Percutaneous Ethanol Injection Treatment, Novel Solution for the Challenge of Recurrent Thyroid Pathology: A Review

In the latter half of the twentieth century, percutaneous ethanol injection (PEI) gained popularity as a non-surgical intervention for benign parathyroid adenoma, septal ablation in hypertrophic cardiomyopathy as well as for hepatocellular carcinoma [1-3].

In the last 25 years, it has quietly inspired a surprising level of interest among clinicians treating thyroid disease. Ablation of autonomously functioning thyroid nodules with PEI was the first proposed application of the procedure in the treatment of thyroid pathology. Livraghi and colleagues published promising results of their PEI treatment trials in autonomous functioning thyroid nodules in 1990 [4]. Since those initial forays, PEI has been evaluated as a treatment option for various presentations including recurrent papillary thyroid cancer (PTC).

PEI has been successful in treating cystic thyroid lesions, solid non-functioning, autonomously functioning and to a certain degree, even in hyper-functioning thyroid nodules [5-8], (Table 1). The proposed mechanism of action of PEI is by inducing sclerosis of the collapsed nodule capsule [8,9]. Complete aspiration may cure a subset of cystic thyroid nodules (Table 2).

Table 1: Studies evaluating percutaneous ethanol treatment in functional thyroid nodules.

Table 2: Studies evaluating percutaneous ethanol treatment in cystic thyroid nodules.

However, many recur and surgical removal will be considered for these mostly benign cystic nodules and solid functional nodules [10]. Thyroid surgery is safe however, there is associated risk of complications even in hands of high volume surgeons and presents a significant financial burden [8]. Therefore, PEI treatment presents an attractive minimally invasive option for these patients with benign nodules. In these patients, complete and lasting disappearance of the treated cystic nodules is a realistic goal of therapy.

Radioactive iodine (RAI) therapy was preferred for treating hyperthyroid state. RAI is usually well tolerated but it can be associated with risks of hematologic abnormalities, reproductive disturbances, and salivary-gland disturbances with repeated doses [11]. In a recent publication, it was concluded that RAI was associated with an over 20% failure rate to treat hyperthyroid state while surgical intervention was 3.44 times more successful than RAI [12]. On the other hand, PEI may be a good treatment option for patients with small functional nodules (<5ml) who defer I-131 therapy and are poor surgical candidates [8]. The injection of ethanol acts by immediate tissue dehydration, protein denaturation, and coagulation necrosis of the vascular endothelium, platelet aggregation, vascular thrombosis and ischemic tissue necrosis (Figure 1) [8,10]. In currently published cases, ablation of the autonomous lesion was followed by return of normal thyroid function nearly 100% of these patients [6,7]. The possibility of subclinical or overt hyperthyroidism necessitates continued follow up with endocrinologist and serum thyroid function testing in the presence of clinical suspicion [6,7]. Despite evidence of some benefit, realistically, therapeutic role of PEI treatment of frankly toxic thyroid nodules is limited [8].

Figure 1: Histological changes in neoplastic thyroid tissue on pretreatment (A) and post-treatment (B) with percutaneous ethanol injection. Image (B) shows signs of fibrosis and necrosis in the thyroid tissue.

While PEI treatment for benign thyroid lesions was the area of initial sustained interest, during 2000s only investigators in Europe and Asia continued to pursue this line of application. Their colleagues in United States have instead focused on the possibility of using this treatment modality in thyroid malignancy, most commonly, PTC. PTC has one of the highest long term survival rates of any malignancy, with 90% survival at 10 years after the initial diagnosis [13,14]. However, as the other thyroid pathologies discussed in this review, it too shares the propensity to recur. Many patients who initially present with an early Stage 1 lesion must return to the operating room for treatment of their local nodal metastases multiple times after their primary operation [13,15,16]. Lobectomy or total thyroidectomy with selective cervical lymph node dissection of the affected regional nodes is the appropriate primary treatment options for PTC. Surgical interventions can be followed by radioactive Iodine-131 ablation of any remaining microscopic and macroscopic disease. In the hands of an experienced surgeon, primary total thyroidectomy has become a relatively low risk surgical procedure with a reported 2% risk of recurrent laryngeal nerve (RLN) injury [15,17,18]. Patients are monitored with ultrasound (US) routine examination for nodes suspicious for neoplastic spread (Figure 2,3). Metastatic lymph nodes are treated with selective neck lymph node dissection during primary thyroid surgery or focused dissection aimed at resecting lymph nodes missed during the initial neck dissection for the disease [15]. Prophylactic lymph node dissection has not been shown to offer a clinically significant benefit in the setting of early Stage 1 PTC to merit routine implementation [19,20]. Ironically, these patients who are most likely to suffer the cycle of local recurrence and reoperation.

Figure 2: Ultrasound image of a sub-centimeter metastatic lymph node exhibiting loss of fatty hilum and eggshell calcifications.

Figure 3: Duplex Ultrasound image of a small metastatic lymph node demonstrating increased vascularity of the lesion.

Reoperation is a significantly more complex procedure compared to primary total thyroidectomy. Each revision central neck surgery presents an increasing potential of significant morbidity. Factors such as variability in natural anatomy of the RLN structure, disruption of tissue planes, surgical distortion of normal anatomic landmarks and adhesion formation caused by previous surgical interventions can contribute to the difficulty of the surgery required to resect a recurrent nodal metastasis [15,17,18,21]. Major complications most commonly associated with revision surgery in the central neck are RLN injury and hypoparathyroidism from inadvertent devascularization or removal of the parathyroid glands [13,15,22]. Additionally, due to the indolent nature of this malignancy, a significant portion of patient population presents with local recurrences in advanced age [13,15]. These patients face increased risk of injury due to the difficulty of dissection associated with redo neck surgery and additional significant health risks associated with general anesthesia. Recently, FDA approved tyrosine kinase inhibitor, sorafenib, for treatment of radioiodine-resistant metastatic differentiated thyroid cancer. However, this treatment carries a significant risk of adverse effects and is not appropriate for controlling locally persistent but limited disease [23].

The potential of PEI treatment in PTC was recognized early and a year following Livraghi work was published, a team at Mayo Clinic treated a patient with central compartment neck nodal metastases [4,24]. The patient had previously undergone three neck reoperations, the last of which was complicated by transection of the RLN. Further surgery would have come at the cost of the very real risk of bilateral RLN paralysis. The team chose to try PEI treatment of the patients’ limited recurrent disease. After the treatment, US examination showed complete disappearance of the treated metastatic lymph nodes [24]. The patient continues to be free of macroscopic disease after 20 years of follow-up. Recurrence of unsightly benign cystic nodules was a good venue to test PEI treatment’s ablation abilities; meanwhile recurrent PTC is arguably the area of greatest potential benefit for widespread adoption of this innovative treatment approach.

Unlike reoperation in the central neck, PEI treatment is a simple minimally invasive procedure and can be safely performed in an outpatient clinic setting under US guidance with local anesthetic. Therefore, ethanol ablation may have a particularly high value in situations when the risks of doing surgery are too great. Locoregional metastases of thyroid carcinoma which are not amenable to surgery, radio-iodine or irradiation can be safely injected with ethanol resulting in a local area of necrosis of pathologic tissue and vasculature [22,24,25-27]. It has proven to be especially useful in treatment of lesions with close proximity to major neurovascular structures without causing permanent nerve or vascular injury [20,22] (Table 3). Persistent vascularity of the lesion on post-treatment US and color Doppler evaluation signals to the treating physician that a repeat PEI treatment is necessary at a later time [8,22,25] (Figure 3). In this way, treatments can be carried out until satisfactory results are achieved without significant increase in risk of complications. Serum thyroglobulin level response to PEI treatment is analogous to that which occurs after surgical resection and appears to be a good predictor of successful therapy when compared with pre-treatment levels. Serum thyroglobulin levels may then be used to monitor the patient for possible recurrence [5,15].

Table 3: Studies evaluating percutaneous ethanol treatment in recurrent lymph nodes metastases in recurrent papillary thyroid carcinoma. Note: *LOE= level of evidence.

Based on existing literature and the degree of potential impact, PEI treatment may have its strongest role in treatment of recurrent PTC in metastatic lymph nodes in regions of the neck where they would be difficult to reach surgically without incurring a significant risk to the patient. At the 83^rd ATA meeting in 2013, a featured presentation focused on the successful treatment of five foci of PTC in three intact thyroids [28]. Following PEI treatment, the hypervascular pattern of metastatic nodes disappeared and thyroglobulin levels dropped to undetectable levels. Each patient was followed with serial thyroglobulin levels and reevaluated with US and color Doppler for over a year without evidence of persistent or recurrent disease [28]. The group presenting this work concluded that PEI of intra-thyroid lesions is well tolerated and may offer an alternative therapy to conventional surgery for papillary thyroid microcarcinoma.

PEI treatment carries its own risk of complications. Pain at the site of injection is the most common adverse effect, typically lasts a few hours before resolution without any serious sequel [7,8,25]. Although PEI is generally a safe and effective treatment, there are sporadic reports of patients experiencing transient hoarseness after the procedure. The transient hoarseness is likely due to RLN irritation and to date, no patients experienced permanent hoarseness [7,8,25]. Rarely, PEI may cause local reaction and fibrosis if it infiltrates into the normal tissue. Overall, PEI is reported to have fewer side effects compared to thermal ablative therapies and has been proven to be effective in treating cystic thyroid nodules, non-functioning nodules, autonomous thyroid adenomas and small lesions of locally recurrent PTC.

To summarize, PEA is a versatile, minimally invasive option that is well tolerated with no lasting adverse effects. It is a safer and more economically attractive option compared to conventional surgical intervention. Future prospective multi-institutional studies are warranted to further compare the oncological outcomes related this approach and re-operative neck surgery.