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Vascular and Interventional Radiology |
1 From the Ultrasound Service, D. Cotugno Hospital, via Roma 8, 80059 Torre del Greco (Na), Italy. From the 1997 RSNA scientific assembly. Received February 9, 1998; revision requested March 3; final revision received April 15, 1999; accepted July 1. Address reprint requests to L.T. (e-mail: assanui@tin.it).
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Abstract |
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MATERIALS AND METHODS: Twelve patients (eight women, four men; age range, 26–76 years) with a large hyperfunctioning thyroid nodule (volume range, 33–90 mL; mean, 46.08 mL) underwent PEI treatment under ultrasonographic (US) guidance. US was used to calculate the volume of the nodules and to assess the diffusion of the ethanol in the lesions during the procedure. When incomplete necrosis of the nodule was depicted at scintigraphy performed 3 months after treatment, additional PEI sessions were performed.
RESULTS: Four to 11 PEI sessions (mean, seven) were performed in each patient, with an injection of 3–14 mL of 99.8% ethanol per session (total amount of ethanol per patient, 30–108 mL; mean, 48.5 mL). At scintigraphy after treatment in all patients, recovery of extranodular uptake, absence of uptake in the nodule, and normalization of thyroid-stimulating hormone (thyrotropin) levels were observed. In all patients, US showed volume reductions of 30%–50% after 3 months and 40%–80% after 6–9 months. Side effects were self-limiting in all patients. During the 6–48-month follow-up, no recurrence was observed.
CONCLUSION: PEI is an effective and safe technique for the treatment of large hyperfunctioning thyroid nodules.
Index terms: Alcohol ablation, 273.1269 • Interventional procedures, 273.1269, 273. 522, 273.529 • Thyroid, hyperthyroidism, 273.522, 273.529 • Thyroid, US, 273.12981, 273.12983, 273.12986 • Ultrasound (US), guidance, 273.12981, 273.12986
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Introduction |
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MATERIALS AND METHODS |
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All 12 patients underwent the following baseline studies before treatment: electrocardiography; chest radiography; analysis of thyroxine (T4), 3,5,3'-triiodothyronine (T3), free thyroxine (FT4), free 3,5,3'-triiodothyronine (FT3), and thyroid-stimulating hormone (TSH) (thyrotropin); thyroid scintigraphy; color Doppler US; and fine-needle biopsy of the thyroid nodule to exclude the presence of malignancy (8). TSH, T4, T3, FT4, and FT3 were measured at our institution with radioimmunoassay by using commercially available kits (normal TSH range, 0.5–4.5 mIU/L).
In all patients, thyroid scintigraphic examinations were performed at institutions other than ours before and after treatment with commercially available gamma cameras and technetium 99m pertechnetate as a tracer. Scintigrams were evaluated by one of two physicians (L.T., A.G.) on our team to detect the presence and size of hyperfunctioning nodules before treatment, the persistence or absence of intranodular uptake after treatment, and the presence of normal or abnormal uptake in the thyroid parenchyma.
For the US study, to calculate nodular volume and to guide the needle during the procedure, we used commercially available machines (ssd-680, Aloka, Tokyo, Japan; 580 Asynchronous, Hitachi, Tokyo, Japan; AU4, Esaote Biomedica, Genova, Italy) with 7.5- or 5-MHz probes. Before starting the treatment, all patients were examined at B-mode US and color Doppler US by the same physician (L.T.) to assess the following parameters: the echogenicity of the nodules, the volume of the nodules, and the presence and extension of perinodular and intranodular arterial flow. The physicians calculated the volume of the nodule automatically with the software available in the US machine by measuring the three orthogonal diameters of the nodule on the vertical and horizontal sectional images.
One of two physicians (L.T., A.G.) on our team performed fine-needle biopsy with a freehand technique under US guidance by using a spinal needle (Yale Spinal, 22-gauge, 90-mm; Becton Dickinson, Fraga, Spain). The cytologic samples were evaluated by an experienced pathologist.
Clinical features and data from the procedure in each patient are reported in the Table.
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All patients underwent multiple sessions of PEI. In each session, we performed multiple punctures to inject the ethanol into different portions of the nodule. The punctures were performed with a freehand technique under US guidance by using a commercially available syringe with a 22-gauge, 30-mm needle filled with 99.8% ethanol (FE.RO.SA.; Barcelona, Spain). A longer needle (Yale Spinal, 22-gauge, 90-mm; Becton Dickinson) was used to inject the alcohol into the deepest portions of very large nodules.
We used real-time US to observe the diffusion of ethanol through all portions of the nodule to establish where to inject the ethanol in each subsequent session. This was assessed by means of the characteristically intense hyperecogenicity that was induced by the injection of the alcohol during the multiple sessions. Furthermore, before each PEI session, all patients underwent US and color Doppler US to determine the ethanol injection site in the nodule.
In these examinations, the following points were particularly considered: (a) US evaluation of nodular echogenicity before each PEI session (changes in echogenicity in a part of or in the whole nodule due to the effect of the ethanol injected in the previous PEI sessions) and (b) power Doppler US evaluation of the lesion before each subsequent session to display vascular signals in the nodule (assumed to be due to the presence of the still-active adenomatous tissue).
The number of punctures to perform and the amount of ethanol to inject per session was not planned in advance; this was dependent on patient compliance. In each session, we injected the amount of ethanol that was compatible with an acceptable degree of patient discomfort. When local pain was reported by the patients during the procedure, the injection was transiently interrupted and was restarted in a different portion of the nodule after a slight displacement of the needle tip along its path.
Large and optimal intralesional diffusion of the ethanol was obtained with a low number of punctures by moving the needle along its path and by positioning the axis of the needle on an oblique angle under real-time monitoring. This was done to inject the ethanol into different portions of the nodule and to prevent the alcohol from escaping through the thyroid veins. To perform these maneuvers, we used a freehand technique.
The total amount of ethanol needed to treat each nodule was not calculated in advance. The procedure was terminated when the following occurred: (a) all portions of the nodule had been apparently perfused with ethanol through the multiple sessions of PEI, and (b) no more intralesional power Doppler US signals were observed.
Sessions of PEI were performed once or twice weekly on an outpatient basis in 10 patients and after hospitalization in the other patients. All patients were clinically monitored for 2 hours after the procedure to detect unusually prolonged pain or possible dysphonia due to an injury of laryngeal nerve. A US study was performed within 2 hours of the PEI session to depict possible complications (neck hematoma, venous thrombosis, etc) only in cases of pain or neck swelling.
Scintigraphy with 99mTc pertechnetate, US, and TSH assay were performed 3 months after treatment. Two physicians (L.T., A.G.) evaluated the scintigrams together, by consensus, to detect the absence or persistence of uptake in the treated nodule and the recovery of uptake in the thyroid parenchyma.
The aim of the treatment was complete ablation of uptake in the hyperfunctioning thyroid nodule, as depicted at scintigraphy (cold nodule), with reuptake in the normal thyroid parenchyma. In cases of incomplete necrosis (persistent uptake in the nodule at scintigraphy), additional sessions of PEI (second cycle) and follow-up examinations (after 3 months) were performed.
In six patients who were treated with methimazole (Tapazole; Eli Lilly, Florence, Italy; 100–200 mg orally daily) and propranolol hydrochloride (Inderal; ICI Italia, Milan, Italy; 40 mg orally daily) medical therapy was stopped after the first cycle of PEI. The other patients did not require further medical treatment.
Follow-up with US, color Doppler US, and analysis of TSH, T3, T4, FT3, and FT4 levels was performed every 3 months during the 1st year and every 6 months afterward. The same physician (L.T.) performed all follow-up color Doppler US examinations to assess the changes in the echogenicity, vascularization, and progressive shrinkage in the treated nodule.
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RESULTS |
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Local pain was reported by all patients at times during the injections. A transient interruption in the injection (20–30 seconds) and a slight displacement of the needle tip in the nodule (2–4 mm) along its path allowed us to continue the injection in all patients without eliciting further pain.
In eight patients, at the examination performed 3 months after treatment, scintigraphy with 99mTc pertechnetate showed the absence of uptake in the treated nodules (completely cold nodules) and showed normal uptake in the thyroid parenchyma (Fig 1b). In these patients, TSH levels after treatment were normal (range, 0.6–3.7 mIU/L). In four patients, scintigraphy showed increased uptake in part of the nodule and showed inhibition of uptake of the normal thyroid parenchyma after the first cycle of PEI (Figs 2b, 3c). In two of these patients, TSH levels persisted below normal levels (0.05 and 0.1 mIU/L); in the other two, TSH levels were already within the normal range after the first cycle of PEI. These four patients underwent additional sessions of PEI (second cycle); after 3 months, they underwent repeat scintigraphy, which showed recovery of extranodular uptake, with absence of uptake in the nodule (Figs 2c, 3d). In all patients, normalization of TSH levels was observed 3 months after treatment.
The US appearance of the nodule and the observation of intranodular diffusion of the ethanol seemed to be more reliable than the findings at color Doppler US to guide the injection of ethanol in the still-untreated portions of the nodule. At US, the portions that were already treated (in which diffusion of ethanol had been observed) appeared shrunken, inhomogeneous, and hypoechoic when compared with the still-active adenomatous tissue. In most patients, color Doppler US failed to show vascular spots in portions of the nodule that had not been perfused with ethanol. Moreover, in the four patients who underwent a second cycle of PEI because of the persistence of active adenomatous tissue (as shown at scintigraphy), both US and color Doppler US failed to show signs and vascular signals in the remnant of viable adenomatous tissue after the first cycle of PEI.
Complications
Pain at the injection site lasted 10–30 minutes after a session of PEI and occurred one to four times in each patient. Pain was self-limiting in all patients; pain medication was never required. Five patients had referred pain in the occipitotemporal region.
A thin hypoechoic layer around the thyroid capsule at the site of the puncture was almost always observed immediately after needle withdrawal. This finding, due to a mild blood effusion, was no longer evident at follow-up US before the subsequent PEI session. At follow-up US before subsequent sessions of PEI, we observed swelling in the neck due to an organized hematoma, which appeared as an inhomogeneous (hypo- and hyperechoic) band (thicknesses of 1.5, 1.5, and 2.5 cm) around the involved thyroid lobe, in only three patients. In these patients, the session was delayed 8–10 days. In no patient did we observe dysphonia, abscess, hypothyroidism, hypoparathyroidism, or jugular venous thrombosis.
Follow-up Examination
During the follow-up of 6–48 months, no recurrence was observed. One patient died after 26 months from causes unrelated to the thyroid disease or treatment. All other patients were alive and euthyroid at the time of this writing.
At color Doppler US performed 3 months after treatment, all nodules showed 30%–50% volume reductions (Fig 3e), and intralesional vascular signals were absent. After 6–9 months, all nodules showed 40%–80% volume reductions (Fig 3f). In one patient with a pretreatment nodular volume of 65 mL, we observed a 6-mL nodule (90% volume reduction) 12 months after treatment.
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DISCUSSION |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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We started performing PEI to treat hyperfunctioning thyroid nodules at our institution in October 1993. Since then, the aim of the treatment has been to achieve complete necrosis in the lesion, even in large nodules. For this reason, patients with incomplete responses (as depicted at scintigraphy) undergo a second cycle of PEI. In our series, scintigraphy showed complete necrosis in the hyperfunctioning thyroid nodule (100% cure rate) in 12 patients with nodules larger than 30 mL who were treated with one or two cycles of PEI; no recurrence was observed at follow-up.
Some authors (2,3,5,6) make reasonable arguments against the use of PEI to treat large hyperfunctioning thyroid nodules based on its low effectiveness, the long duration of therapy, the possible higher rates of complication or new complications, and its high costs. In Monzani et al's (9) experience and in ours, no important complications have been reported, and the treatment appeared to be safe and inexpensive, as it was performed in an outpatient setting. Monzani et al (9) reported an 80% (eight of 10 cases) cure rate for nodules larger than 40 mL. In the present series, we reported a 100% cure rate in nodules larger than 30 mL.
The only aim of some authors (2,3,5,6) who perform PEI is to achieve euthyroidism in the patient; they prefer to stop the treatment when the TSH level returns to normal range, although increased uptake in the nodule and inhibition of the thyroid parenchyma are still present. In our opinion, only a result such as that achieved at surgery (complete ablation of the hot nodule and reuptake in the normal thyroid parenchyma) can prevent the patient from worrying about being sick and can prevent a long-term, expensive follow-up with frequent examinations that would include US, blood tests, and scintigraphic tests. Furthermore, the dramatic shrinkage in the nodule after PEI treatment, with a subsequent normal appearance of the neck, is certainly a desirable result for the patient's well-being.
It is difficult to explain the high failure rates of PEI treatment for large hyperfunctioning thyroid nodules (>30 mL) in other series. It could be due to the low doses of ethanol that most other authors injected in each session. In our series, the mean amount of ethanol injected per session into each patient ranged from 5 to 10 mL; we injected up to 14 mL in a single session. The maximum amount of ethanol per session injected by other authors ranged from 4 to 9 mL. It may be hypothesized that higher doses of ethanol per session amplify the necrotizing effect on the adenomatous tissue by determining the degree of thrombosis in the intranodular vessels, with subsequent ischemic necrosis in other portions of the nodule; low doses of ethanol could be insufficient to cause such an effect.
A similar experience with PEI to treat hepatocellular carcinoma has already been reported (10,11). Our predilection to use the freehand technique, which allowed us to change the position of the needle tip in the nodule, as was suggested by the diffusion of ethanol in the nodule, may have played a role in bringing about the high success rate. These adjustments are not possible when adapters or dedicated probes for interventional US are used.
In our experience, only scintigraphic findings can prove the complete necrosis of the nodule, since we observed a normal hormonal profile and an absence of color Doppler US signals in still-hyperfunctioning nodules after treatment.
In the future, improvement in power Doppler US equipment will probably reduce the number of scintigraphic follow-up examinations necessary to assess the complete effectiveness of treatment with PEI. At present, these techniques do not seem to be sensitive enough for this purpose.
Surgeons may be reasonably worried that ethanol injected into deep, solid nodules may seriously jeopardize possible subsequent surgical treatment because of perinodular fibrosis (12). This problem has been particularly stressed in the case of large hyperfunctioning thyroid nodules. However, a histopathologic examination of the specimens showed the absence of regressive changes and inflammatory reactions in the extranodular thyroid parenchyma in patients who underwent surgery after PEI for hyperfunctioning thyroid nodules. The slight or absent extraglandular effects of the ethanol did not compromise the surgical intervention (4,6,13).
Although PEI is less invasive than surgery, radioactive iodine therapy could be preferred because of its noninvasiveness. However, unlike surgery and PEI, radioactive iodine therapy does not destroy the hyperfunctioning thyroid nodule. In up to 50% (33 of 66 cases) of patients treatedwith this therapy who show a normal hormonal profile, scintigraphy demonstrated nodules that were still autonomous and demonstrated suppression of the extranodular tissue (14). Furthermore, patients with hyperfunctioning thyroid nodules larger than 3 cm in diameter require doses of iodine 131 much higher than those conventionally used to treat small hyperfunctioning thyroid nodules and other thyroid diseases (15). Therefore, hypothyroidism after treatment (reported in up to 44% of patients after conventional doses of 131I) has to be taken into account (16). Thus, in most institutions, the current indications for radioactive iodine treatment are the following: (a) nodule with a diameter less than 3 cm, (b) patient older than 40 years, and (c) presence of diseases that contraindicate surgery (17).
PEI for the treatment of hyperfunctioning thyroid nodules larger than 30 mL seems to be safe, well-tolerated, effective, and inexpensive, as it is for the treatment of smaller nodules. The choice to treat hyperfunctioning thyroid nodules with PEI should not depend on the volume of the nodule, but rather, it should depend on other variables that should be taken into account. Nevertheless, prospective and randomized clinical trials to compare surgery, treatment with radioactive iodine, and PEI are needed to establish the indications for these therapies.
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Footnotes |
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Author contributions: Guarantors of integrity of entire study, L.T., A.G.; study concepts, L.T., G.d.S., A.P.; study design and definition of intellectual content, L.T.; literature research, L.T., A.P.; clinical studies, L.T., N.M., G.d.S., A.P., V.A.; data acquisition, S.T., M.C.F., F.E., L.F., A.V.; data and statistical analyses, L.T., V.A.; manuscript preparation, S.T., M.C.F., F.E., L.F., A.V.; manuscript editing, L.T., F.E.; manuscript review, L.T., A.V.
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References |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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