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Original Studies |
Department of Endocrinology, Odense University Hospital, DK-5000 Odense C, Denmark
Address all correspondence and requests for reprints to: Finn Noe Bennedbæk, M.D., Department of Endocrinology, Odense University Hospital, DK-5000 Odense C, Denmark.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionAddendumReferences |
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In a prospective randomized clinical trial, 50 euthyroid patients with a single solid colloid thyroid nodule causing local discomfort were assigned to a single intranodular injection of sterile 98% ethanol (n = 25) or suppressive doses of L-T4 (n = 25). We aimed at an ethanol dose of 20–50% of the pretreatment nodular volume. The initial daily dose of L-T4 was 1.5 µg/kg BW and was adjusted monthly during the first 6 months to reduce serum TSH to subnormal levels (<0.40 mU/L). Thyroid nodule volume and total thyroid volume were assessed by ultrasound, and thyroid function was determined by routine assays before and during follow-up. Symptom scores before and at 12 months were evaluated by a questionnaire rating pressure symptoms and cosmetic symptoms.
The median ethanol dose given was 21% [95% confidence interval (CI), 18;25] of the pretreatment nodule volume. In this group, the median reduction in nodule volume was 47% (CI, 33;57; P < 0.0001) compared to 9% (CI, -7;22; P = 0.09) in the L-T4 group. The difference between the two treatment regimens was statistically significant (P < 0.0001). The median reduction in perinodular thyroid volume was 20% (CI, 11;31; P = 0.03) in the L-T4 group, whereas no change was seen in the ethanol group (-2.5%; CI, -18;11; P = 0.9). Fourteen of 25 (56%) patients treated with ethanol injection and 8 of 25 (32%) treated with L-T4 had complete relief of symptoms at 12 months of follow-up (P = 0.09). No major side-effects were seen in either group.
Percutaneous ethanol injection therapy administered as a single small
dose results in a satisfactory clinical response in 
50% of patients
by halving the nodule volume. The thyroid nodule-reducing effect of
L-T4 suppressive therapy is insignificant, but
a subjective satisfactory clinical response is seen in a subgroup of
patients, probably explained by the concomitant reduction of
perinodular thyroid volume.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAddendumReferences |
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The therapeutic strategy for the euthyroid patient with a benign solitary solid thyroid nodule that appears cold on a scintiscan is still a matter of debate. The possibilities are observation, L-T4 suppressive therapy, or surgery. Several researchers have addressed the conflicting issue of L-T4 suppressive therapy either as a short term trial as evidence of the benign nature of the nodule or to achieve shrinkage of the nodule (7, 8, 9). Generally, the results have been disappointing in the placebo-controlled studies (reviewed in Ref.8). Although treatment seems at best beneficial in a subgroup of patients with smaller nodules (9), pretreatment variables, such as patient age, nodule duration and pretreatment size, and TRH-induced TSH response, cannot predict nodule responsiveness to L-T4 therapy (10).
The sclerosing properties of absolute ethanol have been recognized for many years and have offered interventional possibilities in the management of various benign as well as malignant lesions (11, 12). The mechanism of action of ethanol appears to be related to a direct coagulative necrosis and local partial or complete small vessel thrombosis (3). Percutaneous ethanol injection therapy (PEIT) is rapid and performed on an out-patient basis. In the treatment of smaller autonomous thyroid nodules (13), cystic thyroid nodules (14), and selected patients with parathyroid tumors (15), it has proven to be a useful method. Recently, preliminary results on the efficacy of PEIT in benign solitary solid cold thyroid nodules were reported (16, 17).
In our opinion there is a need for an effective nonsurgical treatment. The aim of the present study was to determine the effectiveness of a single small dose of sterile 98% ethanol injected into the nodule against that of suppressive L-T4 (TSH <0.4 mU/L).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAddendumReferences |
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Patients who were 20–70 yr of age and had a benign solitary solid cold palpable thyroid nodule causing local discomfort were eligible. Patients were referred by their primary care physicians. Inclusion criteria were 1) [99mTc]pertechnetate scintigraphy demonstrating a solitary cold nodule, 2) ultrasound-demonstrated solitary solid nodule, 3) ultrasound-guided FNAB compatible with a colloid nodule, 4) euthyroidism, 5) normal serum ionized calcium and calcitonin, 6) no major concomitant disease, 7) no medication affecting thyroid function, 8) no history of previous head or neck irradiation, and 9) normal indirect laryngoscopy. All patients lived in an area (county of Funen, Denmark) with a borderline deficient iodine supply. In this area the median urinary iodine excretion is 85 µg/24 h (18). Before enrollment, patients were asked to rate pressure symptoms and cosmetic complaints in a questionnaire as absent, mild, moderate, or severe. The protocol was approved by the ethics committee of the county of Funen (journal no. 94/63) and the National Board of Health (journal no. 5312–97-1994). All patients provided signed informed consent before randomization.
Measurements
FNAB was performed under ultrasound guidance, using a 0.6 x 30-mm hypodermic needle attached to a 10-mL plastic syringe, and a minimum of three samples from each lesion were obtained. Only colloid nodules showing abundant colloid and benign follicular cells in variable proportion were considered for inclusion. The echo pattern was investigated with a real-time 7-megahertz sector transducer (type 8534, Brüel and Kjær, Naerum, Denmark). The total thyroid volume (normal range, 9.6–27.6 mL) and nodule volume were calculated on the basis of an ultrasonic scanning procedure using a 5.5-megahertz compound scanner (type 1846, Brüel and Kjær, Naerum, Denmark) (19). For each patient, ultrasound measurements were performed by the same operator (F.N.B. or L.H.) with blinding toward previous measurements. Intraobserver variation using this accurate cross-sectional method, i.e. coefficient of variation on double determinations, has been assessed previously (20) and was 6.6% (F.N.B.) and 5.1% (L.H.), respectively.
Blood tests included serum total T4 (normal range, 65–135 nmol/L) determined by RIA (Diagnostic Products Corp., Los Angeles, CA), serum total T3 (normal range, 1.00–2.10 nmol/L) determined by RIA (Johnson & Johnson, Clinical Diagnostics, Amersham, UK), and serum TSH (normal range, 0.30–4.0 mU/L) determined by DELFIA (Wallac OY, Turku, Finland). Free T4 and T3 (FT4 and FT3) indexes were calculated multiplying serum T4 and T3 levels by the percent T3 resin uptake. Serum antithyroid peroxidase (anti-TPO) antibodies (normal range, <200 U/mL) were determined by the RIA DYNO test (Brahms Diagnostica, Berlin, Germany). Only patients with normal thyroid hormone and TSH serum levels were considered for inclusion.
Study design and treatment
Random allocation was achieved using a random number generator on a computer. Patients were assigned to 1) oral L-T4 at an initial dose of 1.5 µg/kg BW per day to be taken in one single dose in the morning and individually adjusted after 1, 2, 3, and 6 months to reduce serum TSH to subnormal levels (0.10–0.40 mU/L), continued for 12 months; 2) or a single small intranodular dose of sterile 98% ethanol injected under sonographic control. The aim was an ethanol dose of 20–50% of the pretreatment nodular volume. The dose depended both on the attainment of total intranodular dissemination of the fluid visualized on the television monitor screen and on pain during the procedure demanding premature discontinuation of the injection. All patients in the ethanol group received 1 g oral paracetamol or 1 g oral acidum acetylsalicylicum and local anesthesia with 1 mL sc lidocaine (10 mg/mL) before the treatment.
All patients were evaluated before and after 1, 2, 3, 6, and 12 months, and measurements included serum thyroid hormones, TSH, thyroid nodule volume, and total thyroid volume assessed by ultrasound. At the last visit patients were again asked to rate their present pressure symptoms and cosmetic complaints as none, mild, moderate, or severe. To avoid recall bias, the same questionnaire was completed by the patients immediately after the visit without supervision from any of the team.
Sample size
We know from published data (21) that SD on proportional nodule volume reduction during L-T4 suppressive therapy has been estimated at a level of 40%. Given a type I error of 0.05 (2-sided), a power of 90%, and an a priori estimated clinically relevant difference of 40% gives a sample size of 21 patients in each group. For this study of 2 independent groups of patients with a continuous outcome measure, it is assumed that the proportional change in nodule volume has a normal distribution, i.e. an element of uncertainty; thus, we chose a sample size of 25 patients in each group.
Statistical analysis
Results for continuous measures are reported as medians ±
95% confidence intervals. All comparisons for paired data in the two
treatment groups are based on ANOVA II (observations based on
within-subject differences; serial measurements; TSH and
FT4 index), two-tailed, two-sample t tests for
quantitative variables (TSH and FT4 index in the
L-T4 group), Friedman’s two-way
ANOVA, and Wilcoxon rank sum test for highly skewed quantitative
variables (total thyroid volume and thyroid nodule volume).
Nonparametric independent group comparisons (Mann-Whitney test) were
used for total thyroid volume and thyroid nodule volume between the two
treatment groups. The sign test and 
2 test were used to
test changes in self-estimated ratings (questionnaire). One drop-out in
each group was anticipated. Six months after treatment, two patients in
the PEIT group were operated upon due to unaltered complaints, and the
6-month evaluation was the end point in these two patients. Statistical
analysis is based on intention to treat analysis, and no patients were
excluded.
The computer programs used were confidence interval analysis and SPSS 7.0 (Windows 95).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAddendumReferences |
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)During the 22-month inclusion period, 123 patients had a diagnosis of a solitary solid cold thyroid nodule. Based on FNAB results and/or clinical suspicion or patient preference, 42 of these patients were operated upon, and 31 refused surgery as well as medical treatment.
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. The groups were similar
regarding sex, age, body weight, nodule duration, perinodular thyroid
volume, TSH, FT4 index, FT3 index, serum
calcitonin level, and number of cases with anti-TPO antibodies.
However, randomization resulted in a comparatively higher frequency of
smaller nodules in the L-T4 group.
Thus, 10 of 25 nodules (40%) were less than 5 mL, compared with 4 of
25 nodules (16%) in the PEIT group. Median nodule volume was 9.2 mL in
the PEIT group compared with 7.1 mL in the
L-T4 group (P =
0.14). Nodule volume in both groups showed marked deviations from a
normal distribution skewed toward smaller volumes in the
L-T4 group, thus favoring outcome in
the L-T4 group, as evidenced by
previously published data (9).
Nodule and perinodular volume (Table 2)
The median ethanol dose given was 21% [95% confidence interval (CI), 18;25) of the pretreatment nodular volume. In the PEIT group, the median nodule volume decreased from 9.2 to 6.1 mL at 1 month (P < 0.0002) and 5.1 mL at 12 months (P < 0.0001, 0 vs. 12 months). During the last 11 months, only a small and insignificant change was seen (P = 0.13, 1 vs. 12 months). The overall median reduction at 12 months was 47% (CI, 33;57; P < 0.0001). No change in perinodular thyroid volume was seen during the 12 months of follow-up (-2.5%; CI, -7;22; P = 0.9, 0 vs. 12 months). Two patients were operated on after 6 months because of an unsatisfactory result, i.e. an increase in nodule volume and unaltered complaints. In both cases, the original benign cytological diagnosis was confirmed through histological examination. Four patients had slightly elevated anti-TPO antibodies before treatment, and the reduction in nodule volume exceeded 50% in all.
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Sixteen of 31 patients who declined treatment were followed for a median of 13 months (CI, 10;16), and nodules in this selected group were smaller (median, 4.8 mL; CI, 3.0;10.4); nevertheless, spontaneous nodule growth was seen in most (median, 17%; CI, -3;38).
Thyroid function (Table 2)
In the PEIT group, the serum TSH level and serum thyroid hormone levels were unaltered throughout the 12 months.
The initial median L-T4 dose was 1.56 (CI, 1.44;1.65) µg/kg BW compared with 1.43 (CI, 1.27;1.62) µg/kg at the final evaluation (P = 0.4). In this group, the serum TSH level was less than 0.4 mU/L in all patients at the 1-month evaluation (P < 0.00001, 0 vs. 1 month). At 6 and 12 months, all except one (TSH, 0.49 mU/L) and two patients (TSH, 0.59 and 0.74 mU/L), respectively, still had a serum TSH level less than 0.4 mU/L (P < 0.00001, 0 vs. 6 months; P < 0.00001, 0 vs. 12 months). During the entire follow-up, the corresponding thyroid hormone levels were elevated, but were always within the normal range (FT4: P < 0.0001, 0 vs. 12 months; FT3: P = 0.66, 0 vs. 12 months). Compliance with treatment was satisfactory, although two patients had only partial suppression of TSH. These two patients reported partial relief of neck complaints and had a nodule that was reduced 11% and 33%, respectively.
Questionnaire (Table 3)
Initially, 88% of patients (22 of 25) in both treatment groups
had pressure symptoms or pressure symptoms as well as cosmetic
symptoms, and only 12% (3 of 25) had solely cosmetic complaints.
Likewise, no major differences between the number of patients with no,
mild, moderate, or severe complaints in the two treatment groups were
seen (Table 3).
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). Fifty-four percent (7 of 13) had complete relief of
cosmetic complaints, 8% (1 of 13) had slight improvement, and in 38%
(5 of 13) no improvement was reported (P = 0.008).
In patients treated with L-T4, only
23% (5 of 22) reported complete relief of pressure symptoms, 27% (6
of 22) had slight improvement, and in 50% (11 of 22) complaints were
unaltered (P = 0.001; Table 3). Complete relief of
cosmetic complaints was reported by 33% (4 of 12), slight improvement
was reported by 17% (2 of 12), and no improvement or worsening was
reported by 50% (6 of 12; P = 0.1).
Questionnaire and corresponding objective findings (Table 4)
Complete relief of either pressure symptoms or cosmetic complaints was reported by 56% (14 of 25) treated with PEIT and 32% (8 of 25) treated with L-T4. This difference was suggestive, but not significant (P = 0.09). The corresponding median reductions in nodule volume were 51% (CI, 42;64) and 33% (CI, 12;40), respectively. The remaining 68% (17 of 25) treated with L-T4, reporting partial or no relief or even worsening of symptoms, had only a minor decrease or an increase in nodule volume. Surprisingly, a satisfactory clinical response (subjective and objective) was not obtained in the smallest nodules in the L-T4 group. Forty-four percent (11 of 25) of patients treated with PEIT reported a slight or no improvement of neck discomfort. In this group, however, the largest nodules (6 patients with a median nodule volume of 12.6 mL (CI, 11.3;13.7) only had a 10% (CI, -40;59) reduction in nodule volume, and no relief of complaints was seen. Two of these patients were operated on with a satisfactory result, and histology confirmed the cytological diagnosis based on the ultrasound-guided FNAB. On the other hand, in 76% (19 of 25) of patients treated with PEIT, the nodules were halved, and discomfort vanished or was alleviated. A priori, a dose-response relationship would be expected in patients treated with ethanol injection and was confirmed by our results. Patients with unaltered complaints had minor changes in nodule volume and were actually treated with a smaller dose per mL tissue (15%), unlike the remaining patients who received a dose of 20% or more per mL tissue. The relatively smaller dose given was the result of the instant local and sometimes radiating pain caused by ethanol injection, which prompted cessation of the injection. In 9 patients (9 of 25 = 36%), the planned ethanol injection was limited because of early onset of pain during the injection procedure. They received less than 19% of the pretreatment nodule volume (range, 8–18%). The median nodule volume was 12.8 mL (CI, 10.3;15.4) compared with 6.8 mL (CI, 5.1;9.0; P = 0.001) in the remaining 16 patients.
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In all but one patient receiving PEIT, the injection was accompanied by slight to moderate pain lasting for minutes (median, 0.6 h; CI, 0.2;12.0) and subsequently tenderness lasting 2–3 days (median, 2.5 days; CI, 1.5;3.8). No further side-effects, such as fever, hematomas, transient or permanent dysphonia, or dysthyroid symptoms, were encountered, and no subject developed anti-TPO antibodies. In all patients in the PEIT group, an indirect laryngoscopy was performed by an otorhinolaryngologist before treatment and at the last evaluation, and no cases of vocal cord paralysis were encountered. Five patients receiving L-T4 had symptoms of hyperthyroidism (diarrhea, palpitations, sweating, or tremor) after 1–2 months of treatment. Symptoms disappeared after dose adjustment. Without exception, all patients were treated as out-patients.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAddendumReferences |
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The goal of ethanol injection into nonfunctioning nodules is to achieve necrosis and subsequent volume reduction and to prevent further growth. Limitations when injecting into solid nodules are local or radiating pain that demand termination of the procedure. The instant pain and concomitant tenderness can be alleviated, but not hindered, by the preceding local anesthesia and administration of mild oral analgesics, as 96% of our patients reported slight to moderate pain due to the injection. A serious side-effect related to the ethanol escaping outside the nodule capsule is development of extraglandular fibrosis. This condition may impede subsequent surgery, but in our material two patients were subsequently operated upon, and no extranodular fibrosis was seen; the surgical procedure was uncomplicated. Except for the pain, no side-effects were seen in our series.
TSH is considered the major trophic hormone for the thyroid gland, but its role in controlling thyroid and nonfunctioning thyroid nodule growth is controversial (22). To date, from a clinical point of view, it seems possible that a subgroup of patients with a benign solitary solid cold thyroid nodule do respond to L-T4 suppressive therapy, suggesting nodule growth to be TSH dependent (9). How is this subgroup to be identified before treatment? Recently, La Rosa and colleagues suggested that initial nodule volume (smaller nodules) and certain cytological characteristics (colloid nodules and nodules with degenerative changes if they are small) can predict a clinically relevant response (23). On the other hand, in view of the lack of other nonsurgical alternatives, the beneficial effect of L-T4 has been stressed in several studies, reporting a 50% reduction in up to one third of these nodules. However, the fact that treatment has been a failure in the majority of patients has been generally ignored (9, 24, 25, 26). Others found no reduction in size of colloid nodules within 6 months (21).
A logical end point of therapy, ignored in most clinical trials, should be relief of symptoms, defined by the patient, rather than a definite reduction in nodule volume, although a correlation seems likely. As a consequence, we designed a simple questionnaire to quantify the effects on cosmetic and pressure symptoms. A clinically relevant response, that is complete relief of neck complaints, was obtained in 32% of our patients treated with L-T4, and the corresponding reduction in nodule volume was 33%. A 50% reduction in nodule volume was achieved in none. The nodule-reducing effect of L-T4 was less than that in the above-mentioned studies (9, 24, 25, 26), but corresponded well with an observed success in one third of patients, being far from an expected success rate of 80% if nodules are smaller and classified as colloid nodules, as suggested by La Rosa and colleagues (23). The reduction in perinodular thyroid volume (20% in our study) mimics a response in the nodule itself and thus explains the complete or partial relief of neck complaints in some of our patients despite a rather small reduction in nodule volume. During the first 3 months in our study, there was a small successive, but significant, reduction in nodule volume in the L-T4 group, but 20% of patients also reported hyperthyroid symptoms that were alleviated after minor dose adjustments. The median TSH level during the first 3 months was less than 0.20 mU/L, and it was insignificantly higher, but still less than 0.30 mU/L, during the last 6 months, during which period the nodule volume increased slightly. A paradoxical resistance against therapy occurring after 3 months of therapy as an explanation of renewed growth is a rather speculative hypothesis. More likely, this indicates a narrow dose-response relationship not favoring L-T4 therapy if TSH suppression in the hyperthyroid range is needed to achieve success. Furthermore, life-long treatment could constitute an increased risk of osteoporosis and possibly other side-effects (7, 27).
To achieve a homogeneous study population inevitably implies a selection, and given the various degrees of neck complaints, especially in smaller nodules less than 5 mL, it is not surprising that some refuse further treatment or control once a benign diagnosis has been established. Only nodules causing neck discomfort (defined by the patient and not the clinician) combined with a wish for specific treatment to achieve alleviation were considered for inclusion, and therefore, randomization to no treatment could not be achieved. Based on the results of controlled studies (9, 21, 26), insignificant nodule regression or growth was anticipated. Follow-up data for patients not included in our study, although very selected, indicated spontaneous growth rather than regression and support the contention that colloid nodules cannot be left untreated with impunity.
In conclusion, in our borderline iodine-deficient area, the present study does not support L-T4 therapy of benign solitary solid cold thyroid nodules as a first choice treatment modality. Based on the present study, we have abandoned routine use of L-T4 suppressive therapy for this condition. PEIT as a single small dose of ethanol is superior to L-T4 suppressive therapy, but is still inferior to surgery. Further studies will have to address long term effects and optimum management strategy, including proper ethanol dose and treatment intervals. To date, PEIT is considered an experimental treatment and should be reserved for symptomatic patients who cannot or will not undergo surgery.
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Addendum |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAddendumReferences |
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Footnotes |
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Received September 2, 1997.
Revised November 7, 1997.
Accepted December 9, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAddendumReferences |
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