The emergence of minimally-invasive procedures as a treatment for Thyroid Nodules. Critical Review

The emergence of minimally-invasive procedures as a treatment for Thyroid Nodules.

JOURNAL OF CRITICAL REVIEWS

VOL 7, ISSUE 17, 2020 1783

Roberto Novizio

DR.Guttler’s Comments:

Call me at 310-393-8860 or thyroid.manager@thyroid.com.

1. Dr.Novizio’s review of minimally-invasive procedures as a treatment for Thyroid Nodules is an excellent starting point to understand how these procedures have the potential to change how we as endocrinologist practice medicine.
2. I use ethanol ablation PEI for all neck cysts. Here is a history of the use of ethanol.
3. In 1990, Percutaneous Ethanol Injection (PEI) was for the first time introduced into clinical practice. One of the very first study about the technical feasibility of PEI in the treatment of benign thyroid nodule was conducted and published by Livraghi et al. Eight patients with autonomous thyroid nodules (AFTN) underwent percutaneous ethanol injection under ultrasound guidance.Each patient received three to six injections per lesion, for a total of 36 injections. That was a pioneer study, but results were encouraging: hormonal levels became normal or reached the range of subclinical hypothyroidism, and PEI was risk free and easy to perform.
   During following years, new studies about the efficacy of PEI on AFTN came out. Although the data and technical knowledge about PEI were increasing on AFTN, since ethanol was firstly proposed as an alternative to surgery or radioiodine, nowadays the use of ethanol for this purpose has been sensibly decreased. The reduction of thyroid lesions was not always excellent and not so long-term effective. Moreover, there was the risk of serious side effects (primary caused by ethanol escaping the nodule).
   From about 2000 on, new more efficacy and safer techniques, such as Laser ablation and then Radiofrequency, started to be successfully applied to benign thyroid and AFTN, reducing the role of PEI.However, the sclerosing proprieties of ethanol were successfully applied to a subtype of thyroid nodule: thyroid cystic lesions.First in 2004, Guglielmi proposed, after a consistent study, Ethanol for the first-line treatment of thyroid cystic lesion. From then on, evidences about the indications of PEI for Cystic lesions have grown: moreover, PEI can be used today combined with Laser or RFA to treat big cystic nodules.
4. I use Thyroid RFA for benign nodules and micropapillary thyroid cancers.Here is a history of the use of thyroid RFA.
5. RADIOFREQUENCY ABLATION Radiofrequency ablation (RFA) is a thermal ablation technique, whose first applications after 1980 were largely been on hepatic neoplasm, but also in bone, lung and kidney malignancy. Interestingly, very first studies about the feasibility and efficacy of the application of RFA on thyroid disease didn’t start from benign pathology but started from the possible application in regional recurrence from well-differentiated thyroid malignancy.Specifically,thyroid papillary cancer.About it, one of the very first studies was published in 2001, from Dupuy in Unites States, on 8 patients who had lymph node recurrence after thyroid surgery for well-differentiated thyroid cancer(WTC). The first conclusion on the use of RFA for thyroid was then.“US-guided RFA is an exciting new treatment modality that appears to have a future role in treating locally recurrent WTC”. It took 5 years to have then the first consistent study about the RFA application on benign thyroid nodule: in 2006.  Kim YS shared their initial clinical experience in this field. A total of 35 benign cold thyroid nodules, in 30 euthyroid patients, underwent RFA: 88% of patients reported an improvement of their symptoms, and there were no major complication other than vocal cord palsy in one patient. So RFA seemed to be immediately an effective and safe non-surgical technique to treat benign cold thyroid nodules. During the subsequent years, some studies have strengthened data about the use of radiofrequency both for WTC recurrence and benign nodules. In 2008, the first study on a larger sample of patient was conducted by Jeong. A total of 302 benign nodules in 236 euthyroid patients who underwent RFA between 2002 and 2005: RFA was effective and safe. This is study became one the first milestone about the possible application on a large scale of radiofrequency for the reduction of the volume of benign thyroid nodules.

   In 2008, Baek JH proposed for the first-time radiofrequency ablation as a treatment option for an autonomously functioning thyroid nodule (AFTN), expanding their study in 2009 on 9 patients. Again RFA seemed to be effective and safe for the treatment of AFTN. It is interesting to notice how the RFA application in thyroid, differently from other minimally invasive technique, didn’t start from benign or hyperfuncioning pathology, but it started from malignant pathology, that has been the point of arrival of other techniques. The next step was the endeavor to apply RFA on primary papillary thyroid cancer: Kim HY  in 2010 published a case report on a patient who underwent RFA before the cytological diagnosis of malignancy, later referred and treated with robotic surgery successfully. They understood 2 important tips: 1-the RFA for operable primary thyroid malignancy should be avoided, because of the possibility of remnant viable cancer and undetectable nodal metastasis. 2-Surgery can be feasible method for benign or malignant thyroid nodules previously treated with RFA.To have more consistent data about possible application of RFA on low-risk small papillary thyroid carcinoma (PTC). 2017 Kim JH  published preliminary results on 6 inoperable patients with low-risk PTC treated by RFA, with a follow-up of 48.512.3 months.It was inferred that RFA could be an alternative safe treatment, besides surgery and active surveillance currently used, for managing low-risk small PTC in patients ineligible for surgery. The last study published about this issue came out in 2019. A pilot study involving 133 patients with papillary thyroid microcarcinoma (PTMC), who underwent RF ablation for the treatment of 152 biopsy-proven PTMC. All patients were of high surgical risk or refused to undergo surgery. Follow-up US was performed at 1 week, and 2,6 and 12 months after the initial RFA, and then at every 6-12 months. No patients were referred to surgery, so in short-term RFA seemed to be a safe and effective method. More long-term follow-up are now needed.

ABSTACT:To describe the historical refinements, improvements and pioneer applications of thermal and chemical thyroid minimally-invasive procedures.A Pubmed research was initiated using this research items: “thyroid surgery”, “history of thyroid surgery”; “thyroid thermal ablative techniques” “thermal ablative techniques”; “thyroid nodule”, “thyroid nodule treatments”; Thyroid guidelines”; “ethanol ablation”, “thyroid ethanol ablation”, “thyroid ethanol injections”; “laser ablation” “Thyroid laser ablation”; “radiofrequency ablation” “thyroid radiofrequency ablation”; “HIFU”, “thyroid HIFU”; “microwave” “microwave ablation” “thyroid microwave ablation”.:

Benign and malignant thyroid nodular disease has a millennial history. The necessity to have a safe, efficacy, and cost-effective treatment for non-malignant disorder, by that patients can recovery in a short while, is a milestone of modern medicine. This applies perfectly to thyroid, where nodular benign pathology is particularly common in healthy and young population.Most of new technique, to be tested, started to be applied to benign pathology. This is interestingly not true for radiofrequency ablation.As the data on the incoming procedure became consistent, the trend has been to try to apply it also in low-risk malignant disorder, which then seems to be the real future application of these thermal technique.

INTRODUCTION According to American Thyroid Association’s definition, the term thyroid nodule refers to an “abnormal growth of thyroid cells that forms a lump within the thyroid gland”. The vast majority of thyroid nodules are asymptomatic benign lesions, generally diagnosed through a thyroid ultrasound examination performed for other reasons unrelated to the presence of the nodule itself. Although palpable thyroid nodules can be found only in 1% of men and 5% of women living in iodine-sufficient regions of the world, a thyroid incidentaloma can be diagnosed in up to 70% of the general population by ultrasound (US) or other imaging test such as magnetic resonance imaging(MRI) or computer tomography (CT)1,2.Among all thyroid nodules, just 7-15% of them hides thyroid cancer. Historically, thyroid surgery has been the first-choice therapeutic option for the treatment of both thyroid malignancy and benign thyroid nodules associated to cosmetic or compressive problems. Today, new minimally-invasive treatments are available, and more and more patients with benign thyroid nodule can avoid surgery treatment.The aim of this historical review is to take stock of the situation: only knowing where do we came from, we can understand where we are going to.

SURGICAL TREATMENTS FOR THYROID DISEASES: PRE-21TH CENTURY ERA.Thyroid surgery underwent great changes before becoming the one we know today. The first description of thyroid surgery dates back to Albucasis (Abū l-Qāsim Khalaf ibn ʿAbbās al-Zahrāwī), an Arabic surgeon of the X century who is considered the father of modern surgery. Albucasis reported his experiences in removing a large goiter in 952 AD, just using simple ligaments and hot cautery iron.In XII century, Salerno school played a crucial role in enhancing thyroid surgical procedures. Specifically, Roger Frugardii introduced setons and caustic powders and wrote “Practica chirurgiae” that became the reference text of those years.

Then the feasibility of in-vivo treatment was evaluated by using a low-energy laser in 2 volunteers. The damage was well-defined and correlated with energy used:Laser ablation started to be proposed as a therapeutic tool for highly selected thyroid problems. In 2000 and 2001 laser was applied in Russia in thyroid cyst and goiter with discreet success, but only in 2003 first feasibility studies about the use of laser in the treatment of autonomously functioning thyroid nodule (AFTN) stated to be published. From then on, the experience about the use of laser ablation therapy in benign thyroid pathology have been continuously increasing.In 2011, first Ultrasound-guided percutaneous laser ablation for local treatment of micropapillary thyroid cancer in an otherwise inoperable patient was performed, described in a study published by Papini.The patient was at high surgical risk. She was 81 years old, with decompensated liver cirrhosis, renal failure, and breast cancer recently treated by surgery followed by external beam radiation therapy.She was found to have at US examination an incidental solitary 7x7x8 mm nodule in right lobe, diagnosed as papillary thyroid microcarcinoma by cytology. No cervical or lung metastasis revealed by neck Ultrasound examination and chest computer tomography scan. The first PTMC treatment was well tolerated. Renal and liver function were not affected by treatment.Ultrasound-guided fine needle aspiration biopsy and core needle biopsy performed at 1 and 12 months after LA showed just necrotic material and inflammatory cells with no viable neoplastic cells.

Another fine needle aspiration biopsy performed at 24 months confirmed the absence of malignant cells, showing just inflammatory cells, charred debris and fibrous tissue. No evidence of disease recurrence after 2 years follow-up.In 2013, Valcavi demonstrated for the first time that percutaneous laser ablation is technically feasible for complete micro-papillary thyroid carcinoma (PTMC) histological destruction.Three patients underwent percutaneous ultrasound assisted laser ablation of the PTMC in the operating room and after the minimally invasive procedure, the surgeon directly started a standard total thyroidectomy. Subsequent to surgery, thyroid glands were submitted for histological evaluation. Percutaneous Laser Ablation was demonstrated to be technically feasible for complete histological destruction of PTMC, open the road to a possible use of minimally invasive procedure for the treatment of low risk thyroid cancer.Finally, the first retrospective study on 64 patients was conducted by Lu Zhang et al. and published in 2018. Studies are now on-going about this hot topic, but laser remains a promising method.

RADIOFREQUENCY ABLATION Radiofrequency ablation (RFA) is a thermal ablation technique, whose first applications after 1980 were largely been on hepatic neoplasm, but also in bone, lung and kidney malignancy. Interestingly, very first studies about the feasibility and efficacy of the application of RFA on thyroid disease didn’t start from benign pathology but started from the possible application in regional recurrence from well-differentiated thyroid malignancy.Specifically,thyroid papillary cancer.About it, one of the very first studies was published in 2001, from Dupuy in Unites States, on 8 patients who had lymph node recurrence after thyroid surgery for well-differentiated thyroid cancer(WTC). The first conclusion on the use of RFA for thyroid was then.

“US-guided RFA is an exciting new treatment modality that appears to have a future role in treating locally recurrent WTC”. It took 5 years to have then the first consistent study about the RFA application on benign thyroid nodule: in 2006.  Kim YS shared their initial clinical experience in this field. A total of 35 benign cold thyroid nodules, in 30 euthyroid patients, underwent RFA: 88% of patients reported an improvement of their symptoms, and there were no major complication other than vocal cord palsy in one patient. So RFA seemed to be immediately an effective and safe non-surgical technique to treat benign cold thyroid nodules. During the subsequent years, some studies have strengthened data about the use of radiofrequency both for WTC recurrence and benign nodules. In 2008, the first study on a larger sample of patient was conducted by Jeong. A total of 302 benign nodules in 236 euthyroid patients who underwent RFA between 2002 and 2005: RFA was effective and safe. This is study became one the first milestone about the possible application on a large scale of radiofrequency for the reduction of the volume of benign thyroid nodules.

In 2008, Baek JH proposed for the first-time radiofrequency ablation as a treatment option for an autonomously functioning thyroid nodule (AFTN), expanding their study in 2009 on 9 patients. Again RFA seemed to be effective and safe for the treatment of AFTN. It is interesting to notice how the RFA application in thyroid, differently from other minimally invasive technique, didn’t start from benign or hyperfuncioning pathology, but it started from malignant pathology, that has been the point of arrival of other techniques. The next step was the endeavor to apply RFA on primary papillary thyroid cancer: Kim HY  in 2010 published a case report on a patient who underwent RFA before the cytological diagnosis of malignancy, later referred and treated with robotic surgery successfully. They understood 2 important tips: 1-the RFA for operable primary thyroid malignancy should be avoided, because of the possibility of remnant viable cancer and undetectable nodal metastasis. 2-Surgery can be feasible method for benign or malignant thyroid nodules previously treated with RFA.To have more consistent data about possible application of RFA on low-risk small papillary thyroid carcinoma (PTC). 2017 Kim JH  published preliminary results on 6 inoperable patients with low-risk PTC treated by RFA, with a follow-up of 48.512.3 months.It was inferred that RFA could be an alternative safe treatment, besides surgery and active surveillance currently used, for managing low-risk small PTC in patients ineligible for surgery. The last study published about this issue came out in 2019. A pilot study involving 133 patients with papillary thyroid microcarcinoma (PTMC), who underwent RF ablation for the treatment of 152 biopsy-proven PTMC. All patients were of high surgical risk or refused to undergo surgery. Follow-up US was performed at 1 week, and 2,6 and 12 months after the initial RFA, and then at every 6-12 months. No patients were referred to surgery, so in short-term RFA seemed to be a safe and effective method. More long-term follow-up are now needed.

HIFU .HISTORY of High-Intensity Focused Ultrasound is minimally invasive technique that allows a thermal tissue destruction without the necessity of using a needle, by focusing a beam of ultrasound into a given target. Very first applications of this futuristic treatment have been on prostate and breast cancer, and uterine fibroma. About thyroid, the very first proposal of application came in 2004: Esnault published a preliminary experimental animal study, to assess the feasibility of HIFU to obtain localized ablation of thyroid tissue. They chose the ewe, because its thyroid is easily accessible, and the size is comparable to the human gland. 8 ewes were anesthetized and treated: then they were sacrificed 6-13 days after the procedure, and the anterior part of the neck was fixed in formalin before macroscopic and microscopic examination. That first pioneering study confirmed the possibility of using HIFU to destroy a defined area of thyroid. To have the first feasibility study on a human thyroid we have to go to 2011. Esnault published a single-center feasibility study on 25 patients treated with HIFU, before a scheduled thyroidectomy for multinodular goiter: they could then examine the effects of HIFU on thyroid tissue.To be precise, it is interesting to notice that HIFU was first applied on human on parathyroid by Kovatcheva.   Larger studies with longer follow-up are necessary to better understand the potentialities of this technique.

MICROWAVE ABLATION  MWA Microwave ablation uses a cooled shaft antenna, cabled with a generator capable of produce 1-100 W of power of 2450 MHz, in the form of pulse or continuous energy. The internally cooled antenna is coated with polytetrafluoroethylene to prevent tissue adhesion.Before to be applied to thyroid, microwave ablation technique has been successfully used to treat benign and malignant tumors of liver, lung and kidney. The first experimental and clinical study about the feasibility of ultrasound-guided percutaneous microwave ablation for benign thyroid nodules was published in 2012. Feng tested microwave ablation in 11 benign.thyroid nodules. Actually, one year later, in 2013, a big sample study was published by Yue: 477 benign thyroid nodules in 222 patients underwent microwave ablation and were evaluated at 1, 2, and more than 6 months. So, very quickly, a big study confirmed the safety and the effectiveness of MW ablation.

Immediately, MW was tested in the treatment of solitary T1N0M0 papillary thyroid microcarcinoma. Again, Yue treated 21 patients, with 21 proven solitary papillary carcinoma, measuring less than 10mm in the diameter, without clinically apparent lymph node or distant metastasis at diagnosis. Follow-up consisted in ultrasound in 21 patients, biopsy in 5 patients, and surgical treatment in 3 patients. No recurrence at the treatment site and no distant metastases were detected, with a mean follow-up of 11months. During that short follow-up period, US-guided MW ablation showed to be safe and effective treatment for that type of thyroid cancer.Then evidences about the efficacy of MW on thyroid disease increased.

In 2018, a 3-year follow-up study on 21 nodules diagnosed as PTMC was completed and published. 20 of 21 nodules were completely absorbed and no recurrent nodule was found. Finally, in 2019 a preliminary report of microwave ablation for the primary papillary thyroid microcarcinoma was published. Teng published a feasibility study on a large-cohort of 185 patients who underwent MWA for 206 PTMC nodules. The patients were followed-up. 1 patient had another lesion 1 month after MWA. Again, MWA suggests itself as a safe and effective treatment for low-risk PTMC.Taking a step back, in 2015 Yue published a prospective study on the possible application of MWA also for the locoregional control of recurrent papillary thyroid carcinoma by MWA. This technique shows encouraging results, confirmed in 2019, by another study conducted by Zhou on 14 patients with recurrent PTC treated by MWA (although tumor of the central compartment showed less encouraging results.

DISCUSSION

Medical issues about thyroid surgical treatments have evolved during centuries. From the necessity of keep the patient alive during thyroid surgical procedure, thanks to evolution of medical and surgical techniques, the mainpoint of interest passed to how to treat patients in a minimally invasive way. All interventional procedures have not seen thyroid as first organ of application. Mostly, they have been primary applied to bigger organ, almost always the liver, and then tried on thyroid. It is interesting to notice that these applications started on benign thyroid pathology, and then extended to thyroid cancer or metastatic lymph nodes in inoperable patients, and then in operable patients but with low risk cancer. Very consistent data have been obtain about the efficacy of all minimally invasive technique on benign thyroid nodule, and they may become a primary choice treatment for low risk papillary thyroid cancer if future new knowledge would permit a better understanding of the power of thermal ablation on tumor, and a better selection of patients who may have benefit from these interventions even in malignant pathology, avoiding surgical procedures that sometimes can cause problems themselves.