Treating intra-thyroid parathyroid adenoma by radiofrequency is a valuable alternative to hemithyroidectomy

Abstract Background Parathyroid adenoma (PA) is the most common cause of primary hyperparathyroidism (PHPT). One infrequent scenario (0.7%–6%) is represented by intra-thyroid PA (I-PA), an ectopic variant of the parathyroid gland included in the thyroid parenchyma. Radiofrequency (RF) of I-PA seems to be an excellent alternative to hemithyroidectomy for these patients. The present study aimed to report three cases of PHPT and I-PA treated with RF at two institutions. Materials and methods These two institutions share guidelines for thyroid RF. At both institutions, cases with surgical indication and difficult PA localization are discussed during thyroid multidisciplinary meetings involving all disciplines involved in managing these cases. RF was performed using a Viva RF System generator (STARMED). Ultrasound contrast evaluation was performed using a SonoVue (Bracco). All patients were followed-up by an expert endocrinologist. Results Three cases had indications for treating I-PA. All patients were proposed to undergo RF rather than hemithyroidectomy, and accepted this option. RF of I-PA was performed with a power of 30–50 W and delivering a total between 0.02 and 0.69 Kcal. The active treatment lasted just more than 1 min. Post-treatment follow-up revealed PTH and calcium normalization. Conclusion This study showed highly encouraging results in favor of treating I-PA with RF.


Introduction
Parathyroid adenoma (PA) is the most common cause of primary hyperparathyroidism (PHPT).According to the literature and guidelines, patients have to be treated in the presence of PHPT-related complications, such as osteoporosis, kidney stones, hypertension, muscle fatigue, and other minor inconveniences [1].Localizing the PA in a patient with PHPT is formally required only in the presence of such features.While ultrasound (US) is the first-line imaging procedure to localize PA, sestamibi scintiscan (SS) can be useful as a second chance/proof, and the recently introduced 18 F fluorocholine PET/CT can solve cases with double-negative or discordant US/SS results [2][3][4].In addition to imaging, PTH measurement in washout fluids from fine-needle aspiration (FNA-PTH) may be considered in difficult cases [5].Once PA is localized, surgical removal is the traditional treatment to achieve normalization of PTH and calcium levels and then cure/prevent PHPT complications.In recent years, with the advent and rapid worldwide diffusion of thermal ablation of thyroid nodules, the possibility of treating PA with radiofrequency (RF) has increased.In fact, by minimally invasive non-surgical procedures, the same result as surgical removal might be achieved, avoiding surgery-related charges and inconveniences (i.e., high costs, general anesthesia, hospitalization, operative complications, etc.) [6].However, since PA is often localized in the dangerous triangle of the neck, this non-surgical option must be carefully performed by highly experienced operators.
In this field, one infrequent scenario is represented by intrathyroid PA (I-PA).This ectopic variant of the parathyroid gland is found in the thyroid parenchyma, with an incidence varying from 0.7% to 6% [7].To date, even if there is no clear consensus about both optimal localization modalities and adequate therapeutic procedures for I-PA, thyroid lobectomy remains the traditional approach in these cases.However, considering the good efficacy combined with a negligible rate of complications when treating PA with RF [6,8-11], RF treatment of I-PA seems to be an excellent option for patients, although the efficacy of laser treatment seems to be superior with 92% success rate [12].In fact, the procedure can take a very short time because of the expected small size of I-PAs, the presence of thyroid parenchyma represents a reassurance to avoid complications that can involve extra-thyroidal structures, and the patient's preference is likely high.One case of I-PA treated with RF has been reported [13].A patient was subjected to RF management according to intraoperative PTH measurement, and the results showed complete restoration of PTH and calcium levels.Publishing new data in this setting of PHPT could then play a role in promoting this option as a major alternative to surgery.
The present study aimed to report three cases of patients with PHPT and I-PA treated with RF at two institutions sharing guidelines in the field of thyroid RF.These three cases were treated sequentially one after the other, that is, the second case was based on the experience of the first one, and the third case was based on the experience of the first two.Both the preoperative diagnostic work-up to localize I-PAs and therapeutic technical data are detailed.Results over time were collected and described.The relevant advantages of this therapy are discussed.

Institutional management for localizing PA in PHPT
At our two institutions, patients diagnosed with PHPT were evaluated by clinical endocrinologists and then treated surgically when appropriate.Before the surgeon's evaluation, the localization work-up included US, which was performed by endocrinologists during clinical assessment, as the first-line procedure.In addition, SS may be performed when US is negative or doubtful.Finally, 18 F fluorocholine PET/CT was indicated when US and SS were discordant or negative.In addition, FNA-PTH is considered in selected cases with uncertain US findings and further negative or inconclusive imaging results [5].Cases with clear surgical indications and difficult PA localization are discussed at the institutional thyroid multidisciplinary meeting (MDM) involving all disciplines involved in managing these cases and chaired by a senior thyroid-experienced endocrinologist (PT at Ente Ospedaliero Cantonale and MD at Mauriziano Hospital).During discussion of difficult cases, Thyroid MDM decision can be in favor of alternatives to surgery according to patient-specific features (i.e., patient's age and preference/refuse, location of PA, comorbidity, potential operative complications, etc.).

Institutional management of thyroid RF
Our institutions collaborate closely in the field of thyroid RF treatment of thyroid nodules and share guidelines [14].Before planning the treatment, the patients are fully informed about the benefits, risks, and charges of the procedure.Informed consent is obtained from all cases.Later, patients undergo coagulation tests, blood counts, and evaluation of motility of the vocal cords.Thermal ablation is performed with the patient placed on a bed in the supine position, with a hyperextended neck and pillow under the shoulders.A needle cannula is placed in the anti-decubital vein of the arm to assist patients with venous access if needed.The operator is positioned at the head of the patient in order to be able to treat right and left side nodules.Some minutes before the treatment, local anesthesia is performed with a 22 G needle injecting 10 mL of Mepivacaine Hydrochloride NM 1.5% around the thyroid capsule.Just before inserting the RF needle, US contrast evaluation is performed with an injection of Sonovue (Bracco) (2.5 mL).This modality allows the collection of baseline data on nodule vascularization to be compared with the post-procedure results collected immediately after finishing the treatment.Trans-isthmic needle access is typically performed.RF is always performed using Viva RF System generator, under US control, using an 18 G needle (STARMED Starfixed monopolar 18 G 9 cm), with "moving-shot" technique.After treatment, patients are admitted to the hospital for two hours and then discharged after a post-procedure neck US to exclude late complications.All data of treatment (i.e., power used, energy delivered, duration of in-to-out procedure and active treatment, and complications) and patients (individual characteristics, lesion volume, and patient tolerability) are systematically recorded and retrospectively analyzed.All patients are followed up by endocrinologists for at least 12 months after RF.

Selection of I-PA patients for RF therapy
Patients diagnosed with I-PA are generally discussed at our institutional Thyroid MDM because of the difficulty in localizing the PA.In all patients with PHPT, surgery is indicated after assessing PHPT-related consequences [3].Alternatively, at our institutions, we may select for RF patients (1) with surgical indication due to PHPT complications, (2) with single I-PA, and (3) after imaging-guided appropriate exclusion of further PAs.In addition, the patient's clinical history, thyroid status, and preference are fully considered when treating I-PA with RF rather than surgery.

RF procedure to treat I-PA
The procedure to treat I-PA was substantially similar to that used for thyroid nodule.Pretreatment evaluation was not different, and the procedures performed just before treatment were the same.Regarding the energy to be delivered, three issues needed specific care: (1) the capsule of I-PA must be crossed by RF needle; (2) complete necrosis of parathyroid cells must be achieved; (3) thyroid parenchyma must be saved from the treatment to avoid hypothyroidism later.In order to cross the parathyroid capsule a slight pulse of energy was delivered, and this allowed to comfortably entry into the gland.To achieve the other two goals, the general rule of energy/mL was followed [14].Basically, we hypothesized that this procedure could guarantees to achieve cell necrosis and avoid hypothyroidism, as usually occurs when treating thyroid nodules.

Ethics
Patients included in this study gave informed consent to publish.According to the local ethics rules, since the present is a small series of cases, the approval by ethics committee was waived.

Case 1
A healthy 46-year-old female with elevated PTH levels was initially assessed for specific PHPT complications.Pre-visit laboratory data showed PTH 11.74 pmol/L, calcium corrected 2.64 mmol/L, and vitamin D 64 nmol/L.Bone densitometry with GE-Lunar iDXA revealed significant osteoporosis.No PHPT-related clinical symptoms were observed in this patient.No kidney stones were suspected.Imaging evaluations then began to localize the PA.Initial thyroid/neck US showed a single hypoechoic lesion with a diameter of 4 � 7 � 5 mm (estimated volume 0.08 mL) in the lower third of the right thyroid lobe.In particular, the lesion showed a hyperechoic capsule and vascular hilum, which are typical features of PAs [2].Based on this result, SS was required, and the result was negative for hyperfunctioning parathyroid tissue.Subsequently, 18 F fluorocholine PET/CT was performed with detection of tracer uptake corresponding to the intra-thyroid lesion localized in the US.Since thyroid 18 F fluorocholine uptake requires further assessment [15], a biopsy was performed to measure FNA-PTH, which presented very high levels (530 pmol/L).After strong proof of I-PA, the patient was proposed to undergo RF rather than hemithyroidectomy, and she accepted this option.The RF of I-PA was performed with an average power of 50 W, delivering a total of 0.69 Kcal.The active treatment took 1 min and 9 s.Post-treatment followup revealed PTH normalization.Before the treatment the patient was euthyroid, and thyroid function unchanged after the treatment.Figure 1 illustrates the trend of the biochemical tests and Figure 2(A) displays the imaging results.

Case 2
A 54-year-old female with normocalcemic PHPT and hypovitaminosis D, with other neoplasms in her clinical history, was referred to the endocrinology service to search for PA.During the initial endocrinological visit, US revealed a hypoechoic intrathyroid lesion with peripheral vascularization and diameters of 10 � 4 � 3 mm (estimated volume 0.08 mL).Owing to this presentation, the lesion was immediately suspected to be I-PA.Subsequent SS confirmed suspicious US findings.In particular, at SS, the PA was suspected to presence of PA located posterior to the lower third of the right thyroid lobe.Subsequently, PHPT complication status was assessed.Bone densitometry with GE-Lunar iDXA showed osteoporosis, but no other PHPT-related inconveniences were observed.RF was then proposed to the patient and performed.The procedure was completed using an average power of 40 W and total energy of 0.02 Kcal, and taking 1 min and 27 s.The post-treatment follow-up showed normalization of PTH levels just 1 h after the procedure, following swinging biochemical values over time.The patient was euthyroid before and after the treatment.Figure 1 illustrates the trend of the biochemical tests and Figure 2(B) displays the imaging results.

Case 3
A 47-year-old female with palpitations and hypertension was diagnosed with a suspicious 10 mm thyroid nodule, and a biopsy was performed.Due to the US presentation suggestive of PA, FNA-PTH was measured, and its value was 511 pmol/L, consistent with I-PA.Because osteoporosis and  kidney stones were not present, the patient was referred for clinical follow-up.Subsequently, the patient was hospitalized for tachycardia and severe blood pressure increase, and it was decided to treat I-PA.At RF, I-PA presented an estimated volume of 0.22 mL.The RF procedure was performed using a power of 30 W, delivering a total energy of 0.28 Kcal.The treatment took 1 min and 28 s.During follow-up, the PTH and calcium levels rapidly decreased.The patient was euthyroid, and thyroid function remained normal after the treatment.Figure 1

Discussion
Traditionally, PHPT with complications is treated by surgery to remove the PA.Consequently, when a patient with PHPT has I-PA, hemithyroidectomy is performed.As this surgical procedure is more extended than parathyroidectomy, alternatives should have a significant impact on the therapy of infrequent cases.Ablation of eutopic PA with RF is associated with non-negligible risks due to the location of the lesion.High attention must be paid to the "dangerous triangle", where the recurrent nerves run from both sides to the trachea and near the esophagus.In addition, care must be taken with respect to the common carotid artery, internal jugular vein, and vagus nerve.The hydrodissection technique of injecting 5% dextrose can be useful in reducing risk [16].These risks affecting the treatment of eutopic PA are virtually absent when the PA is intra-thyroidal.In particular, I-PA can be used to treat thyroid nodules.The trans-isthmic approach is recommended in I-PA, and the risk of complications is likely inferior to that observed with the ablation of thyroid nodules (i.e., pain, hematoma on access site, bleeding in case a vessel is crossed, vocal cords transient stunning, thermal burn of the skin), with the huge advantage that the lesion is very small, thus requiring shorter timing and lower energy.
The three cases we described were treated sequentially at two institutions that shared the thyroid RF approach.In particular, the third patient enjoyed the experience we had with the first two treatments.This is the reason why we had differences regarding the collection of data and probably somewhat different findings after treatment.Overall, we can be satisfied by looking at achievements: (1) in all cases, we could demonstrate by US the completeness of thermal ablation with significant shrinking of I-PAs and absence of vascular signal; (2) from a biochemical point of view, we recorded reduction/normalization of PTH over time, and very rapidly in cases 2 and 3; (3) importantly, no complications were recorded; (4) even if we currently have no long-term followup data, the results obtained over at least 6 months of observation are strongly encouraging.The different post-treatment data among the cases, particularly in case 2, could be due to the lower energy received.This data further underlines the importance of delivering adequate energy per lesion volume [14,17].From a clinical standpoint, this preliminary study can pave the way to consider RF as a first-line treatment option in selected patients with I-PA who require therapy.
The issue of cost-effectiveness must also be considered.The cost of hemithyroidectomy is expected to range from 5,000 to 9,000 euros according to country and local reimbursement rules.On the other hand, RF can have a charge of approximately 1,000-2,500 euros.In addition, while pre-and post-procedure work-up is not dissimilar between surgery and RF, hospitalization is completely different taking 2-3 days for surgical patients and a half day for patients undergoing thermal ablation.These relevant differences must be taken into account, and both operators and patients must be aware of these figures.
In conclusion, this study showed highly encouraging results in favor of treating I-PA with RF.We advise future studies, comparing surgery and thermal ablation, and adopting well-structured inclusion criteria and procedural guidelines.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Figure 1 .
Figure 1.PTH and calcium value before and after RF.Continuous lines indicate the PTH values.The dotted lines indicate calcium levels.RF: radiofrequency.

Figure 2 .
Figure 2. Imaging of the three cases.(A) Initial localization of I-PA was achieved by ultrasound (US) and 18 F fluorocholine PET/CT.Pre-and post-operative contrastenhanced US demonstrated the complete treatment of the lesion.During follow-up, I-PA showed strong hypoechogenicity.(B) Initial localization of I-PA was achieved by US and scintiscan.Pre-and post-operative contrast-enhanced US demonstrated the complete treatment of the lesion.During follow-up, I-PA showed strong hypoechogenicity.(C) I-PA was initially suspected at thyroid US.FNA-PTH was then performed and the results did not indicate for further imaging procedure.One month later, US and US and contrast-enhanced US demonstrated good the RF efficacy.
illustrates the trend of the biochemical tests and Figure 2(C) displays the imaging results.