The majority of patients with well-differentiated thyroid cancer (WDTC), whether derived from the follicular cell or the C-cell, present with a focal, often palpable, intrathyroidal primary lesion, but at initial diagnosis, many such tumors have already spread to regional lymph nodes, mainly in the neck (1). The prevalence of such neck nodal metastases (NNM) at presentation varies significantly among the various histological subtypes of WDTC but approaches 40% (2) in both papillary thyroid cancer (PTC) and medullary thyroid cancer (MTC). A significant number of WDTC patients, despite potentially curative primary surgery, are also found to have NNM discovered at months to years after the date of the initial operation. Historically, postoperative “recurrence” within 30 postoperative years occurs in NNM, despite apparently complete primary surgical resection, in 9–20% of PTC and about 25% of MTC patients (2, 3). As detection limits of tumor markers progressively diminish, and high-resolution ultrasound (US) allows the identification of NNM as small as 2–3 mm diameter, increasing numbers of tiny NNM are being confirmed (4) by US-guided biopsy (USGB). What to do with such nonthreatening disease is a dilemma increasingly faced by thyroidologists in contemporary clinical practice (5, 6).

Clearly, radioiodine remnant ablation (RRA) rarely prevents the discovery of postoperative NNM in follicular cell-derived cancers (FCDC), and reoperative compartment-oriented surgery, recommended by most clinical management guidelines (5, 6) produces a biochemical remission in PTC only 30–50% of the time (79). Stereotactic radiotherapy has recently been employed in Korea to treat recurrent NNM in WDTC, but follow-up in these patients (7 PTC; 2 MTC) has been short, and new metastases in 4 of 9 patients developed in “nontarget regional nodes” (10). In this issue of JCEM, a study from Norway (11) describes the latest chapter in a series of papers (1215) describing the efficacy of ultrasound-guided percutaneous ethanol ablation (UPEA) in treating NNM in WDTC.

Ultrasound-guided percutaneous ethanol injections (UPEI) have been employed since the 1980s for the palliative treatment of small hepatocellular carcinomas. In 1988, UPEI was successfully employed by Charboneau and Hay at the Mayo Clinic (16) to ablate a parathyroid adenoma, which had resulted in persistent hyperparathyroidism in an elderly patient considered unsuitable for neck re-exploration. By 1990, UPEI was being employed in many European centers to treat autonomously functioning thyroid adenomas (17), and it had also been used to treat an inoperable FCDC (18). UPEA was first used at the Mayo Clinic in 1991 to treat two left central compartment NNM (9 mm and 1.1 cm diameter) in a 46-yr-old psychiatrist with stage IV MTC who had undergone three prior neck surgeries, had previously undergone transection of his right recurrent laryngeal nerve and was facing a possible tracheostomy, if he were to undergo further surgical resection. His two injected level VI nodes disappeared on careful US scanning within 10 months and did not recur after 20 yr of follow-up (Hay, I. D., and J. W. Charboneau, unpublished data).

The first PTC patient treated with UPEA at Mayo was a 34-yr-old woman who had previously undergone a total thyroidectomy and left radical neck dissection, successful remnant ablation with 135 mCi of 131I and, additionally, 5400 cGy of external irradiation (12). Despite this aggressive initial therapy, she was left with a 32 × 10 × 10 mm mass of tumor adjacent to the left carotid bulb, deemed to be inoperable. Over a period of 10 months, during May 1993 through March 2004, this patient received a total of 1.4 cc of 95% ethanol by US-guided injections over three sessions. Now, at 18 yr after first treatment, her serum thyroglobulin (Tg) is <0.1 ng/ml, her whole-body 2-fluoro-2-deoxy-d-glucose positron emission tomography-computed tomography scan is negative and her latest US only shows an avascular node of 6 × 5 × 8 mm adjacent to the left common carotid artery.

Between November 1993 and April 2000, a further 13 PTC patients, who had undergone adequate primary surgical resection and postoperative RRA, presented to Mayo Clinic with a limited number of “recurrent” NNM (one to five involved nodes). Twenty-nine NNM in these 14 study patients were treated during 1993–2000 with UPEA (12). Mean follow-up was 18 months (range, from 2 months to 6 yr 5 months). All treated nodes decreased in volume (from a mean volume of 492 mm3 at treatment to a mean of 20 mm3 after 2 yr); blood flow within the NNM, as measured by color Doppler, was totally eliminated. In 12 (86%) of the 14 patients, UPEA successfully controlled all known metastatic adenopathy. The other two patients developed further NNM at 19 and 26 months after successful UPEA, and these later-onset nodes were considered anatomically unsuitable for alcohol ablation and were successfully treated by surgical resection. Most patients experienced brief discomfort at the injection site, but none developed transient or permanent hoarseness.

Lewis and colleagues (12) concluded that UPEA was a valuable treatment option for patients with limited NNM from PTC who were not amenable to further surgical or radioiodine therapy. They emphasized that UPEA was far less invasive than neck re-exploration, could be repeated without technical difficulty, and required minimal recovery time. At the time of their 2001 manuscript acceptance (12), the procedural cost for a single UPEI was $836, as against costs of approximately $9,800–$12,000 for surgical neck exploration. Almost a decade later, the average charge for each of 75 UPEA procedures (current procedural terminology code 38999), performed during 2010 at Mayo for 53 patients with FCDC or MTC, was $1,583, a fraction of the $35,000 to $45,000 charges estimated (including all hospitalization costs) for either a central compartment node dissection or a unilateral modified radical neck dissection (current procedural terminology codes 38720 or 38724).

The multidisciplinary thyroid team at the Norwegian Radium Hospital (Oslo, Norway), apparently “inspired” (11) by the promising results reported by Lewis et al. (12), introduced UPEI to their practice in 2004. In the paper by Heilo et al. (11), published in this issue of JCEM, they describe their experience of treating 69 PTC patients during 2004–2009. All of their patients had been treated with thyroidectomy and RRA. Lymph node status was determined by USGB and/or by raised levels of Tg in washouts from the cytological needle. Guided by US, 0.1 to 1.0 ml of 99.5% ethanol was injected into each selected NNM. Sixty-three patients with 109 NNM were treated and followed on average for 38 months (range 3–72).

In total, 101 of 109 (93%) of the NNM responded to PEI treatment: 92 (84%) completely and nine incompletely. Two did not respond, and four progressed. Two lymph nodes, previously considered successfully treated, showed evidence of malignancy during follow-up. Serum Tg values were available from 62 patients before PEI and from 60 at the end of follow-up. Of 51 patients without Tg antibodies, 13 had undetectable serum Tg levels (<0.2 μg/liter) before PEI, despite biopsy-proven metastatic disease. Of the 38 patients with elevated serum Tg values before PEI, 30 patients had undetectable values after PEI treatment. Heilo et al. (11) concluded that UPEA seems to be an excellent alternative to surgery in patients with a limited number of NNM from PTC and should probably replace “berry picking” surgery.

Potential complications of UPEA include damage to recurrent laryngeal nerves, parathyroid injury, and local pain or discomfort, likely related to local leakage of small amounts of ethanol into surrounding soft tissue. To date, very few complications have been reported. Of six PTC patients treated with UPEA at Rhode Island Hospital (Providence, RI), one experienced temporary hoarseness, which recovered within 3–4 h (13). One (6%) of 16 UPEI-treated PTC patients from Yonsei University (Seoul, Korea) had “voice change,” which disappeared after 5 d (14). In the 2008 report of Kim et al. (15), one of 27 PTC patients (4%) experienced temporary hoarseness after UPEA. Lastly, in the present Norwegian study (11), no major complications were recognized, and “less than 10%” of 63 treated PTC patients experienced minor local discomfort.

With the publication of this Norwegian long-term follow-up study (11), there should now be little doubt about the efficacy of UPEA in eliminating selected NNM in patients with PTC. Clearly, the technique, first described in Minnesota (12, 16), has been successfully duplicated in other parts of the United States (13), in Asia (14, 15), and in Europe (11). In the Mayo practice, during 1991–2000, more than half of the UPEA procedures were carried out in stage IVC patients who had evidence of distant metastases, and, in these circumstances, the procedure was considered palliative. However, since 2001, more than 80% of UPEA procedures have been performed in patients with disease confined to the neck (pT1 or T2, N1a or N1b, M0), where residual nodal disease was minimal, and the procedure might potentially be considered as curative. Further long-term follow-up studies are indicated to determine whether, in selected PTC cases, UPEA can significantly improve future locoregional recurrence rates.

Clearly, there may always be a role for PUEA in palliation, when selected patients with advanced WDTC, rather than being appropriately concerned with potentially life-threatening distant metastases, become obsessed with the more easily visualized (and treated) NNM. However, it should be that much greater population of patients with localized node-positive PTC, who have not experienced an optimized surgical approach (19) and have proved resistant to the still probably over-used and relatively ineffective RRA (20), that will probably most benefit from this safe, cheap, and effective means of eliminating nonthreatening NNM in PTC. Although the technique requires an ability to recognize pathologic NNM on high-resolution US and necessitates special skill in USGB of awkwardly situated and increasingly small NNM, such skills can be learned, and, globally, many interested clinicians are indeed presently acquiring such talents in a variety of university and private practice settings.

The current American Thyroid Association revised Management Guidelines (5) conclude with a section entitled: “What are directions for future research?” Under the section on “small cervical lymph node metastases,” the authors state that “future research must consider the dilemma of minimizing iatrogenic patient harm vs. preventing cancer morbidity and (perhaps) mortality. Perhaps techniques will be developed to safely remove or destroy small cervical nodal metastases, which in some cases would otherwise progress to overt, clinically significant metastases” (5). There seems little doubt that UPEA has, as of 2011, “come of age,” and certainly at Mayo, it has found its place in the mainstream of techniques used to treat and locally control recurrent nodes in PTC. With the increasing numbers of international series being published, which reinforce the messages of the 2002 AJR paper (12), it is to be hoped that an increasing number of institutions (particularly in North America), will encourage their physicians to develop similar skills comparable to the radiologists in Rochester and Oslo, who have, in recent years, provided a valuable service for their WDTC patients with NNM considered to be “not amenable to conventional retreatment with surgery, radioiodine, or external irradiation” (12).

I do PEI in my center for  recurrent lymph node disease after the initial; total thyroidectomy and neck dissection.

Call Matt at 310-393-8860 for details.

Richard Guttler MD,FACE,ECNU

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