
Seroma	120	AXLN/BCS	24	22	1–2	10	IDC	-	6	Resolved
Serious discharge	220	MRM	50	21	1–3	16	MUC	NACT	7	Resolved

^aRecurrence- 7 days after removal of povidone iodine sclerotherapy drain. QTY quantity, BMI body mass index, LN lymph node, AXLN/BCS axillary lymph node dissection in breast conservation surgery, MRM modified radical mastectomy, HPR histopathological report, NACT neoadjuvant chemotherapy, IDC infiltrating ductal carcinoma-10 (71.42%), LOB lobular carcinoma-1 (7.1%), MED medullary carcinoma-1 (7.1%), MET metaplastic carcinoma-1 (7.1%), MUC mucinous carcinoma-1 (7.1%)

With regards to risk factors, there was significant statistical relationship of the quantity of serous discharge with the level of ALND (p = 0.04), NACT (p = 0.005), and the number of axillary lymph nodes harvested without NACT (p = 0.025) (Tables 4 and 5). There was no statistical difference in the quantity of serous discharge with respect to age (p = 0.072), BMI (p = 0.432), type of surgery (BCS vs. MRM) (p = 0.28), and total number of axillary lymph nodes (p = 0.679).

Table 4.

Analysis of correlation of serous discharge with risk factors and treatment duration

	Quantity
Variable	N	Correlation coefficient (95% CI)	p-value
Agea	14	0.495 (-0.051, 1.042)	0.072
BMIa	14	− 0.228 (− 0.841, 0.384)	0.432
LN NO: b	14	− 0.122 (− 0.590, 0.386)	0.679
LN NO: (NON NACT) a	6	0.868 (0.119, 1.00)	0.025
a Pearson’s Correlation
b Spearman’s Rho Correlation
		Quantity (Mean + / − SD, median (Q1, Q2)	p-value
Type of surgery	BCS/AXLN	180.00 (145.00, 215.00)	0.280a
	MRM	190.00 (190.00, 220.00)
AXLN Level	1–2	164 ± 42.78	0.04b
	1–3	203.33 ± 22.3
NACT	No	161.6 ± 29.27	0.005b
	Yes	210 ± 23.91
a Mann Whitney U-test
b Students’ t-test
	Treatment daysa
Variable	N	Correlation coefficient (95% CI)	p-value
Quantity	14	0.818 (− 0.551, 0.935)	< 0.001
aSpearman’s Rho correlation

BMI, body mass index; LN, lymph node; NACT, neoadjuvant chemotherapy; BCS/AXLN, breast conservation surgery/axillary lymph node dissection; MRM, modified radical mastectomy

Table 5.

Studies on sclerotherapy in persistent post-operative seromas in breast cancer surgery

Year	Sclerotherapy	Dwell time	Indication	Type	Patient no:	Outcome	Comp	Ref
1983	Tetracycline 2 g	1 h	Post MRM Seroma	OBS	5	100% effective	Pain	[26]
1986	Tetracycline 2 g	1 h	Post-MRM seroma	RCT	Drain (6) vs. drain + tetracycline (8)	4/8 recurrences	3/8 Severe pain study aborted	[27]
2003	S/c octreotide 0.1 mg	Tid × 5 days	BCS/MRM/AXLN	RCT	Drain (136) vs. drain + S/C Octreotide (125)	Reduction in quantity and duration	No diff	[28]
2006	Talc 4 g + pressure dressing	24 h	Post-MRM Seroma	CR	1	Effective	Pain	[13]
2008	10–30 mL 95% ethyl alcohol (sclerosant), 1% povidone iodine (catheter irrigant)	20–30 min, 2–3/day	Post-MRM Seroma	OBS	16 pts (18 seromas)	Av. duration — 3 days 3/16 recurrences	7/16 (44%) infection	[2]
2019	Doxycycline 200 mg, 100 mg	1 h	BCS (1), MRM (1)	CR	2	100% effective	NA	[29]

Comp, complication; BCS, breast conservation surgery; Ref, reference; ALND, axillary lymph node dissection; OBS, observational study; S/C, subcutaneous; RCT, randomized controlled trial; Tid, three times a day; CR, case report; NA, not available; MRM, modified radical mastectomy; Av, average

Discussion

Seromas are common complications faced by breast cancer surgeons. These fluid collections often cause discomfort, pain, esthetic deformity, or compression of neighboring structures. In certain circumstances, they may become infected and present as abscesses. Procedures including percutaneous aspiration, drain placement, and even return to the operating room may be required for resolution.

Collections of serous fluid develop through a multifactorial process. Inflammation as well as transected blood vessels and lymphatic channels contribute to the accumulation of plasma, lymph, and inflammatory exudate, in a surgically created space. It has been postulated that formation of seromas may be due to an acute inflammatory reaction following surgical trauma or increased fibrinolytic activity in serum and lymph [3].

Shear forces might produce or maintain the dead area preventing apposition and adhesion of the tissue surfaces. Morel-Lavallée lesions are distinctive samples of connective tissue fluid collections, specifically formed after blunt trauma [4]. Although the cause for seroma remains uncertain, there are many known risk factors and predictors like age, breast size, co-morbid conditions (e.g., elevated BMI), previous surgical biopsy, and previous NACT [5–7]. Seroma formation is also affected by a range of surgical techniques and use of various cautery devices, as well as different methods used to obliterate dead space, timing of shoulder physiotherapy, and drain removal [8–11]. Minimizing these risks by reducing dead space and maintaining lymphatic integrity are the main tenets of preventing seroma formation. Unfortunately, seromas may form, nonetheless. While most serous collections resolve with conservative management, some require repeat drainage or additional therapies ranging from the injection of a sclerosant to excision of the cavity lining.

An irritating substance, which induces a fibrotic response, is used to seal the dead space of the seroma cavity. Most recommendations are derived from the experience of thoracic surgery addressing pleural effusions. Commonly used substances for malignant pleural effusions include ethanol, doxycycline, bleomycin, and talc [12]. Few published reports have documented the use of sclerosants to treat persistent seromas after breast cancer surgery. Those that exist suggest that this treatment is effective and well-tolerated [2, 13, 26, 29]. However, a comprehensive comparative analysis of the various possible options is lacking.

Being a water-soluble, nonionic surfactant polymer (polyvinyl pyrrolidone), povidone iodine releases iodine slowly; the solution contains free iodine at 0.1% concentration and has been used as a sclerosant in various studies [2, 14]. Few studies have been conducted with regards to its efficacy. The advantages of using povidone iodine is that it is effective, readily available, inexpensive, and causes minimal side-effects compared with aforementioned sclerosing agents. It also has local antiseptic, antibacterial, and antifungal actions. It is convenient to prepare in the desired concentrations.

The results of our present study (Tables 2 and 3) shows the effectiveness of the use of 10% povidone iodine as an efficient sclerosant, with 93% (n = 13/14) effectiveness. In one patient, recurrence of seroma occurred (60 mL) 7 days after the removal of the drain, which resolved after 2 consecutive aspirations over a period of 14 days. Povidone iodine has been used as a sclerosant for various other indications such as lymphatic cysts, lymphocele, and chyluria, quite successfully [15–17]. It has also been used in various concentrations, with different dwell times and varying durations of drain placement, in a plethora of studies [14–17]. For example, during treatment of postoperative lymphoceles, povidone iodine was instilled and left for 30 min twice daily and then spontaneous drainage was allowed. In these studies, the total time that the drain was left in situ ranged from 15 to 37 days [14–17].

We used 10% povidone iodine in our study. In our patients, however, the drain was placed only for a mean 6.71 days. Duration of the treatment was related to the amount of the initial serous discharge and cavity size. The larger the amount of the serous discharge and seroma formation, the longer it took for the sclerosant to be effective (p = 0.001) (Table 4).

Skin exposure to povidone iodine causes irritation rather than allergic dermatitis. In a well conducted study, allergy to povidone iodine was present in only 2 out of 500 patients (prevalence: 0.4%) [18]. In a systemic review, no significant adverse reactions were noticed with iodine with regards to allergic responses or cytotoxicity [19]. In our study, however, there were no reported side-effects of povidone iodine including redness, itching, upper limb lymphedema, edema of skin flaps, or any systemic manifestations like fever or anaphylactoid reactions. Another serious complication one could envisage is secondary wound infection. Seven out of 16 patients in Throckmorton study had infection at a median of 11 (range 4 to 29) days after the start of 1% povidone iodine sclerotherapy. Six of 10 patients who did not receive prophylactic antibiotics, developed an infection at the mastectomy site. One of 5 patients (20%) who received prophylactic antibiotics developed an infection [2]. However, there was no instance of wound infection, possibly due to the antibiotic prophylaxis, antiseptic nature and higher concentration (10%) of the povidone iodine, strict aseptic technique of instillation, and close observation of the patients.

Various other sclerosants have been used in the place of povidone iodine like ethanol, doxycycline, bleomycin, talc, and OK-432. Each of these sclerosants appear to act in their unique way with varying degrees of efficacy and side-effects. Ethanol is a common pleurodesis agent and causes sclerosis through protein coagulation and hyperosmolar cell destruction, which ultimately leads to tissue necrosis. The resulting inflammatory reaction causes fibrosis [20]. Polidocanol, an approved sclerosant for varicose veins, promotes vascular sclerosis by provoking endothelial inflammation [21]. Both of the above cause intense pain.

Talc (hydrated magnesium silicate) is one of the most commonly used agents in the treatment of subcutaneous fluid collections but acts through a poorly defined mechanism. When used in pleurodesis, talc stimulates a fibrotic reaction involving polymorphonucleocytes as well as cytokines, interleukin 8, and fibroblast growth factor [13].

Hypotheses for the sclerosing action of doxycycline include the destruction of mesothelial cells lining the pseudocyst as well as the inhibition of fibrinolysis and the induction of fibroblast growth factors. It is well tolerated with minimal adverse reactions and is widely available. Occasionally, doxycycline sclerotherapy can result in cellulitis, scarring, skin excoriation, and Horner’s syndrome. Tooth discoloration and medication allergies may also occur [22].

Being an anticancer drug, bleomycin was demonstrated to have sclerosing effect on endothelial cells through non-specific inflammatory reaction. It should be noted that bleomycin can cause serious complication of pulmonary fibrosis. Deaths have even been reported in relation to bleomycin sclerotherapy [23].

Sclerosants that stimulate tissue adhesion without an inflammatory response have been reported as well. Fibrin glue contains fibrinogen, factor XIII, thrombin, and calcium to stimulate the terminal phase of the clotting cascade. The fibrin clot that is subsequently produced ensures the adherence of tissue surfaces together without stimulating inflammation [24].

OK-432, which is a lyophilized mixture of group 1 Streptococcus pyogenes of human origin is a known immunomodulator anticancer drug. Activation of the immune system (macrophages, NK cells, and LAK cytotoxic T lymphocytes) damages the lymphatic endothelium, leading to the sclerosant effect [25].

The results indicating a relationship between quantity of serous discharge and risk factors (Table 4) suggested the following: increased seroma formation during higher levels (up to level 3) of axillary lymph nodes may be due to the transection of additional axillary lymphatic vessels. Reasons behind increased seroma collection in patients with NACT may be due to the transection of the diffuse, hard-to-visualize, newly formed lymphatic channels; increased efflux of lymph due to fibrosis; and obliteration of lymphatic channels due to NACT. There was a correlation between the quantity of the serous discharge and total number of axillary lymph nodes harvested after correcting for the influence of NACT. We did not identify a correlation between the quantity of serous discharge and age, BMI, and type of surgery. Studies that include more patients are required to verify this lack of correlation.

Limitations of the Study

This was a non-randomized observational case series study with a small sample size and no controls. Retrospective cohort studies inherently carry the risk of biases in measurement and selection. We feel however that this is an important study wherein povidone iodine sclerosant instillation was standardized in a unique manner with respect to the concentration, dwell time, and dosage. Also, it is very difficult to obtain larger sample size considering the relatively reduced incidence of seroma complications in breast cancer study despite the fact that this was a 3-year study. We are pleased to report preliminary encouraging results showing that this regimen was associated with rapid resolution of persistent seromas in breast cancer surgery and will be useful to practicing breast cancer clinicians.

The study is ongoing to accrue a larger sample size. Furthermore, regression analysis is being planned after adequate data is obtained. Dwell times and concentration of povidone iodine sclerotherapy can be further optimized to reduce the exposure to povidone iodine. This may be compared to other commonly used sclerosants such as doxycycline, in a randomized control trial.

Conclusion

Instillation of 10% povidone iodine sclerosant resulted in 93% resolution of all persistent seromas and serous discharge at the end of the treatment. There was, however, a small recurrent collection of serous fluid in 1 patient which responded to 2 successive aspirations over a period of 7 days. Ten percent povidone iodine sclerotherapy has been found to be very effective, minimally invasive, and safe for the treatment of seroma and persistent serous drainage in our study, with no side-effects.

An ideal sclerosing agent has not been identified yet in the management of seromas in breast cancer patients. We believe that 10% povidone sclerotherapy comes close to being such an ideal sclerosing agent in the management of persistent seroma and serous discharge in breast cancer surgery patients when used in an appropriate manner. However, a well conducted, randomized controlled prospective trial is necessary to compare the efficacy and complications of povidone iodine with other sclerosing agents.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contribution

RCS: Conceptualization, formal analysis and investigation, writing — original draft preparation, writing — review and editin, resources. MB: conceptualization, writing — review and editing, supervision, resources. VP: methodology, writing — review and editing. KGT: methodology. NSG: methodology.

Declarations

Conflict of Interest

The authors declare no competing intersts.