Ethanol Injection for Thyroid Lesions and Other Selected Indications

Number: 0395

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses ethanol injection for thyroid lesions and other selected indications.

1. Medical Necessity

   1. Aetna considers ethanol injection sclerotherapy medically necessary for the treatment of thyroglossal duct cysts when all of the following selection criteria are met:

      1. A monocystic lesion is present; and
      2. Cystographic studies indicate that there is no extravasation; and
      3. Cytologic studies show that the lesion is benign.

      Note: It may be medically necessary to repeat injections after 1 month in cases of recurrence of cyst.

      Aetna considers ethanol injection sclerotherapy of thyroglossal duct cysts experimental, investigational, or unproven when these criteria are not met.

   2. Aetna considers ethanol injection sclerotherapy medically necessary for symptomatic venous malformations of the head and neck.
   3. Aetna considers absolute ethanol injection medically necessary for overt upper gastro-intestinal bleeding.
   4. Aetna considers ethanol ablation medically necessary for the treatment of benign thyroid nodules.

2. Experimental, Investigational, or Unproven

   The following procedures are considered experimental, investigational, or unproven because the effectiveness of these approaches has not been established:

   1. Ethanol sclerotherapy for the treatment of endometrioma
   2. Intradiscal radiopaque gelified ethanol injection for the treatment of lumbar disc herniation
   3. Percutaneous ethanol injection for the treatment of thyroid cancer
   4. Ultrasound-guided ethanol sclerotherapy for the treatment of Warthin's tumor.

3. Related Policies

   • CPB 0207 - Prolotherapy and Sclerotherapy

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
Ethanol ablation - no specific code
43236	Esophagogastroduodenoscopy, flexible, transoral; with directed submucosal injection(s), any substance
49185	Sclerotherapy of a fluid collection (eg, lymphocele, cyst, or seroma), percutaneous, including contrast injection(s), sclerosant injection(s), diagnostic study, imaging guidance (eg, ultrasound, fluoroscopy) and radiological supervision and interpretation when performed
Other CPT codes related to the CPB:
60300	Aspiration and/or injection, thyroid cyst
76942	Ultrasonic guidance for needle placement (e.g., biopsy, aspiration, injection, localization device), imaging supervision and interpretation
77012	Computed tomography guidance for needle placement (e.g., biopsy, aspiration, injection, localization device), radiological supervision and interpretation
HCPCS codes covered if selection criteria are met:
Absolute ethanol injection, intradiscal radiopaque gelified ethanol injection - no specific code
ICD-10 codes covered if selection criteria are met:
D34	Benign neoplasm of thyroid gland
K28.0 – K28.9	Gastrojejunal ulcer [Overt upper gastrointestinal bleeding]
K29.71	Gastritis, unspecified, with bleeding [Overt upper gastrointestinal bleeding]
K92.2	Gastrointestinal hemorrhage, unspecified [Overt upper gastrointestinal bleeding]
Q89.2	Congenital malformations of other endocrine glands [thyroglossal duct cyst]
ICD-10 codes not covered for indications listed in the CPB:
C73	Malignant neoplasm of thyroid gland
D11.0	Benign neoplasm of parotid gland [Warthin’s tumor]
M51.05	Intervertebral disc disorders with myelopathy, thoracolumbar region [Lumbar disc herniation]
M51.06	Intervertebral disc disorders with myelopathy, lumbar region [Lumbar disc herniation]
M51.15	Intervertebral disc disorders with radiculopathy, thoracolumbar region [Lumbar disc herniation]
M51.16	Intervertebral disc disorders with radiculopathy, lumbar region [Lumbar disc herniation]
M51.17	Intervertebral disc disorders with radiculopathy, lumbosacral region [Lumbar disc herniation]
M51.25	Other intervertebral disc displacement, thoracolumbar region [Lumbar disc herniation]
M51.26	Other intervertebral disc displacement, lumbar region [Lumbar disc herniation]
M51.27	Other intervertebral disc displacement, lumbosacral region [Lumbar disc herniation]
M51.35	Other intervertebral disc degeneration, thoracolumbar region [Lumbar disc herniation]
M51.360-M51.369	Other intervertebral disc degeneration, lumbar region [Lumbar disc herniation]
M51.370-M51.379	Other intervertebral disc degeneration, lumbosacral region [Lumbar disc herniation]
M51.45	Schmorl's nodes, thoracolumbar region [Lumbar disc herniation]
M51.46	Schmorl's nodes, lumbar region [Lumbar disc herniation]
M51.47	Schmorl's nodes, lumbosacral region [Lumbar disc herniation]
M51.85	Other intervertebral disc disorders, thoracolumbar region [Lumbar disc herniation]
M51.86	Other intervertebral disc disorders, lumbar region [Lumbar disc herniation]
M51.87	Other intervertebral disc disorders, lumbosacral region [Lumbar disc herniation]
M51.9	Unspecified thoracic, thoracolumbar and lumbosacral intervertebral disc disorder [Lumbar disc herniation]
M51.A0-M51.A5	Other lumbar and lumbosacral annulus fibrosus disc defects [Lumbar disc herniation]
N80.00 – N80.9, N80.A0 - N80.D9	Endometriosis [Endometrioma]

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Background

The thyroglossal duct cyst (TGDC) is the commonest congenital neck mass and the second commonest of all childhood cervical masses.  An anterior midline neck mass presenting before the age of 20 and displaying vertical movement with tongue protrusion and swallowing is the hallmark of this lesion.  For recurrent or persistently infected TGDC, the traditional treatment is a Sistrunk operation – excision of the cyst, the tract connecting it to the foramen cecum, and the central portion of the hyoid bone.

Another approach in treating TGDC is ethanol injection sclerotherapy.  Injection is performed under sonographic guidance.  Studies have shown that ethanol sclerotherapy is safe and effective in treating benign, monocystic TGDC.

Guidelines on thyroid nodules from the American Association of Clinical Endocrinologists and the Associazione Medici Endocrinologi (2006) stated that percutaneous ethanol injection is useful in the treatment of benign cystic thyroid lesions.

Surgery is the gold standard for the treatment of patients with recurrent well-differentiated thyroid cancer (WTC).  Percutaneous ethanol injection is a new minimally invasive surgical option for the treatment of this disease.  Monchik and colleagues (2006) evaluated the long-term effectiveness of radiofrequency ablation (RFA) and percutaneous ethanol injection in the treatment of patients with local recurrence or focal distant metastases of WTC.  A total of 20 patients underwent treatment of biopsy-proven recurrent WTC in the neck: 16 of these patients had lesions treated by ultrasound (US)-guided RFA (mean size, 17.0 mm; range of 8 to 40 mm), while 6 had US-guided ethanol injection treatment (mean size, 11.4 mm; range of 6 to 15 mm).  A total of 4 patients underwent RFA treatment of focal distant metastases from WTC: 3 of these patients had CT-guided RFA of bone metastases (mean size, 40.0 mm; range of 30 to 60 mm), and 1 patient underwent RFA for a solitary lung metastasis (size, 27 mm).  Patients were then followed with routine US, whole body scan, and/or serum thyroglobulin levels for recurrence at the treatment site.  No recurrent disease was detected at the treatment site in 14 of the 16 patients treated with RFA and in all 6 patients treated with ethanol injection at a mean follow-up of 40.7 and 18.7 months, respectively.  Two of the 3 patients treated for bone metastases are free of disease at the treatment site at 44 and 53 months of follow-up, respectively.  The patient who underwent RFA for a solitary lung metastasis is free of disease at the treatment site at 10 months of follow-up.  No complications were experienced in the group treated by ethanol injection, while 1 minor skin burn and 1 permanent vocal cord paralysis occurred in the RFA treatment group.  The authors concluded that RFA and ethanol ablation show promise as alternatives to surgical treatment of recurrent WTC in patients with difficult re-operations.  They stated that further long-term follow-up studies are needed to ascertain the precise role these therapies should play in the treatment of recurrent WTC and if certain more invasive surgical procedures can be replaced.

Lim et al (2007) evaluated the local therapeutic effect of percutaneous ethanol injection therapy (PEIT) in recurrent thyroid cancers.  These researchers performed ultrasound-guided PEIT on 24 recurrent lesions (8 in thyroid beds and 16 in neck nodes) of 16 papillary thyroid carcinoma patients.  Ethanol was injected at 3-month intervals under sonographic guidance.  All patients tolerated PEIT well with only mild local pain, although 1 patient complained of transient hoarseness after the procedure.  The median diameter of lesions was significantly reduced, from 9.9 mm (range of 5.5 to 25.0 mm) to 5.3 mm (range of 0.0 to 17.0 mm) by PEIT.   Four recurrent lesions disappeared sonographically.  The authors concluded that PEIT may be an alternative treatment option for locally recurrent thyroid carcinomas in properly selected patients.  However, a prospective, long-term follow-up study is needed to determine the effect of PEIT on patient survival and tumor recurrence.

Verges et al (2011) described a new procedure of ethanol sclerotherapy without US guidance for the treatment of pure thyroid cysts.  A total of 9 patients with recurrent large thyroid cysts following aspiration, and showing symptoms of compression and/or cosmetic complaints were treated by ethanol injection without US guidance and followed for up to 11 years.  After ethanol injection, mean cyst volume was significantly reduced (9.9 +/- 13.6 versus 31.3 +/- 34.1 ml, p = 0.007) and the mean percentage volume reduction was 72.7 %.  A size reduction of the thyroid lesion more than 50 % was achieved in 8 of the 9 patients (89 %).  Compressive symptoms and cosmetic complaints totally disappeared after sclerotherapy in all patients.  During a mean follow-up of 48 months (ranging from 12 to 135 months), no recurrences were observed.  The treatment was well-tolerated with no major side effects.  The authors concluded that non-US-guided ethanol sclerotherapy is a safe and "easy-to-use" procedure to treat benign thyroid cysts effectively.

Guenette et al (2013) evaluated the clinical outcomes of US-guided percutaneous RF ablation and PEI as salvage therapy for loco-regional recurrence after resection of well-differentiated thyroid carcinoma.  There were 42 loco-regional, biopsy-proven, papillary and follicular thyroid carcinoma lesions (0.5 to 3.7 cm) treated, 21 with RF ablation and 21 with PEI.  Of treated lesions, 35 were located in the lateral compartments, and 7 were located in the central compartment.  Data points in the retrospective analysis, determined beforehand by the investigators, were progression at the ablation site, serum thyroglobulin levels before and after the procedure, and procedural complications.  Average follow-up after RF ablation was 61.3 months and after PEI was 38.5 months.  No progression was detected in the region of ablation for any of the lesions treated with RF ablation.  Local progression was detected 4 to 11 months after ablation in 5 of the 21 lesions treated with PEI, 3 in the lateral compartment and 2 in the central compartment; all of the lesions were successfully re-treated with repeat PEI, RF ablation, or surgery.  Permanent vocal cord paralysis occurred after 1 RF ablation procedure of a lateral compartment supraclavicular node.  There were no complications after PEI.  The authors concluded that this case series provided long-term follow-up evidence of the safety and effectiveness of US-guided RF ablation and PEI for control of loco-regional recurrence of well-differentiated thyroid carcinoma after surgery.  The findings of this case-series study need to be validated by well-designed studies.

Papillary Thyroid Cancer

Fontenot et al (2015) stated that re-operation for recurrent papillary thyroid cancer (PTC) can be associated with a high rate of complications and failure to provide lasting remission.  Percutaneous ethanol injection may be an effective non-surgical management option for locally recurrent PTC.  In a systematic analysis of the current literature, these investigators compared the effectiveness and complications related to PEI versus re-operative surgical intervention for treatment of locally recurrent PTC.  Original studies were identified using the keywords "thyroid/ethanol" and "recurrent thyroid cancer/repeat surgery".  Studies evaluating re-operation or PEI for lymph node metastases in patients with primary surgery of total thyroidectomy with appropriate lymph node dissection where indicated were included in the analysis for both re-operation and PEI.  Animal studies, single-case reports, and studies with fewer than 10 lesions were excluded.  Outcomes included interval to detection of recurrence, success and failure rates, recurrence rates, complication rates, and follow-up duration.  Between-group outcome differences were calculated using random-effects models, and pooled data cross-tabulation and logistic regression analysis were used.  In all, 945 publications were identified, and 27 studies met the inclusion criteria.  There were no studies that directly compared the 2 treatment techniques.  A total of 1,617 patients were included in this analysis; 168 (11.4 %) were treated with PEI, and 1,449 (88.6 %) were treated with re-operation.  Re-operation was successful in 94.8 % of cases compared with an 87.5 % success rate for PEI (odds ratio [OR], 2.58; 95 % confidence interval [CI]: 1.55 to 4.31; p < 0.001).  The recurrence rates for PEI and re-operation at the site of the treated lesion or elsewhere in the neck were also similar (OR, 1.07; 95 % CI: 0.65 to 1.77; p = 0.78).  Re-operation was associated with a 3.5 % pooled risk of complications, while PEI incurred a pooled risk of 1.2 % (OR, 2.9; 95 % CI: 0.72 to 12.3; p = 0.08).  However, most studies did not report routine pre-operative and post-operative laryngoscopies, an evaluation needed for accurate neural complication analysis associated with each procedure.  The authors concluded that high-quality, well-designed studies are needed to evaluate the feasibility of incorporating PEI into the treatment protocol of PTC.  They noted that although presently inferior to re-operation, PEI has the potential to be a widely accepted and effective non-surgical treatment option for limited recurrent PTC in poor surgical candidates or patients seeking to avoid multiple re-operations.

Ultrasound-Guided Percutaneous Ethanol Injection for the Treatment of Thyroid Nodules

Felicio and colleagues (2016) noted that US-guided PEI has been proposed for treatment of benign thyroid nodules (TNs).  However, there is no consensus for the optimal amount of ethanol injection, number of applications, and time to re-evaluation in order to achieve maximum volume reduction with minimum adverse effects (AEs).  These investigators analyzed the effectiveness of an US-guided PEI protocol to treat solid and mixed TNs based on a new target outcome.  They performed a prospective study evaluating the results of PEI in 52 patients with benign solid and mixed TNs.  The ethanol dose was fixed in 30 % of the nodular volume per session.  Patients returned 1 month after each session for US re-evaluation.  Therapeutic success was defined as volume reduction of at least 30 % associated with disappearance of clinical symptoms and a complete esthetic satisfaction reported by the patient.  These researchers performed a mean of 2.8 ± 1.9 PEI sessions, with an average total volume of ethanol injected of 9.1 ± 10.3 ml, and a follow-up time of 10.0 ± 8.7 months.  There was a reduction of at least 50 % of the initial nodular volume in 33 patients (63.5 %).  In 11 patients (21.2 %), the reduction did not reach 50 % (mean reduction of 31 ± 11 %), but 6 of them reported esthetically satisfactory results and treatment was stopped.  The therapeutic success rate considering the patients with esthetic improvement was 75 %.  There were no severe complications.  The authors concluded that their protocol was safe and effective in treating solid and mixed benign TNs.

An UpToDate review on “Diagnostic approach to and treatment of thyroid nodules” (Ross, 2017) states that “Ablation techniques – Benign, autonomous, and cystic thyroid nodules can be treated by ultrasound-guided injection of ethanol or sclerosing agents and by ultrasound-directed physical energy.  These approaches have not gained widespread acceptance in the United States because of potential complications, including occasional reports of prolonged pain after the procedure”.

Ethanol Sclerotherapy for the Treatment of Endometrioma

Goncalves and co-workers (2016) stated that ovarian endometriosis is present in 17 % to 44 % of women with endometriosis.  The primary treatment is surgery; however, ultrasound (US)-guided aspiration is a less invasive alternative.  In a systematic review, these investigators examined the effectiveness of US-guided aspiration in the treatment of recurrent ovarian endometrioma. Multiple databases were searched for articles published between 1994 and 2014 using the keywords "ultrasound-guided aspiration", "ovarian", and "endometriosis"; randomized controlled trials (RCTs) and observational studies published in English, Portuguese, or Spanish were included.  Two researchers independently extracted and reviewed the data.  The main outcome of interest was the recurrence rate.  A total of 8 studies were eligible.  Ovarian endometriosis was associated with high recurrence rates after 1 US-guided aspiration (28.9 % to 91.5 %); but involved less ovarian manipulation.  The results of aspiration followed by sclerotherapy were not uniform, but overall the addition of a sclerosing agent did not appear to significantly reduce the likelihood of recurrence (13.3 % to 75.0 %).  Repeated aspiration of the cysts could reduce the recurrence rate to 5.4 % by the 6th aspiration.  The authors concluded that repeated US-guided aspiration of ovarian endometriomas could be performed for the treatment of recurrent ovarian endometriosis; however, further studies comparing the effectiveness of this procedure and ovarian surgery are needed.

In a systematic review and meta-analysis, Cohen and associates (2017) examined the efficacy of sclerotherapy for ovarian endometrioma on the risk of recurrence, clinical symptoms, and reproductive function.  These researchers carried out an electronic-based search with the use of PubMed, Embase, Ovid Medline, Google Scholar, Clinicaltrials.gov, and the Cochrane Central Register of Controlled Trials.  Main outcome measures included recurrence rate, symptoms relief, fertility outcome, and AEs.  A total of 18 studies were included in this review.  The overall recurrence rates of endometrioma after sclerotherapy ranged from 0 % to 62.5 %.  The risk of recurrence was significantly higher in women who were treated by means of ethanol washing than by means of ethanol retention.  The number of oocytes retrieved was higher after endometrioma sclerotherapy compared with laparoscopic cystectomy, but clinical pregnancy rates were similar.  There was no difference in the number of oocytes retrieved and the clinical pregnancy rates between the sclerotherapy-treated group with and the untreated group.  The authors concluded that sclerotherapy for ovarian endometrioma may be considered in symptomatic women who plan to conceive.  Moreover, these researchers stated that the ideal ethanol concentration and volume for endometrioma sclerotherapy remains to be determined; and there is no beneficial effect of endometrioma sclerotherapy compared with no treatment regarding improvement of IVF outcome.

The authors concluded that drawbacks of this systematic review included the small number of studies that could be examined and the paucity of randomized trials.  Accordingly, risk of bias, especially selection bias, could occur.  Furthermore, the sample sizes in most of the included studies were too small to draw a conclusion.  Like other meta-analyses, this study may be confounded by the high clinical heterogeneity between the included studies due to differences in study designs and patient inclusion criteria.

Aflatoonian and Tabibnejad (2020) noted that endometrioma is a common high-recurrence gynecological disease that affects infertility.  Surgical resection using laparotomy or laparoscopy is a standard treatment.  Moreover, sclerotherapy has been reported to be effective as a non-invasive alternative for treating endometrioma.  In a retrospective study, these researchers examined if ethanol retention or aspiration following sclerotherapy would improve pregnancy outcome in infertile women with endometrioma.  Hospital records of 43 women with recurrent or bilateral endometrioma who had undergone trans-vaginal US sclerotherapy were reviewed.  They were selected to receive either ethanol for 10 mins, ethanol injection, irrigation, and then aspiration or total retention without aspiration based on the surgeon's decision.  Subjects were followed-up for 3, 6 and 12 months for natural or artificial conception as well as for cyst recurrence.  Chemical pregnancy was positive in 52 % of the women in the aspiration group and 53.8 % in the retention group.  Ongoing pregnancy (44 % versus 46.2 %, p = 0.584) and live-birth (40 % versus 46.2 %, p = 0.490) were reported marginally higher in the retention group compared with the aspiration group, and the differences were not statistically significant.  Moreover, the recurrence rates were found to be 48.1 % and 37.5 % in the aspiration and retention groups, respectively (p = 0.542).  The cysts size in the retention group was significantly correlated to the recurrence rate.  The authors concluded that both the aspiration and left in-situ of ethanol 95 % sclerotherapy had similar impact on the treatment of ovarian endometrioma regarding pregnancy and recurrence rate; however, larger, randomized studies with strict inclusion criteria are needed to evaluate the effect of endometrioma sclerotherapy on bilateral cyst and improvement of assisted reproductive technology (ART) outcome.

In a retrospective, cohort study, Miquel and colleagues (2020) examined the impact of ethanol sclerotherapy (EST) for endometrioma on in-vitro fertilization (IVF) cumulative live-birth rates (CLBR) in women with moderate-to-severe endometriosis.  This trial included women with moderate-to-severe endometriosis (revised American Fertility Society stage III to IV) and endometrioma who underwent IVF with the ultra-long agonist protocol.  These researchers compared 2 groups: women undergoing EST for endometrioma before IVF (EST group), and women whose endometrioma was left in-situ during IVF (No-EST group).  The primary outcome was the CLBR per IVF cycle, including fresh and frozen embryo transfers.  The secondary endpoints included the complication rate, number of mature oocytes retrieved, clinical pregnancy rate and pregnancy loss rate.  A total of 74 women were included in the study, with 37 in the EST group and 37 in the No-EST group, representing 67 and 69 IVF cycles, respectively.  The population and cycle characteristics were comparable between the 2 groups, especially the ovarian response to stimulation.  The CLBR was significantly increased in the EST group compared to the No-EST group (31.3 % versus 14.5 %, p = 0.03).  The clinical and biochemical pregnancy rates were significantly increased in the EST group (37.3 % versus 15.9 %, p = 0.01; and 43.3 % versus 23.2 %, p = 0.01, respectively).  Multi-variate analysis revealed a significantly increased chance of live-birth in women exposed to EST before IVF with an adjusted OR of 2.68 (95 % CI: 1.13 to 6.36, p = 0.02).  In the EST group, these investigators reported 1 major complication Clavien and Dindo classification grade-III, complication involving an ovarian abscess that needed a laparoscopic drainage.  The authors concluded that EST was an interesting technique to improve IVF success rates in women with moderate-to-severe endometriosis.  These researchers stated that EST could be discussed before IVF as 1st-line therapy in infertile women, especially among those with pre-existing diminished ovarian reserve; however, the cost-effectiveness of EST should be further examined, and large, randomized trials are needed to better evaluate the CLBR and safety of EST before IVF.

The authors stated that despite bias induced by a retrospective survey, including the possibility of confounding factors, the findings of this study suggested that EST associated with a long agonist protocol could be an interesting technique to improve IVF success rates in women with moderate-to-severe endometriosis.  To ensure the comparability of the 2 groups, these researchers performed a matching procedure based on age, body mass index (BMI) and smoking status, which are potential confounding factors.  They limited their analysis to small-to-medium endometriomas sizes (25 to 65 mm of diameter); thus, these findings could not be extrapolated to larger cysts.  The EST procedure was based on Yasbeck's protocol and Cohen’s meta-analysis, which both described the sclerotherapy of cysts up to 65 mm.  However, in the authors’ experience, they had gradually increased the size of endometriomas eligible for sclerotherapy from 65 to 100 mm in diameter.  A recent study also reported the successful sclerotherapy of endometriomas up to 100 mm.  It would be interesting to study IVF live-birth rates after EST of cysts measuring 65 to 100 mm.  Moreover, the management of endometriosis should be multi-disciplinary, reproducible and standardized to improve the quality of care.  The development of reference centers dedicated to the care of women with endometriosis is potentially useful to achieve this goal.

Rosini et al (2023) stated that the most common sites of implantation of endometriotic tissue are the ovaries.  Endometriomas are present in most cases of endometriosis (up to 45 %).  Although laparoscopic cystectomy is the standard of care (SOC) in endometrioma, new strategies have been established to minimize iatrogenic injuries to ovarian tissue.  Sclerotherapy consists of injecting alcohol into the endometrioma to denature the amino acidic components of its pseudo-capsule.  In a systematic review and meta-analysis, these investigators compared clinical and pregnancy outcomes in surgery and sclerotherapy.  Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, these researchers systematically searched PubMed, Embase, Scopus, Google Scholar, Clinical-trials.gov, and the Cochrane Central Register of Controlled Trials databases in January 2023, adopting the string "Endometriosis and sclerotherapy".  They made no limitations on the country and year of publication, and included the studies containing success rate (SR), recurrence rate (RR), pregnancy rate (PR) before and after the procedure.  These investigators used comparative studies for meta-analysis.  A total of 29 studies met inclusion criteria, 7 retrospective, observational studies, and 22 prospective studies; and 8 comparative studies were enrolled in meta-analysis.  Patients were analyzed regarding the number of recurrences and pregnancies in surgery, and compared with sclerotherapy.  A total of 4 studies showed SR greater than 80.0 %, and only 2 had SR of less than 80.0 %, of which 1 consisted of tetracycline instillation.  Only 1 study had 100 % PR, the other 14 reported PR of greater than 30.0 %, whereas 6 had PR of less than 30.0 %, of which 1 showed 0.0 % PR with ethanol injection at 2/3 of the cyst fluid volume.  Meta-analysis highlighted a non-significant lower incidence of recurrence in the surgery group compared to the sclerotherapy group (p = 0.87).  In parallel, the surgery group showed a non-significant better PR than the sclerotherapy group (p = 0.08).  The authors concluded that despite sclerotherapy having a minor incidence of post-operative complications compared to surgery, the latter was associated with a lower RR and better PR.  However, those data asserted the importance of a targeted therapy according to pre-operative conditions and reproductive potential.  Moreover, these researchers stated that further evidence is needed to optimize and standardize the amount and duration of ethanol injection.

Sclerotherapy for the Treatment of Low-Flow Vascular Malformations of the Head and Neck

Guidelines on venous malformations of the head and neck (Zheng, et al., 2013) state that venous malformations are among the most common vascular malformations together with lymphatic malformation. Venous malformations exhibit a low flow rate because they are post-capillary lesions and have no arteriovenous (AV) shunts. Absolute ethanol sclerotherapy is recommended alone or with laser therapy, surgery or PYM injection for deep type II and IV venous malformations. In addition, sclerotherapy can be considered as the main treatment to be used in combination with laser therapy, surgery or other treatments for deep and superficial mixed venous malformations.  For patients with venous malformations in the floor of the mouth, base of the tongue, oropharynx, and larynx, appropriate methods include a combination of sclerotherapy, laser treatment, and surgery depending on the extent of the lesion.  For large tongue lesions, sclerotherapy can be first conducted to reduce intraoperative blood loss associated with surgical debulking of macroglossia. Laser and further sclerotherapy are subsequently applied. Another alternative involves sclerotherapy first; glossoplasty followed. 

In a retrospective study, Ierardi and colleagues (2020) examined the safety and effectiveness of percutaneous sclerotherapy using gelified ethanol in patients with low-flow malformations (LFMs) of the head and neck regions.  They analyzed treatment outcome data of 6 patients who presented with 6 LFMs (3 lymphatic and 3 venous).  Median diameter of LFMs was 6 cm (interquartile range [IQR], 4.5 to 8.5 cm).  Data regarding pain, functional and/or cosmetic issues were assessed.  Diagnosis was performed clinically and confirmed by Doppler US, while extension of disease was evaluated by magnetic resonance imaging (MRI).  Percutaneous puncture was carried out with 23-G needle directly or with US guidance.  All the LFMs were treated with gelified ethanol injection.  The median volume injected per treatment session was 4.4 ml.  Technical and clinical success were obtained in all cases.  No recurrences were recorded during a median follow up of 17 months (IQR, 12 to 19 months).  Among the 6 patients, 5 had complete relief (83 %) and 1 showed improvement of symptoms.  The median VAS score was 7 (IQR, 6 to 7.5) before and 0 (IQR, 0 to 0) after treatment.  All patients had functional and esthetic improvement (100 %); 4 patients (66.7 %) exhibited very good acceptance and 2 patients (33.3 %) good acceptance.  No major complications or systemic side effects were observed.  The authors concluded that gelified ethanol percutaneous sclerotherapy was easy to handle, well-tolerated, safe and effective in the short-term follow-up.  Moreover, these researchers stated that studies with larger sample size and longer follow-up are needed for further conclusions.

The authors stated that this study had drawbacks, such as its retrospective nature and the paucity of patients (n = 6) that has not allowed any statistical analysis.  Furthermore, the indication to treatment was given by experienced interventional radiologists and surgeons, but no strict and specific protocol was used.  Clinical outcomes were based primarily on subjective follow-up visits and less on post-procedural imaging; although imaging could be considered a good way to objectify results, these researchers believed that relying on clinical assessments and subjective symptoms of patients is the best way to measure treatment outcomes, since these are the true endpoints of the process.

An UpToDate chapter (Boon, et al., 2021) states that management of patients with venous malformations involves an interdisciplinary team including a dermatologist, an interventional radiologist, a hematologist, and a plastic and/or vascular surgeon, ideally in a specialized center for vascular anomalies. Treatment should be individualized and may include supportive therapies (compression, medical management of coagulopathy, and pain control), sclerotherapy, and surgery, alone or in combination. 

Ultrasound-Guided Ethanol Sclerotherapy for the Treatment of Warthin's Tumor

Mamidi and colleagues (2020) noted that presently the 1^st-line treatment for Warthin's tumor (WT) is parotidectomy.  There is a paucity of data examining the safety and efficacy of non-surgical treatments for patients not amenable to surgery.  Ultrasound (US)-guided ethanol sclerotherapy (UGES) has been successfully used for the management of lymphangiomas of the head and neck, thyroid nodules, and thyroid cysts.  These researchers reported the 1st study to implement and evaluate the success of UGES for the treatment of WT.  They described the findings of 2 patients with WT, with a total of 3 masses, who underwent UGES.  All procedures were carried out in the clinic. The primary outcome measured was the tumor volume reduction rate (VRR), patient satisfaction, and complications observed at follow-up.  Both patients exhibited a significant reduction in tumor size at follow-up; VRR for the 3 treated tumors were 67.30 %, 98.32 %, and 55.73 %.  Patient were very satisfied with the results and noted significant cosmetic improvement.  No complications were observed at follow-up.  The authors concluded that US-guided ethanol sclerotherapy may be a viable option for conservative treatment of Warthin's tumor in patients unsuitable or unwilling to undergo surgical resection.  These preliminary findings need to be validated in well-designed studies.

Furthermore, an UpToDate review on “Salivary gland tumors: Treatment of locoregional disease” (Lydiatt and Quivey, 2021) does not mention ethanol sclerotherapy as a management / therapeutic option.

Absolute Ethanol Injection for Overt Upper Gastro-Intestinal Bleeding

On behalf of the American College of Gastroenterology (ACG), Laine and colleagues (2021) carried out systematic reviews addressing pre-defined clinical questions to develop recommendations with the GRADE approach regarding management of patients with overt upper gastro-intestinal (GI) bleeding.  These investigators suggested risk assessment in the emergency department to identify very-low-risk patients (e.g., Glasgow-Blatchford score = 0 to 1) who may be discharged with out-patient follow-up.  For patients hospitalized with upper GI bleeding, these researchers suggested red blood cell (RBC) transfusion at a threshold of 7 g/dL.  Erythromycin infusion was suggested before endoscopy, and endoscopy was suggested within 24 hours following presentation.  Endoscopic therapy was recommended for ulcers with active spurting or oozing and for non-bleeding visible vessels.  Endoscopic therapy with bipolar electrocoagulation, heater probe, and absolute ethanol injection was recommended, and low- to very-low-quality evidence also supported clips, argon plasma coagulation, and soft monopolar electrocoagulation; hemostatic powder spray TC-325 was suggested for actively bleeding ulcers and over-the-scope clips for recurrent ulcer bleeding after previous successful hemostasis.  After endoscopic hemostasis, high-dose proton pump inhibitor (PPI) therapy was recommended continuously or intermittently for 3 days, followed by twice-daily oral PPI for the first 2 weeks of therapy following endoscopy.  Repeat endoscopy was suggested for recurrent bleeding, and if endoscopic therapy failed, transcatheter embolization was suggested.

Ethanol Ablation for the Treatment of Benign Thyroid Nodule

Yang et al (2021) noted that US-guided minimally invasive procedures are widely used to treat thyroid diseases.  These researchers examined the safety and effectiveness of ethanol ablation (EA) in comparison with other non-surgical options in the treatment of benign thyroid cystic nodules.  These researchers carried out a systematic search of studies on EA for thyroid cystic nodules, mainly in the Ovid-Medline and Embase, Web of Science, and Cochrane databases.  The standardized mean difference (SMD) of the volume reduction ratio (VRR) after EA versus other non-surgical treatments comprised the primary outcome, whereas the OR of therapeutic success rates between the 2 groups comprised the secondary outcome.  The meta-analysis included 19 studies (4 RCTs and 15 non-randomized studies) with 1,514 participants.  The cumulative VRR of EA was 83.908 % (95 % CI: 79.358 % to 88.457 %).  EA had a significantly higher pooled VRR (SMD, 0.381; 95 % CI: 0.028 to 0.734; p = 0.030), but not a significantly higher pooled therapeutic success rate (OR, 0.867; 95 % CI: 0.132 to 5.689; p = 0.880), than other forms of non-surgical management including RFA, polidocanol sclerotherapy, and simple aspiration with or without saline flush.  However, the VRR and therapeutic success rate were not significantly different between EA and RFA.  Major complications were recorded only in 6 patients (0.53 %) with self-limiting dysphonia.  The authors concluded that the role of EA as the 1st-line treatment for benign thyroid cysts and predominantly cystic nodules is supported by its high effectiveness and good safety profile compared to other currently available non-surgical options.

He et al (2021) stated that percutaneous ablation is currently deemed an additionally therapeutic option for benign thyroid nodules in the world; however, possibly different effect among the ablation modalities is unclear.  In a network meta-analysis, these researchers examined the effectiveness and complications of thermal/chemical ablation.  PubMed, Embase and the Cochrane Library databases were searched from 1980 to 2020.  Studies of adults with thyroid benign nodules under percutaneous ablation therapy were included.  Percentage mean volume change, symptom score change, cosmetic score change, and complications were evaluated by network meta-analysis.  In the network meta-analysis, RFA with 2 treatment sessions group was associated with the highest reduction for the mean volume change during 6-month follow-up (MD = 79.09 and 95 % CI: 48.23 to 89.94).  There was no significant difference in the incidence of complications.  Subgroup analysis showed that 2 sessions of RFA ranked the highest probability (surface under the cumulative ranking curve (SUCRA) values 77.9) of being the most effective treatment for solid or predominantly solid benign nodules; EA ranked 1st (SUCRA value 81.1) in the treatment for cyst or predominantly cyst benign nodules.  The authors concluded that RFA appeared to be superior to other US-guided percutaneous ablation in reducing benign thyroid nodule volume during short- and long-term follow-up.  In the subgroup analysis, RFA with 2 treatment sessions showed the most significant effectiveness for solid benign thyroid nodules, and EA showed more effectiveness to decrease the volume of cyst benign thyroid nodules.

Alfaro et al (2021) examined the safety and effectiveness of US-guided percutaneous ethanol injection therapy (US-PEIT) for the treatment of recurrent symptomatic thyroid cysts.  The study comprised 33 consecutive patients (age of 51 ± 12 years, 76 % women) with symptomatic benign thyroid cysts relapsed after drainage and benign cytology prior to treatment.  Through US, maximum cyst diameter and volume were determined, and the content of the cyst was drained.  These researchers then instilled between 2 and 4 ml of ethanol (according to initial volume).  They followed-up with US at 1, 3, 6 and 12 months, and calculated the total volume and the VRR.  These researchers evaluated the perceived pain using a visual analog scale (VAS).  The initial median cyst volume was 11.6 ml (8.5 to 16.5).  A single session of US-PEIT was needed in 22 patients (67 %), 2 in 8 (24 %) and 3 in 3 (9 %).  During PEIT, 49 % of the patients experienced virtually no pain, 39 % mild pain, and 12 % moderate pain.  There were no complications.  After 6 months of follow-up the median VRR was 93 % (84 to 98).  All the patients achieved a volume reduction of more than 50 %, 94 % of more than 70 %, and 56 % of more than 90 %; 24 patients completed 1 year of follow-up, achieving a VRR of 97 % (93 to 98).  The authors concluded that US-PEIT has proven to be a safe and treatment of symptomatic thyroid cysts.  For this reason it can be considered as the 1st-line of treatment and included in the portfolio of services of a high-resolution consultation.

Jeong et al (2022) noted that RFA and EA are safe and effective for the treatment of benign symptomatic thyroid nodules (BSTNs); however, relatively little is known regarding the effects of these procedures on patients' quality of life (QOL).  In a prospective, multi-center study, these investigators examined the effects of RFA and EA on changes in thyroid-specific QOL in patients with BSTNs and assessed the volume reduction and safety of these procedures.  A total of 86 consecutive patients with 86 BSTNs were prospectively included from 2 medical centers.  RFA was performed for 55 BSTNs with solidity of 50 % or greater; and EA was carried out for 31 BSTNs with solidity of less than 50 %.  QOL was evaluated using an 11-scale, multiple-choice thyroid-specific QOL questionnaire.  Nodule characteristics and QOL were assessed at diagnosis and 1, 6, and 12 months after treatment.  Overall QOL was rated from 0 (good) to 4 (poor).  The mean longest size and volume of the index nodule were 4.2 ± 1.5 cm and 21.6 ± 22.1 mL, respectively.  Patients received 1.1 treatments on average (range of 1 to 2).  Significant post-treatment volume reductions were noted; however, the EA group showed a higher volume reduction than the RFA group at 1 (78.7 % to 16.1 % versus 49.1 % to 15.8 %), 6 (86.3 % to 21.7 % versus 73.0 % to 14.5 %), and 12 (90.9 % to 14.9 % versus 80.3 % to 12.4 %) months.  The score for each scale of the QOL questionnaire improved significantly during follow-up (all p < 0.001).  Overall QOL improved significantly, from 1.7 ± 0.9 at diagnosis to 0.6 ± 0.7 at the 12-month follow-up (p < 0.001).  There were no major complications.  The authors concluded that both RFA and EA were safe and effective in reducing nodule volume and improving thyroid-specific QOL in patients with BSTNs.

Cesareo et al (2022) stated that percutaneous ethanol injection (PEI) is used for the treatment of benign cystic thyroid nodules.  In a systematic review and meta-analysis, these investigators obtained strong evidence of its long-term safety and effectiveness.  PubMed, CENTRAL, Scopus and Web of Science databases were searched until November 2020 for studies reporting data on VRR, compressive symptoms, and cosmetic concerns.  Associated complications were assessed.  A random-effects model was designed to pool the data.  Out of 385 studies, 9  examining 1,667 nodules were finally included.  Overall, VRR at 6, 12, 24, 36, 60 and 120 months was 77 %, 81 %, 72 %, 68 %, 74 % and 69 %, respectively.  Significant reductions in the compressive symptoms and cosmetic concerns were observed.  No permanent complications were observed.  The authors concluded that the findings of this meta-analysis showed that PEI could significantly reduce the volume of benign cystic thyroid nodules.  This reduction was already effective at 6 months post-treatment, and the effect was stable over time.

The French Society of Endocrinology (SFE), French Association of Endocrine Surgery (AFCE) and French Society of Nuclear Medicine (SFMN)’s consensus on “The management of thyroid nodules: Thermal ablation” (Hamou et al, 2022) noted that in 2018, the Korean Society of Thyroid Radiology issued recommendations on the use of ethanol to treat thyroid nodules.  It concluded that ethanol should be the 1st-line treatment for cystic and predominantly cystic nodules.  A review of the literature supported this view; EA is a very effective technique, providing 85 % to 95 % volume reduction for purely cystic nodules, and 60 % to 90 % for mixed nodules with cystic predominance.

Halenka et al (2023) stated that US-PEIT is used in patients with recurrent symptomatic thyroid cysts as a credible alternative to surgery.  Young patients commonly do not wish to undergo surgery and prefer EA, if available.  The effect of this approach on QOL is an essential factor in deciding on the therapeutic options, especially in the young with a long life expectancy and no co-morbidity.  These researchers carried out US-PEIT in a cohort of young patients, 15 to 30 years of age, from 2015 to 2020.  Subjects’ general QOL, self-reported compression symptoms, and neck appearance were evaluated.  The cohort comprised 59 patients with 63 cysts, more women than men, with a mean age of 23.8 years.  About 1.5 ml of injected alcohol were needed to reach a 90.7 % mean cyst volume reduction ratio in 12 months.  The method did not fail in any of the patients; a single US-PEIT session was undertaken in 46 % of them.  The procedure significantly improved each of the patients' symptoms with a significant total score difference (p < 0.001).  The total symptom score correlated with the initial cyst volume (p = 0.002; r = 0.395).  The mean QOL score by SF-36 6 months after the last US-PEIT was significantly different for physical component summary 56.5 (p < 0.001) but not different for mental component summary 47.7 (p = 0.125), compared to age-corresponding norms.  The authors concluded that US-PEIT was a safe and effective method for the young, resulting in improvements in cosmetic and subjective complaints, and should also be considered as 1st-line treatment in the young.

Furthermore, an UpToDate review on “Diagnostic approach to and treatment of thyroid nodules” (Ross, 2024) states that “For symptomatic or cosmetically concerning benign nodules, we suggest surgery (typically lobectomy).  Where expertise is available, ultrasound-guided ablation techniques are an alternative”.

Intradiscal Radiopaque Gelified Ethanol Injection for the Treatment of Lumbar Disc Herniation

In a randomized, double-blind, single-center study, Hashemi et al (2025) reported on a new fluoroscopy-guided intradiscal radiopaque gelified ethanol injection technique using the antero-posterior view and compared it to conventional oblique view.  Intradiscal procedures, are minimally invasive techniques that aim to reduce pain associated with lumbar disc herniation by modifying the disc material and decreasing pressure on surrounding nerves.  Patients with radicular leg pain were randomly assigned to receive a radiopaque gelified ethanol injection via an antero-posterior view or oblique view.  The primary outcomes were procedure time, complication rates, and radiation exposure.  A total of 70 patients were randomized to each group (n = 35 for each group).  There were no serious complications in either group.  Radiation exposure was significantly lower in the antero-posterior view group (36.92 versus 50.46 µGray/m2 [µGy/m2; p = 0.007).  The procedure time was also significantly lower in the antero-posterior group (171 seconds versus 287 seconds; p = 0.001).  The authors concluded that an antero-posterior view radiopaque gelified ethanol injection is a promising alternative to the conventional oblique view technique for radicular leg pain management.  This novel approach offered a safer and more efficient therapeutic option, reducing radiation exposure and procedure time without compromising clinical outcomes.  Its potential to minimize patient discomfort and enhance overall management of radicular leg pain warrants further investigation and widespread adoption.

The authors stated that the drawbacks of this study included the relatively small sample size, the single-center design of the study, and the short follow-up period (14 days).  These researchers were also limited in only including patients with moderate body habitus (adults with a BMI between 24 and 30), and patients with only L3 or L4 disc herniation, which might restrict the generalizability of these findings.

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References