6 URRENT PINION
Thermal ablation in adrenal disorders: a discussion of the technology, the clinical evidence and the future
Padraig Donlon and Michael Conall Dennedy
Purpose of review
To summarise the emerging role of thermal ablation as a therapeutic modality in the management of functioning adrenal tumours and metastases to the adrenal gland.
Recent findings
Observational evidence has demonstrated the benefit of thermal ablation in (i) resolving adrenal endocrinopathy arising from benign adenomas, (ii) treating solitary metastases to the adrenal and (iii) controlling metastatic adrenocortical carcinoma and phaeochromocytoma/paraganglioma.
Summary
Microwave thermal ablation offers a promising, minimally invasive therapeutic modality for the management of functioning adrenocortical adenomas and adrenal metastases. Appropriate technological design, treatment planning and choice of imaging modality are necessary to overcome technical challenges associated with this emerging therapeutic approach.
Keywords
adrenal adenoma, adrenal tumour, Cushing’s syndrome, microwave thermal ablation, primary aldosteronism
INTRODUCTION
The past decade has seen the widespread application of minimally invasive technologies to thermally ablate solid tumours within large organs, using radio- frequency electrical energy (RFA), microwave ther- mal ablation (MWA), cryoablation, high-intensity focused ultrasound and laser [1]. Thermal ablation has largely been applied within the clinical setting to inoperable malignancies or metastases within the liver or kidney, with more recent applications to tumours of the bone, lung and breast [2,3]. The modality is largely safe, well-tolerated and efficacious within these settings. It is usually delivered using radiological image-guidance, most commonly via Computed Tomography (CT) or ultrasound [4]. How- ever, thermal ablation remains an emerging therapy and the majority of currently supporting evidence comes from longitudinal cohort studies. Large ran- domised controlled trials are lacking in the area, although important studies such as the Liver resec- tion surgery versus thermal ablation for colorectal LiVer MetAstases trial aim to fill this gap [5,6].
Although the clinical focus of thermal tumour ablation has been malignancy, this therapeutic modality offers exciting and paradigm-shifting potential to provide definitive therapy to benign
endocrine tumours, particularly within the context of systemic endocrinopathy [7-10]. In this regard, several case series and small observational studies have examined the efficacy and safety of both RFA and MWA in the setting of thyroid, parathyroid and adrenal tumours [11]. This article focusses on the application of microwave and radiofrequency ther- mal ablation to the adrenal gland and provides (i) a review of the technology behind thermal ablation, (ii) an overview of its clinical use in adrenal disorders and (iii) a brief discussion of future direction.
Adrenal Research Laboratory, The Discipline of Pharmacology and Therapeutics, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Ireland
Correspondence to Michael Conall Dennedy, MD, PHD, FRCPI, Senior Lecturer in Therapeutics, Discipline of Pharmacology and Therapeutics, 3.13, Lambe Institute for Translational Research, National University of Ireland Galway, Costello Road, Galway H91V4AY, Ireland. E-mail: michael.dennedy@nuigalway.ie
Curr Opin Endocrinol Diabetes Obes 2021, 28:291-302 DOI:10.1097/MED.0000000000000627
This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
KEY POINTS
· Thermal therapy is a potentially viable alternative treatment to surgery for adrenal tumours, which can allow preservation of normal tissue of the gland.
· All ablation procedures of the adrenal gland require pre adrenergic blockade in order to prevent intraoperative hypertenisve crisis.
· Thermal therapy has the potential to provide a curative treatment to those patients with bilateral adrenal disease.
· Thermal therapy is generally less invasive than surgery, can provide a shorter operative time, shorter hospital stay, and provide lower complication rates.
· From the studied reviews its success in treating endocrinopathies and controlling adrenal metastases is similar to that of adrenalectomy.
BIOLOGICAL EFFECTS OF THERMAL ABLATION
The objective of thermal ablation is to produce a core tissue temperature >50°℃ in order to induce cell death by coagulative necrosis [12]. The principle therapeutic challenge relates to reaching a core temperature that covers the entire tumour volume, but which does not damage adjacent critical tissues or organs. In addition to coagulative necrosis within the so-called ablation zone, an inflammatory infil- trate is typically seen within the intervening transi- tion zone between the area of effective ablation and adjacent healthy tissue (Fig. 1) [13]. Immune infil- trates of monocyte/macrophages, neutrophils, den- dritic cells, natural killer cells, and lymphocytes have all been demonstrated within the transition zone across varying tissue types following both RFA and MWA [14]. Interestingly similar immune infil- trates have also been described in metastatic depos- its remote from the ablated tumour site, as well as within the circulating blood following ablation [13,15]. Several mechanisms have been proposed for this response including the effect of tumour ablation to cause a local release of damage associated molecular patterns, such as heat shock proteins and HMGB1. When released extracellularly, these mol- ecules act as chemoattractant chemokines that stim- ulate a local and sometimes systemic immune response [16]. The immune response to thermal ablation is an exciting area of research and is hypothesised to play a role in modulating sponta- neous regression of distant tumour metastasis fol- lowing ablation of a primary tumour or metastatic lesions [17]. Tumour specific T cell responses observed following thermal ablation therapy have
been associated with increased tumour-free survival in humans [18]. Supporting data for this association, generated in animal models demonstrate resistance to graft re-growth in animals subjected to a tumour rechallenge following previous thermal ablation [17]. Tumour immunoediting is an interesting fea- ture of thermal ablation that offers the potential for systemic augmentation with immune therapy in order to maximise patient outcomes.
THERMAL ABLATION: TECHNOLOGY AND APPROACH
Systems for delivering RFA and MWA are both illus- trated in Fig. 1. Briefly, both systems use an energy generator to transmit electrical or microwave energy at varying doses via an applicator probe to a tissue targeted for thermal ablation. Conversion to ther- mal energy occurs at tissue-level and relies upon tissue properties, such as water content (MWA) and electrical impedance (RFA). Applicator probes are usually rigid, although flexible applicator designs are also available [19]. Probes are typically guided to their target tissue/tumour through an introducer needle using radiological image guid- ance via CT or ultrasound. Pulsed (RFA) or constant (MWA) energy is delivered to the target over a period of 5-20 min, with the aim of reaching a core tem- perature >50℃ within the targeted tissue or tumour, delivered over a cumulative time period of 4-5 min.
Although the general principle of delivering thermal energy to a targeted tissue or tumour is similar between both systems, the technology and the manner of heating differs considerably. Radio- frequency has traditionally been more commonly utilised within the clinical setting, yet MWA offers several advantages and the technology to effectively and precisely deliver MWA has recently advanced. An illustration of the heating patterns for RFA and MWA is provided in Fig. 2 and a comparison of both modalities is provided in Table 1 [4].
Radiofrequency ablation has principally been used to target hepatic tumours. However, the past decade has seen its indications expand to other organs/tissues. Temperatures ranging between 60 and 100℃ are generated at the applicator tip, via alternating current, at frequencies from 100- 500 kHz. Effective RFA requires that targeted tissue has low electrical impedance. Consequently, RFA is limited technically by the following: (i) heating is only achieved immediately adjacent to the applica- tor and (ii) high temperatures at the applicator tip dehydrate tissue, increases electrical impedance and hinders energy penetration into circumjacent tissue [19]. This is typically overcome by delivering pulsed
(a)
Applicator Handle
Applicator Shaft
Temperature Monitor
Radiating Tip
Coolant Inflow
Coolant Outflow
Cable/Electrode wire
(b)
RFA
Coolant Outflow
Coolant Inflow
Active Electrode
Insulated Electrode
Thermocouple
Electrode
(c)
MWA
(d)
Directional MWA
Coolant Outflow
Coolant Outflow
Coolant Inflow
Coolant Inflow
Inner Conducter
Outer Conducter
Inner Conducter
Outer Conducter
Bracket
Reflector
RFA over a more prolonged duration in order to achieve sufficient penetration. Challenges of tissue penetration are further compounded by heat sink, whereby applied temperatures are reduced by adja- cent large blood vessels absorbing heat and carrying it away through the effects of blood flow, thereby decreasing the hyperthermic efficiency of RFA [20].
MWA produces heat through electrical hystere- sis. It provides better tissue healing and efficiency when compared to RFA and is less susceptible to heat sink. An electromagnetic field between 900 and 2500 MHz is delivered to targeted tissues via a co- axial cable. This field causes polar molecules (usually water) to constantly realign with the oscillating
(a)
First Generation MWA
RFA
Cooled MWA
Directional MWA
Ablation Zone
Hyperthermia Zone
Tumour
Blood Vessel
Heat Sink Effect
(b)
Monopolar RFA 2 min
Monopolar RFA 10 min
Directional MWA 30 W, 5min
Omni-directional MWA 30 W, 5min
120
110
I
100
Temperature [C]
90
80
70
60
1 cm
50
40
| RFA | MWA | |
|---|---|---|
| Heating mechanism | Results in hyperthermia via electric current which relies upon tissue conductivity and ion content. (-) | Results in hyperthermia via electromagnetic energy which relies upon tissue polar molecule (water) content. (+) |
| Grounding pad | Requires the use of grounding pads which can result in burns (-) | Does not require grounding pads (+) |
| Heating efficiency | Inefficient at higher temperatures due to tissue desiccation resulting in increase impedence (-) | Rapid heating and little effect of tissue desiccation(+) |
| Heat sink | Heat sink effect can be a major issue for well vascularised organs (-) | Less susceptible to heat sink (+) |
| Procedure time | More procedural time (-) | Less procedural time (+) |
| Ablation volume | Smaller ablation sizes (-) | Larger ablation sizes(+) |
| Ablation zone | Unpredictable (-) | Predictable, allowing for better treatment planning (+) |
| Procedural pain | Higher level of pain (-) | Less level of pain (+) |
Advantages (+), Disadvantage (-).
electric field. Molecular rotation increases kinetic energy that is converted to heat within targeted tissues. Heat conductance using this modality favours tissues with a high percentage of water such as solid organs and tumours [21,22]. Microwave systems typically provide better tissue penetration compared to RFA as they do not require paths of low electrical impedance [23]. They can also produce larger, more precise, spherical ablation zones within a shorter application time, using constant rather than pulsed energy delivery [24"",25”,26”]. Multiple synergistic antennae can also be synchronously used to deliver focused energy to single large tumours or even to simultaneously target multiple tumour loci [27].
Microwave however is not without its chal- lenges. Generation and transmission of microwave energy have traditionally been difficult to achieve and must be carried in coaxial cables, which of wider gauge than that of the simple wires used in RFA applicators [28]. Cable heating presents a greater challenge for MWA, when compared to RFA and therefore these systems must be cooled, using water or gas, both of which add to the complexity and diameter of the applicator antennae [22,25"",28, 29"",30,31]. It is due to these complexities that the advancement and broader use of MWA in the clinic have lagged behind RFA [32].
ADRENAL TUMOURS AND THE ROLE OF THERMAL ABLATION
Tumours of the adrenal gland have an estimated prevalence of 3-10% in the population aged >50 years and are commonly picked up as so-called incidentalomas on abdominal imaging [33]. Over- all, 80% of adrenal incidentalomas are of no clinical significance [34]. For the remaining 20%, surgical resection/adrenalectomy is the definitive treatment of choice where indicated [35-38] The following tumours of the adrenal gland are typically resected: (i) benign functioning unilateral tumours associated with systemic endocrinopathy[39]; (ii) adrenocorti- cal carcinoma (ACC) [38]; (iii) phaeochromocytoma [40]; (iv) solitary metastasis to the adrenal gland [41](Table 2). Bilateral functioning tumours of the adrenal are usually not amenable to resection due to the lack of widespread, feasible options for adrenal sparing surgery compounded by the difficulty in identifying and localising specific hyperfunctioning regions within the adrenal [42]. Uncommonly, where severe systemic endocrinopathy is driven by disease in both glands, bilateral adrenalectomy is undertaken [43,44]. However this involves a con- siderable prognostic trade-off between patient-spe- cific implications of endocrinopathy, which must be
balanced with the inevitable complication of life- long adrenocortical insufficiency [36].
Adrenalectomy, where possible, represents the current treatment of choice for definitive manage- ment of adrenal disease. In this regard the approach to adrenalectomy has advanced considerably over the past two decades [45]. Laparoscopic adrenalectomy is now the surgical technique of choice, with some centres offering retroperitineoscopic approaches [46]. Although not widely available, adrenocortical sparing surgery has also been undertaken for bilateral disease localised within the adrenal [46,47]. None- theless, adrenalectomy remains a skilled surgical pro- cedure, requiring general anaesthetic within an often high-risk population and representing the resource- intensive costs associated with hospitalisation, oper- ating room use and the personal and economic impli- cations of the recovery period.
Thermal ablation of the adrenal gland may over- come some surgery associated challenges. This per- cutaneous and minimally invasive technique offers the potential for fast and effective therapy to disrupt adrenal tumours while reducing patient discomfort, cost and hospitalised days [48""]. Its indications are additionally broadened to those unwilling or unfit for adrenalectomy due to co-morbidity [49]. It is in this regard that thermal therapy has been trialed amongst small cohorts as a (i) minimally invasive alternative to definitive management of benign adrenal adenomas [39,50-56], (ii) adrenal metasta- ses in patients unsuitable for surgery and [3,10,48"",57-59] (iii) for local management of met- astatic adrenal cancers [60"",61"",62,63""].
Advancement of thermal ablation of the adrenal gland through specifically designed precision appli- cation systems provides the opportunity to selec- tively disrupt localised, diseased tissue within one or both adrenal glands while leaving nontargeted adja- cent normal tissue unaffected - thereby minimising the risk of postprocedural adrenocortical insuffi- ciency [24""]. This makes thermal therapy a poten- tially paradigm shifting candidate for definitive management of unilateral adrenal tumours, as well as offering an exciting option for definitive manage- ment of endocrinopathy driven by bilateral local- ised adrenal disease [24""]. However, significant progress must be made in terms of applicator design and generation of clinical evidence before these clinical applications can be introduced in a safe and consistent manner.
ADRENAL ABLATION: CURRENT CLINICAL EVIDENCE
Current evidence supporting thermal ablation of adrenal disorders arises from small observational
| Author | Year | Ablation | Tumour | Size | Patient No. | Residual | Recurrence | Biochemical Resolution | Complications | Follow Up |
|---|---|---|---|---|---|---|---|---|---|---|
| Arima et al. [51] | 2007 | RFA | Adenoma, Cushing's | 2.0-3.5 cm | 4 | 100% | Hypertensive crisis (25%), Pneumothorax (25%) | 46 months | ||
| Nishi et al. [52] | 2012 | RFA | Adenoma, Cushing's | 3 cm | 1 | 100% | Adrenal hypofunction which recovered after 18 months | 5 years | ||
| Chini et al. [3] | 2004 | RFA | Metastasis to adrenal | 2.8 cm | 1 | 100% | Severe hypertension (249/ 140 mm Hg) and narrow complex tachycardia (140 bpm). | |||
| Frenk et al. [57] | 2017 | RFA, MWA, Cryo | Metastasis to adrenal | <5 cm | 38 | 4% | 24% | Hypertensive Crisis (57%), Intermittent urinary retention (6%), Acute cholecystitis (2%), Pneumothorax (2%), | 37 months | |
| Hasegawa et al. [58] | 2015 | RFA | Metastasis to adrenal | 1.2-8.2 cm | 35 | 6% | 23% | Acute Renal Failure (3%), Heart Failure (3%), Hypertensive Crisis (66%), Hepatic hematoma (3%) | 30.1 months | |
| Liu et al. [48""] | 2020 | RFA | Metastasis to adrenal | 1-9 cm | 29 | 24% | Ascites (3.5%), Pain (28%), Ventricular fibrillation (3.5%), Hypertensive crisis (13.7%), Bradycardia (3.5%) | 24.5 months | ||
| Wolf et al. [64] | 2012 | RFA, MWA | Metastasis to adrenal | 2-8 cm | 19 | 5% | 15% after first ablation, 5% after second ablation | 14 months | ||
| Mendiratta-Lala et al. [53] | 2010 | RFA | All Neoplasm, (APA, cortisol- secreting. testosterone- secreting) | <3.2 cm | 13 | 100% | Hypertension (15.4%), Adrenocortical insufficiency recovered after 15 months (8%) | 41.4 months | ||
| Mayo-Smith et al. [11] | 2004 | RFA | All Neoplasm (metastases, PA, APA) | 1-8 cm | 12 | 15.4% | Retroperitoneal hematoma (8%) | 11.2 months | ||
| Abbas et al. | 2013 | RFA, Cryo | APA | 1.5-2.5 cm | 5 | 60% | Hypertensive crisis (100%) | 12 months | ||
| Liu et al. [39] | 2016 | RFA | APA | 1.6 cm | 24 | 96% | Pneumothorax (4.2%), Retroperitoneal hematoma (12.5%) | 21.2 months |
| Author | Year | Ablation | Tumour | Size | Patient No. | Residual | Recurrence | Biochemical Resolution | Complications | Follow Up |
|---|---|---|---|---|---|---|---|---|---|---|
| Liu et al. [10] | 2016 | RFA | APA | 1.5 cm | 36 | 92% | Pneumothorax (8%), Retroperitoneal hematoma (8%), Infected retroperitoneal hematoma (3%) | 6.2 years | ||
| Sarwar et al. [55] | 2016 | RFA | APA | <4 cm | 12 | Cured hypertension (17%), Fewer antihypertensives (58%) | 463 days | |||
| Szejnfeld et al. [56] | 2015 | RFA | Conns and Cushings Syndrome | 1.5-3.4 cm | 11 | 100% | 24 months | |||
| Delijou et al. [62] | 2018 | RFA | Metastatic PPGL | 21 | Hypertensive Crisis (4.8%), Post ablation bleeding (4.8%), argon gas embolism (4.8%) | |||||
| Kohlenberg et al. [63""] | 2019 | FA, Cryo | Metastatic PPGL | 5.5 cm | 31 patients, 123 lesions, 80 lesions examined | 14% | Pain, fever (14%), Gastrointestinal bleeding (3.2%), Hypertensive crisis (14%) | 60 months | ||
| Fintelmann et al. [59] | 2016 | RFA, MWA, Cryo | Metastasis to adrenal | 0.7-11.3 cm | 57 | Hypertensive crisis (43%), Adrenal insufficiency (22%), Ventricular tachycardia (1.4%) | ||||
| Ren et al. [68] | 2016 | MWA | All Neoplasms (metastases, cortical adenomas, pheo) | 33 | 15.2% | 100% | 24 months | |||
| Liu et al. [60""] | 2019 | RFA | ACC | 6.3 cm | 1 | 12 month | ||||
| Veltri et al. [61""] | 2020 | RFA, MWA | ACC | 14-43.5 cm | 16 | 21.8% | Intrahepatic hematoma (6.2%) | 42 months |
ACC, Adrenocortical carcinoma; APA, aldosterone producing adenoma; Cryo, cryoablation; MWA, microwave ablation; PA/PGL, pheochromocytoma/paraganglioma; RFA, radiofrequency ablation.
clinical studies and case series using RFA, MWA and cryoablation (Table 2). These studies have docu- mented short and intermediate term outcomes for unilateral aldosterone producing adenomas (APA) [8,39,50,53,55,56], cortisol secreting adenoma [51- 53], Adrenocorticotropic Hormone-dependent Cushing’s disease [53,56], adrenal metastases and pheochromocytoma [60"",61"",62,63""]. The approach to ablation has not been consistent across all studies and definitions of clinical response to therapy vary in accordance with underlying pathol- ogy [30-47,48""]. For malignancy and metastasis to the adrenal, success is determined by change in tumour characteristics on imaging, specifically (i) tumour-size reduction, (ii) absence of local tumour progression or (iii) progression/recurrence-free sur- vival [11,48"",51,57,58,63"",64]. For APA, phaeo- chromocytoma and Cushing’s syndrome, success is additionally determined by biochemical resolu- tion/improvement of endocrinopathy and resolu- tion of hypertension [51-54,65]. In spite of the inhomogeneity of treatment approach and lack of standardised outcome reporting, the current data are encouraging in support of adrenal ablation. A summary of specific studies in which adrenal abla- tion has been applied is provided in Table 2.
Outcomes for biochemical resolution of endo- crinopathy in the setting of unilateral APA, or corti- sol-secreting adenoma is high for studies using both RFA and MWA. In general, all studies have demon- strated cure of endocrinopathy in both settings for 75-100% of cases after a single ablation and 100% following repeated ablation. For APA, complete res- olution of hypertension occurs in approximately 45%, with complete or partial resolution in 90% following thermal ablation. This is comparable with unilateral adrenalectomy [8,39,51,52,66,67].
For metastases to the adrenal gland, both MWA and RFA have demonstrated high efficacy of tumour ablation, demonstrating postprocedural presence of residual tumour in fewer than 25%, with similarly low recurrence rates (<25%). Overall survival rates have not been evaluated due to the lack of a com- parator and the heterogeneity of the underlying primary malignancy in these studies [3,48"",57, 58,64,68].
Staged, bilateral RFA was undertaken in a small case series of 5 patients with severe Adrenocortico- tropic Hormone-dependent Cushing’s disease, unre- solved following hypophysectomy. In all patients, there was a resolution of hypercortisolaemia, as well as Cushingoid clinical features following ablation. However, there is no long-term follow-up of disease recurrence [69]. Adrenal thermal ablation of phaeo- chromocytoma has had variable success. Hyperten- sive crisis (HTC) arising from tumoral degranulation
of stored catecholamine remains a high risk and adrenalectomy remains the unquestionable treat- ment of choice [62,63"",70].
METASTATIC CANCERS OF THE ADRENAL
Localised therapy is now recommended for the management of metastatic tumour bulk in patients with ACC [71]. Evidence for this approach is evolv- ing for metastatic adrenal malignancy, albeit that it is a well-healed modality for disease control in other malignancies [12]. Most recently, a single case series of 16 patients has described efficacy of CT-guided RFA to the liver and lung for oligometastatic ACC. The results of this study are encouraging, reporting radiological evidence of complete ablation in 97% of targeted lesions. Local progression was low and occurred in larger lesions, with an overall rate of 24% and a median local progression-free survival of 21 months [61""]. Single case studies have demon- strated efficacy of this approach for spinal metastasis from ACC [60""]. Similarly, localised therapy has been used to treat metastatic deposits from phaeo- chromocytoma/paraganglioma (PGGL), not fully controlled with chemotherapy or Peptide Receptor Radionuclide Therapy alone [62,63""]. A recent case series described the outcomes of 31 patients with metastatic PGGL all of whom were alpha blocked for 7-14 days prior to ablation and treated with a com- bination of RFA, cryoablation or ethanol injection. Ablation of metastasis to bone, liver and pelvis achieved local control in 74-94%. Tumour progres- sion was reported in 6-26% (median time to pro- gression 16 months). Symptoms related to catecholamine excess also improved in patients treated using this modality and procedural HTC was reported in 14% [62,63""].
The data for both indications are promising and demonstrate the efficacy of palliative ablation of metastases arising from adrenal malignancy in expe- rienced hands. However, ablating metastases within large organs is the traditional indication for thermal ablation and the indication for which currently approved technology has been optimised. This is in contrast to thermal ablation to the adrenal gland itself, which remains challenging.
COMPLICATIONS
HTC, arising from medullary degranulation repre- sents the greatest risk of adrenal ablation irrespec- tive of cortical or medullary aetiology [24"",57,63”]. The risk for medullary degranulation and transient catecholamine crisis is highlighted by two studies in swine that demonstrated transient hypertension and catecholamine crisis with respective use of
MWA and RFA to ablate normal adrenal glands. Catecholamine crisis occurred even when limited ablation of a small adrenal volume <1 cm3 was undertaken with minimal medullary destruction, indicating the risk for widespread medullary degran- ulation even in the presence of limited and localized insult [24"",72]. These findings have been borne out in human studies where HTC is demonstrated in as high as 57% of individuals undergoing ablation [57]. HTC is frequently accompanied by ventricular arrhythmia in the setting of catecholamine excess [48""]. In studies using preprocedural alpha adrener- gic blockade, rates of HTC are reduced significantly for ablation of adrenocortical lesions (Table 2) [63""]. Therefore, peri-procedural alpha blockade should be routinely undertaken for all thermal ablation pro- cedures to the adrenal gland. Additionally, adrenal ablation should only be undertaken following firm biochemical diagnosis of the underlying lesion. Spe- cifically, ablation of large primary phaeochromocy- tomas should reserved for exceptional conditions, where gold-standard therapeutic approach is not possible. and performed following adequate prepro- cedural alpha adrenergic blockade and with peri- procedural anaesthetic support. HTC mandating procedural stoppage and emergency pharmacologi- cal intervention adversely impacts patient safety and therapeutic outcome, as well as carrying signifi- cant health economic implications [40].
Technical complications and structural damage are slightly higher for adrenal ablation when com- pared to ablation in other organs, due to the narrow window of approach [33]. These include pneumo- thorax [39,51,54,57], haemorrhage, vascular throm- bosis and visceral perforation [11,39,54,58,61"",62, 63”] (Table 2). Where patients with Cushing’s syn- drome have been treated, adrenocortical insuffi- ciency, as expected has occurred [53]. Pain is a common minor complication of RFA that requires anaesthetic or sedation, and occurs less frequently with the use of MWA [5].
TECHNICAL CHALLENGES AND IMAGE- GUIDED APPROACHES
Ablation of the adrenal gland remains a highly skilled procedure and presents greater technical challenges for the operator when compared to hepatic or renal ablation [33]. Most currently avail- able thermal ablation technology is not engineered with adrenal therapeutics in mind. At present, approved RFA and MWA delivery systems are engi- neered to treat malignancy within large organs, aiming to ablate large tissue volumes, i.e., targeted tumour plus margins [5,19]. The adrenal is a small gland, affected predominantly by benign adenomas.
Ideal application of adrenal thermal ablation should aim to (i) selectively ablate the offending tumour, while (ii) avoiding nearby critical structures and simultaneously (iii) preserving adjacent normal adrenal, thus minimising the risk of adrenocortical insufficiency and peri-procedural hypertensive cat- echolamine crisis. To optimally achieve these ther- apeutic outcomes mandates the specific design of appropriate applicator antennae [24""].
Current image-guidance for adrenal ablation favours CT fluoroscopy over ultrasound [33]. This imaging modality offers clearer visualisation of the adrenals and critically also identifies adjacent struc- tures, such as lung, colon and major vessels e.g. the splenic artery and the inferior vena cava. Ultrasound does not provide adequate resolution of the adrenal nor the surrounding structures to safely inform probe placement for adrenal ablation [73]. More- over, ultrasound imaging is further hampered by steam generation during the thermal ablation pro- cedure itself [74]. Nonetheless, some investigators have advocated an approach to the left adrenal gland using endoscopic ultrasound [75]. During CT fluoroscopy, patients are placed in the prone or ipsilateral decubitus position [48"",76]. The for- mer provides the largest approach window and minimises the contact between the adrenal and adjacent organs. The latter reduces respiratory excursion of the diaphragm and reduces the trans- pleural path, thereby minimising the risk for pne- muothorax [77]. Hydrodissection can be used in order to increase the space between the targeted adrenal and adjacent critical structures [78]. Advance treatment planning between the interven- tional radiologist and endocrinologist is recom- mended in order to inform the optimum approach with will maximise therapeutic efficacy and patient safety.
FUTURE DIRECTIONS FOR THERMAL ABLATION OF ADRENAL DISORDERS
Thermal ablation, as a therapeutic approach to adre- nal tumours is in its infancy and does not yet represent a feasible routine alternative to gold-stan- dard adrenalectomy. High quality supporting evi- dence for the use of adrenal ablation is not yet available and as such randomized controlled trials and direct head-to-head comparisons with surgery are necessary to fully evaluate its benefit. Undoubt- edly thermal ablation offers promise to increase the scope for delivery of definitive therapy for adrenal endocrinopathies in unilateral and perhaps bilateral disease [24"",69,79]. However, significant challenges remain in the development of the technology. Cur- rent off-the-shelf ablation systems need to undergo
design modifications to facilitate safer approach to the adrenal and to provide precision selective abla- tion of adrenal adenomas. Recent animal studies suggest that side-firing probes may offer superior precision for ablation of adrenal lesions [19,21,24"",25”,26”,28,29"",31,80].
Development of precision treatment planning systems is also necessary. This should incorporate the following (i) high resolution structural imaging, to inform the window of approach [64]; (ii) func- tional [42,81] imaging, to identify the intra-adrenal target and (iii) preprocedural computerized simula- tion [22] of thermal ablation pattern, to inform the dose and duration of ablation. Many of the elements to develop proper treatment planning exist, such as high resolution structural imaging and simulators. However, reliable functioning imaging of adreno- cortical lesions remains a challenge, and modalities such as 11C Metomidate PET/CT are not widely available [42,81].
The management of metastatic lesions arising from adrenal malignancy is also an exciting area for further investigation. The immune editing capabil- ity of thermal ablation has not been studied in this context specifically for adrenal disease. However, emerging data in other malignancies have demon- strated regression of multiple remote metastases following thermal ablation of a single lesion [82]. A possible mechanism for this effect is the marked change in the immunological milieu of these metas- tases, which demonstrate a change in monocyte/ macrophage polarization and a lymphocyte infiltra- tion [17]. It has been suggested that in this regard, thermal ablation may increase the sensitivity of therapy resistant metastases to immune checkpoint inhibitors [83]. This represents an exciting prospect for investigation in the context of improving treat- ment response to immune therapy for lymphocyte poor ACC [84].
CONCLUSION
In summary, thermal ablation of adrenal disease, while in its infancy shows promise but requires significant evidence generation to support its use. With technological advance and improved systems for treatment planning, this modality offers poten- tial to shift the paradigm whereby we approach definitive management of adrenal endocrinopathy, as well as improving the prognosis and overall sur- vival of patients with widespread ACC and PGGL.
Acknowledgements
We thank Anna Bottiglieri, Laura Farina, Kate Warde, and Nathan Mullen for their imput and advice. We also
thank Punit Prakash, Faraz Chamani, and Austin Pfan- nenstiel for contributing the mathematical model images.
Financial support and sponsorship
This work is supported by the National Institutes of Health (NIH) and Science Foundation Ireland.
Conflicts of interest
M.C.D. is currently receiving a grant from the National Institutes of Health (NIH) and Science Foundation Ireland. P.T.D. is carrying out work funded by the National Institutes of Health (NIH) and Science Foun- dation Ireland.
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Demonstrates the development of non penetrative directional probes which are highly useful for the treatment of adrenal tumours.
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Demonstrates the ability of thermal therapy to imporve metastatic adrencortical carcinoma patients quality of life.
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Demonstrates the need for preablation adrenergic blockade in the treatment of any metastatic pheochromocytoma and paraganglioma.
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