1 IN THE NAME OF GOD

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3 Alcohol Ablation It’s indication, Efficacy, and Safety in Thyroid Disease

4 Alcohol Ablation It’s indication, Efficacy, and Safety in Thyroid DiseaseBy: Dr Mozhgan Karymyfar Assistant Prof. of Endocrinology Isfahan University Of Medical Sciences

5 According to Martino and Bogazzi, percutaneous ethanol injection (PEI) was first used to treat thyroid nodules in 1878 Since then, PEI has been used in Europe, North America and Asia, to treat both benign and malignant disease, including thyroid nodules parathyroid adenomas Hepatocellular carcinoma and most recently, islet cell tumors including insulinomas.

6 Since the early 1990s, ultrasound-guided percutaneous ethanol injection (UPEI) has been extensively used in the management of benign thyroid nodules. Its role, as an alternative to thyroid surgery or radioactive iodine (RAI) administration, was reviewed in an earlier issue of Thyroid International, published in 2000 by Professor Enio Martino and Dr Fausto Bogazzi of the University of Pisa, Italy.

7 Minimally invasive treatment options of benign thyroid nodules(1)Most thyroid nodules are benign and remain asymptomatic, but some grow progressively and may cause local symptoms or elicit anxiety. Surgery is a much used therapeutic approach for thyroid lesions that, even if benign at FNA, are steadily growing over time. DIAGNOSIS OF ENDOCRINE DISEASE Thyroid ultrasound (US) and US-assisted procedures: from the shadows into an array of applications European Journal of Endocrinology (2014) 170, R133–R146(R1)

8 Minimally invasive treatment options of benign thyroid nodules(2)However, surgery is: Expensive may necessitate life-long thyroid hormone substitution therapy and may be followed, even if infrequently, by permanent complications There is also increasing focus on the side-effects, including the effect on quality of life, not traditionally considered in this context. (R1)

9 Minimally invasive treatment options of benign thyroid nodules(3)Over the last two decades non-surgical, minimally invasive techniques have been proposed for the treatment of benign thyroid nodules when surgery is contraindicated or declined. (R1)

10 Minimally invasive treatment options of benign thyroid nodules(4)PEIT was the first therapeutic procedure proposed in 1990 for hyperfunctioning nodules . Owing to the limitations of PEIT, in the management of solid thyroid lesions, various hyperthermic methods have, over the past 10–15 years, been introduced for the treatment of benign thyroid lesions. Laser ablation therapy (LAT), the first method proposed in 2000 for size reduction of benign solid thyroid nodules Radiofrequency ablation (RFA) , introduced in 2007, have achieved increasing acceptance for use in selected patients. Additional therapeutic modalities, such as focused US and microwaves , are presently under evaluation and have yet to gain wider acceptance. R1

11 Percutaneous Ethanol Injection Therapy(PEIT)

12 The injection of 95% ethanol into thyroid tissue induces:Thrombosis of small vessels and Lysis of the cell membrane and protein denaturation Irregular area of coagulative necrosis surrounded by interstitial oedema Granulomatous inflammation Over time, these histological changes are followed by Fibrosis ,Progressive shrinkage and reduction of the volume of the treated lesion DIAGNOSIS OF ENDOCRINE DISEASE Thyroid ultrasound (US) and US-assisted procedures: from the shadows into an array of applications European Journal of Endocrinology (2014) 170, R133–R146(R1)

13 Non-functioning benign thyroid nodulesSurgery may be considered for Growing solid nodules that are benign on repeat cytology if they are large (>4 cm), causing compressive or structural symptoms or based upon clinical concern ATA 2015

14 Non-functioning benign thyroid nodules(1)PEIT (percutaneous ethanol injection therapy)may effectively reduce the size of solid thyroid nodules. Several non-randomised trials, heterogeneous as for nodule size, ethanol volume and length of follow-up, demonstrate a significant decrease in nodule volume after PEIT. R1

15 Non-functioning benign thyroid nodules(2)In a 12-month randomised study, a single PEIT session induced a nearly 50% volume reduction, while (TSH)-suppression with levothyroxine had no significant effect on nodule reduction . Repeat treatment seemed only to increase the efficacy of PEIT marginally . These observations were confirmed in a randomised study that demonstrated a reduction just over 50% after three PEIT sessions . R1

16 The major limitations of PEITThe non-predictable diffusion of ethanol within solid lesions and The leakage of ethanol into neck tissues Owing to alcohol seepage, the majority of patients experience moderate to severe cervical pain lasting from minutes to hours . Local fibrosis (In our experience, a possible complication is the development of ) that may make less manageable a subsequent thyroid surgery if needed R1

17 Complication Recurrent laryngeal nerve palsy Transient dysphoniaMajor side-effects, fortunately not common Transient dysphonia Mild to moderate local pain Graves’ disease (rarely) In most cases, no change in thyroid function or thyroid autoimmunity has been reported Horner’s syndrome Necrosis of the larynx and the skin Flushing * Dizziness* R *= ATA 2015

18 Horner's syndrome Horner's syndrome is a classic neurologic syndrome whose signs include Miosis Ptosis Anhidrosis. can result from a lesion anywhere along a three-neuron sympathetic (adrenergic) pathway that originates in the hypothalamus

19 Sympathetic pathway for pupillary innervation

20 Currently, and in accordance with relevant guidelines, PEIT is not the procedure of choice for non-surgical treatment of solid thyroid nodules. It should be restricted to highly selected patients. R1

21 Recurrent cystic thyroid nodules(1)RECOMMENDATION 28 (ATA 2015) Recurrent cystic thyroid nodules with benign cytology should be considered for Surgical removal or percutaneous ethanol injection (PEI) based on compressive symptoms and cosmetic concerns. Asymptomatic cystic nodules may be followed conservatively. (Weak recommendation, Low-quality evidence)

22 Recurrent cystic thyroid nodules(2)Recurrence (fluid reaccumulation), which can be seen in 60–90% of patients For those patients with subsequent recurrent symptomatic cystic fluid accumulation Surgical removal, generally by hemithyroidectomy, or Percutaneous ethanol injection (PEI) ATA 2015

23 Recurrent cystic thyroid nodules(3)A 75–85% success rate after PEI A 7–38% success rate in controls treated by simple cyst evacuation or saline injection(Four controlled studies demonstrated) Success was achieved after an average of two PEI treatments. ATA 2015

24 Study inclusion criteria were local discomfort or cosmetic damage ULTRASOUND-GUIDED PERCUTANEOUS ETHANOL INJECTION THERAPY IN THYROID CYSTIC NODULES Methods: We present preliminary data of a controlled randomized study involving 281 patients (221 women and 60 men; 18 to 85 years old) with benign thyroid cystic nodules. Study inclusion criteria were local discomfort or cosmetic damage cystic volume more than 2 mL 50% or more fluid component, benignity as confirmed by cytologic specimen obtained by US-guided fine-needle aspiration biopsy (FNAB) euthyroidism. Endocrine Practice: May 2004, Vol. 10, No. 3, pp (R2)

25 Exclusion criteria were inadequate Suspicious positive FNAB cytology ULTRASOUND-GUIDED PERCUTANEOUS ETHANOL INJECTION THERAPY IN THYROID CYSTIC NODULES Exclusion criteria were inadequate Suspicious positive FNAB cytology High serum calcitonin Contralateral laryngeal cord palsy By random assignment, 138 patients underwent simple cyst evacuation, and 143 underwent cyst evacuation plus PEI by a skilled operator using a US-guided technique. The amount of ethanol injected was 50 to 70% of the cystic fluid extracted. R2

26 ULTRASOUND-GUIDED PERCUTANEOUS ETHANOL INJECTION THERAPY IN THYROID CYSTIC NODULESResults: Before treatment, the mean (±SD) nodule volume was 19.0 ± 19.0 mL versus 20.0 ± 13.4 mL in the PEI versus the simple evacuation group (no significant difference). After 1 year, volumes were 5.5 ± 11.7 mL versus 16.4 ± 13.7 mL (P<0.001), with a median 85.6% versus 7.3% reduction, respectively (P<0.001), of the initial volume. The median nodule volume reduction after PEI was 88.8% and 65.8% in empty body and mixed thyroid cysts, respectively. Compressive and cosmetic symptoms disappeared in 74.8% and 80.0% of patients treated with PEI versus 24.4% and 37.4% of patients treated with simple evacuation, respectively (P<0.001). Side effects were minor. R2

27 ULTRASOUND-GUIDED PERCUTANEOUS ETHANOL INJECTION THERAPY IN THYROID CYSTIC NODULESConclusion: These data provide definitive evidence that PEI is a safe and effective treatment for thyroid cystic nodules. Unicameral thyroid cysts are the most suitable candidate nodules for PEI. R2

28 Treatment of Recurrent Thyroid Cysts with Ethanol: A Randomized Double-Blind Controlled TrialSubjects Eligible subjects included patients who were 20–70 yr of age and had a benign solitary cold palpable thyroid nodule causing local discomfort and/or cosmetic complaints. Patients were referred by their primary care physicians. Inclusion criteria were: 1) [99mTc]pertechnetate scintigraphy demonstrating a solitary cold nodule; 2) US-demonstrated solitary or prominent [additional nodule(s) 1 cmdetected on US but not on the scintiscan] anechoic cystic lesion with no or less than 10% solid component and cyst volume at least 2 ml; 3) recurrence of the cyst fluid more than 1 month after primary aspiration; 4) cytological samples, obtained by FNAB under sonographic guidance, of the cyst fluid, the cyst wall and, if present, a residual solid component, to rule out malignancy; 5) euthyroidism; 6) normal serum calcitonin; 7) no major concomitant disease; 8) no medication affecting thyroid function; 9) no history of previous head or neck irradiation; and 10) normal indirect laryngoscopy. The Journal of Clinical Endocrinology & Metabolism 88(12):5773–5777 Denmark(R3)

29 Cystic nodules This covers thyroid nodules thatare purely cystic (the minority) or predominantly cystic (the majority). US-guided percutaneous drainage is the treatment of choice, but most cystic lesions (about 80%) refill and enlarge over time . Several non-randomised studies , in both colloid and haemorrhagic lesions, have reported good efficacy, a favourable sideeffect profile and the preservation of thyroid function. R1

30 A randomised study in recurrent thyroid cysts comparedpercutaneous cyst drainage followed by ethanol flushing and subsequent aspiration with cyst drainage followed by flushing with isotonic saline . After a single session: a significant volume reduction was obtained in 82% of cases in the PEIT group, while the cure rate in the saline group was only 18%. The success rate was inversely correlated with the baseline cyst volume and Number of previous aspirations. Pain, if any, is usually mild and rapidly self-resolving and the risk of dysphonia is very low. In a follow-up study of thyroid lesions treated with PEIT, the volume reduction of the cysts was fairly stable after 5 years. The major endocrine society guidelines state that treatment of recurrent benign thyroid cysts with ethanol is a clinically effective non-surgical option for thyroid cysts that recur after repeat aspirations.(R1)

31 Ethanol ablation Ethanol ablation generally involvesremoving as much of the cyst fluid as possible under ultrasound guidance, and then instilling an amount of 99 percent ethanol equal to 50 percent of the aspirated volume into the thyroid cyst cavity. In some series the ethanol is removed after five minutes, and in other reports the fluid is allowed to remain in the cyst cavity. In randomized trials, ethanol ablation effectively reduces the size of benign cystic thyroid nodules . (R1)

32 perspective of both the physician and the patient.Percutaneous Ethanol Injection for Benign Cystic Thyroid Nodules: Is Aspiration of Ethanol-Mixed Fluid Advantageous? CONCLUSION: Percutaneous ethanol injection without aspiration of ethanol-mixed fluid seems to be the preferable method of treatment of benign cystic thyroid nodules from the perspective of both the physician and the patient. American Society of Neuroradiology (26, September 2005)R4 South Korea

33 Toxic Thyroid Nodules

34 Functioning thyroid nodulesHyperfunctioning lesions account for 5–10% of all thyroid nodules . Malignancy is extremely rare and radioiodine 131I is considered as the first-line therapy in the majority of patients because normalisation of thyroid function is attained in most cases and the reduction of nodule volume is about 30–45% within 1–2 years. (R1)

35 Percutaneous Ethanol Injection plus Radioiodine Versus Radioiodine Alone in the Treatment of Large Toxic Thyroid Nodules Conclusion: We demonstrated that RAI, alone or with PEI, can be considered a valid alternative for TTNs larger than 4 cm when surgery is either refused or contraindicated. PEI plus RAI can be considered when marked shrinkage of a nodule is required or when reduction of the RAI dose can prevent hospitalization. NONSURGICAL TREATMENT OF LARGE TTNS • Zingrillo et al.(R5) Rome, Italy

36 Functioning thyroid nodulesOne study in 132 patients treated with multiple sessions demonstrated normalisation of serum TSH in all pretoxic adenomas and in 71% of toxic adenomas . Nodule volume reduction was similar to that reported for cold thyroid nodules. Moderate to severe cervical pain was frequently encountered . several PEIT-sessions are necessary for a complete treatment and that the recurrence of hyperthyroidism and the regrowth of the treated nodules are common . Based on these considerations, with the exception of the infrequent conditions in which 131I is contraindicated or ineffective efficacy and side effects are in favour of 131I when compared with PEIT. (R1)

37 Treatment of Cervical Lymph Node Metastases in Patients with Papillary Thyroid Carcinoma With PEIT

38 RECOMMENDATION 71 ATA 2015 Therapeutic compartmental central and/or lateral neck dissection in a previously operated compartment, sparing uninvolved vital structures, should be performed for patients with biopsy proven persistent or recurrent disease for central neck nodes greater than or equal to 8 mm and lateral neck nodes greater than or equal to 10 mm in the smallest dimension which can be localized on anatomic imaging. (Strong recommendation, Moderate-quality evidence)

39 Metastatic Lymph Node PEI for patients with metastatic lymph node (LN) is gaining interest as a nonsurgical directed therapy for patients with recurrent DTC. Most of the studies limited PEI to patients who had undergone previous neck dissections and RAI treatment, those who had FNA proven DTC in the lymph node and those with no known distant metastases. ATA 2015

40 One of the first studies examining the effectiveness of local metastatic lymph node control by PEI treated 14 patients with 29 lymph nodes . Twelve of 14 patients had good loco-regional control in this study with short-term follow-up (mean 18 months). The largest study to date treated 63 patients with 109 metastatic lymph nodes between the years 92 lymph nodes (84%) were successfully ablated in this retrospective study with a mean follow-up of 38 months, and most required 1-3 treatment sessions. Minor complications have included brief discomfort at the PEI site. There were no major complications. ATA 2015

41 A recent study retrospectively reviewed 25 patients who had 37 lymph nodes ablatedbetween the years , with a relatively long follow-up of a mean of 65 months. All lymph nodes were successfully ‘ablated’ in 1-5 treatment sessions by lack of flow on US. Most of the lymph nodes decreased in size and 46% completely disappeared. Serum Tg levels were reduced in most patients and brought into an acceptable range (< 2.4 ng/ml) in 82% of patients with negative Tg antibodies. There were no serious or long-term complications. Another recent study also demonstrated safety and efficacy of PEI in 21 patients with 41 metastatic lymph nodes . These investigators treated patients with only one session and 24% of patients had a recurrence at the site of the injection. ATA 2015

42 Limitations of many of the studies included(ATA)small numbers of patients relatively shortterm follow-up many patients with small lymph nodes (<5-8 mm) A general consensus from studies and reviews is that PEI should be considered in patients who are poor surgical candidates. Many patients will likely need more than one treatment session and lymph nodes > 2 cm may be difficult to treat with PEI. Focal PEI treatment does represent a non-surgical form of “berry picking” which has been condemned in the surgical literature for many years as incomplete treatment. ATA 2015

43 Formal neck compartmental dissectionis still the first-line therapy in DTC patients with clinically apparent or progressive lymph node metastases. When deciding for the optimal strategy of care for a patient’s lymph node metastases, previous treatment modalities should also be taken into consideration. ATA2015

44 surgeries and, in order to completely excise tumor, his UPEI had not previously been used to treat “recurrent’ NNM in differentiated thyroid cancer when, in 1991, a 46-year old psychiatrist presented to Mayo Clinic with stage IV medullary thyroid carcinoma. He had a history of three previous neck surgeries and, in order to completely excise tumor, his right recurrent laryngeal nerve (RLN) had been sacrificed. Unfortunately, he now had two NNM in left level VI, which threatened his remaining RLN, as well as his livelihood. He underwent successful ultrasound-guided percutaneous ethanol ablation (UPEA) of two left central compartment NNM. His injected NNM disappeared on careful ultrasound scanning within 10 months, and did not recur after twenty years of follow-up. Percutaneous ethanol ablation of neck nodal metastases in papillary thyroid carcinoma Thyroid International · 2–2012 Merck KGaA, Darmstadt, Germany, D Darmstadt ISSN (R6)

45 The role of PEI in treating recurrent NNM in differentiated thyroid cancer had not been established when, in 1991, PUEA was successfully used to treat the central compartment nodes of a 46-year old Mayo Clinic patient with medullary thyroid carcinoma. Our first opportunity to treat NNM in PTC came in 1993, with the referral to Mayo of a 34 year old woman, diagnosed with PTC in 1989 after the discovery of a palpable node in the neck. R6

46 She initially underwent total thyroidectomy with left radical neck dissection. At the time of surgery, an unresectable tumor mass of 32 x 10 x 10 mm adjacent to the left carotid bulb was discovered, and was considered unresectable. She underwent remnant ablation with 135 mCi of 131I. In 1991, the carotid-bulb mass was found to be enlarging and her neck subsequently received 5400 cGy of external beam radiation. She was referred in 1992 to Mayo Clinic after undergoing elsewhere a second neck surgery, where the surgeon again judged the mass to be unresectable. R6

47 Mayo surgeons were also unwilling to consider a third surgery and it was felt that the patient would not benefit from further RAI or external irradiation. She was initially observed with serial imaging, but the mass enlarged over time. In May 1993, the node measured 3.2 cm in length by 1 cm in AP and transverse dimension. Under sterile conditions and real-time guidance, a total of 0.5 cc of 95 % ethanol was carefully injected by Prof J William Charboneau into multiple areas of the node. Over a period of ten months, the patient received, under US-guidance, a total of 1.4 cc of 95 % ethanol in three sessions, injected directly into the inoperable mass. R6

48 From 1995 through 2012, the patient has regularlyattended Mayo for follow-up. In 2003, her Tg autoantibody disappeared and, from 2004 through 2012, her serum Tg levels on thyroid hormone suppressive therapy have been < 0.1 ng/ml. CT scans of neck and chest have been unremarkable and a recent whole body 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography-computed tomography (PET-CT) scan was entirely negative. Her most recent neck ultrasound showed only an avascular node measuring 6 x 5 x 8 mm adjacent to the left common carotid artery. No pathologic nodes were seen in the remainder of the examined neck. R6

49 Indications for UPEA in node-positive PTCUPEA can be used to successfully treat PTC patients With: NNM who are poor surgical candidates Would prefer not to undergo further surgery or have disease that is unresponsive to previous RAI administration. to control local disease in the setting of patients who had concomitant distant metastases. to control limited “outbreaks” of persistent or recurrent regional NNM

50 UPEA Procedural DetailsUltrasonography should be performed by a skilled operator who is able to identify normal from pathological lymph nodes. Metastatic lymph nodes may be large, rounded, have microcalcification and loss of the fatty hilum. At baseline prior to UPEA and at every follow-up visit, the treated nodes are measured in size and volume and perfusion, as evidenced by Doppler flow, is documented.

51 The procedure is considered successfulas illustrated reduction in size of the lymph node and elimination of vascular flow by Doppler

52 Minimize the risk of complicationsTo treat a NNM successfully, and to minimize the risk of complications such as nerve damage and severe pain, the NNM being treated must be continually monitored with real-time HRS with grey scale and color Doppler. The goal of the treatment is to disperse the ethanol throughout the NNM, while minimizing the amount of ethanol that leaks into the adjacent normal tissues. When treating a very small lesion (less than 5 mm diameter), the needle can be placed in the center of the NNM followed by the slow injection of the ethanol. The ethanol being injected is echogenic on ultrasound because of microbubbles present in the ethanol.

53 The treatment is considered completewhen the ethanol has dispersed throughout the NNM and no flow can be identified in the NNM on color Doppler. Larger NNM often require the needle to be repositioned several times to treat the entire node. Likewise, if the ethanol is not dispersing well, the needle should be repositioned before the ethanol is injected. Most of the NNM that we have treated require less than 1 cc of ethanol per treatment session.

54 Ethanol disperses poorlyIn some NNM, the ethanol disperses poorly and requires higher pressures to inject. These are often NNM that have been previously treated and are more firm and fibrotic. While monitoring the injection on the real-time ultrasound, the physician may see the ethanol leaking into the surrounding tissue or along the needle track. This sort of extravasation must be avoided to minimize the risk of severe pain and nerve damage.

55 UPEA-treated patients typically have a second treatment on the following day. Prior to the second injection, the NNM is carefully surveyed to see if there is any residual blood flow on color Doppler. If blood flow is seen, this area of the NNM is thoroughly treated with ethanol, followed by a second treatment of the remainder of the NNM. Occasionally, a very small NNM can be treated in only one session.

56 Favorable response to UPEA in a 26-year old man with pTNM stage I PTCFavorable response to UPEA in a 26-year old man with pTNM stage I PTC. A. Transverse sonogram performed before treatment shows a pretracheal 13 x 3 x 10 mm NNM, that is hypervascular on color Doppler.R6

57 B. Colour Doppler transverse sonogram shows that, at 4 months after ablation, the treated NNM is avascular and smaller in size, now measuring 9 x 2 x 6 mm.

58 C. At 10 months after ablation, there is continued involution of the ablated and avascular NNM, which is very indistinct on grey scale images and is now measuring only 8 x 1 x 3 mm.

59 Complications Complications can be divided into one of two categories: either those caused by placement of the needle or those caused by injection of the ethanol. Complications from placement of the needle would include bleeding and transient RLN injury. Complications from injection (and local extravasation) of ethanol may include neck pain, which is mild and usually responsive to conservative management, transient or permanent hoarseness secondary to RLN injury (which is fortunately extremely rare) and future fibrosis of adjacent neck tissues (which could represent a hazard if the patient had a subsequent neck re-exploration).

60 Transverse sonograms of metastatic adenopathy in 48-year-old woman with papillary thyroid carcinoma. A, Sonogram reveals 8 × 9 mm lymph node (arrow) with needle in place.

61 B, Image obtained at initial injection with small volume of ethanol shows echogenic region in posterior aspect of lymph node (arrowhead) due to microbubble formation.

62 C, Image obtained after repositioning of needle shows another site in lymph node (arrow) being treated.

63 D, Image obtained 9 months after percutaneous ethanol injection shows that size of treated lymph node (cursors) has decreased markedly.

64 AJR:178, March 2002 Percutaneous Ethanol Injection for Treatment of Cervical Lymph Node Metastases in Patients with Papillary Thyroid Carcinoma

65 27-year-old woman with papillary thyroid carcinoma.A, Standard diagram used to map location of each lymph node (to facilitate follow-up and communication between sonographic examinations) shows several left internal jugular nodes were identified, with one node (arrow) located between internal jugular vein and common carotid artery. SMG = submandibular gland. B, Corresponding transverse sonogram reveals lymph node (cursors). CCA = common carotid artery, JUG = internal jugular vein.

66 Persistent perfusion after initial percutaneous ethanol injection requiring retreatment in 36- year-old man with papillary thyroid carcinoma. A, Longitudinal sonogram shows enlarged biopsy-confirmed metastatic lymph node (cursors).

67 B, Power Doppler sonogram reveals uniform perfusion before percutaneous ethanol injection.

68 C, Longitudinal sonogram obtained 9 weeks after percutaneous ethanol injection shows size of lymph node is unchanged, and there is evidence of slight residual perfusion. Because of these findings, percutaneous ethanol injection treatment was repeated.

69 D, Longitudinal sonogram obtained 14 weeks after C reveals that size of lymph node (arrows) has decreased dramatically. No perfusion on power Doppler sonography is shown.

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71 parathyroid gland

72 Enlarged parathyroid gland in secondary hyperparathyroidism caused by chronic renal failure.

73 Abundant blood vessels are observed in the parathyroid gland in the left panel.

74 Fusion 3D image of enlarged parathyroid gland in secondary hyperparathyroidism. Increased blood flow can be seen from all angles.

75 A 3D image before PEIT is shown on the left and after PEIT on the right. When these images are compared, it is evident that there is no blood flow in the parathyroid gland after PEIT.

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