Radiofrequency Thermal Ablation of Hepatic Metastases of Adrenocortical Cancer - A Case Report and Review of the Literature
Authors
Affiliation
J. Bauditz®, M. Quinkler®, W. Wermke
Internal Medicine, Center for Gastroenterology, Hepatology and Endocrinology, Charité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany
Key words
· hepatic metastases
adrenocortical cancer radiofrequency thermal ablation
· heat sink effects
liver
Abstract
& Aim: Radiofrequency thermal ablation (RFA) has shown promise as a technique for treating solid tumors. This method has been suggested as an alternative to surgery in patients with adreno- cortical carcinoma (ACC).
Materials and Methods: We reviewed the liter- ature, and report the case of a patient with stage 4 ACC who received intraoperative and percuta- neous RFA of two liver metastasis according to a standard ablation protocol.
Results: Post-interventional imaging in our patient demonstrated that after both interven- tions, a stellar-like structure of vital tumor tissue
had remained within the coagulation necrosis. This was the starting point of a fast and progres- sive tumor recurrence. We suspect heat-sink effects of blood vessels in the highly vascular- ized metastasis to cause the tumor recurrence. In literature, there are only a few reports of RFA in ACC patients. In addition, there is no large ran- domized trial investigating the efficacy of RFA against surgery in those patients.
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Conclusions: Presently, RFA in ACC should be restricted to patients in whom surgery is con- traindicated. It is necessary that strongly vas- cularized ACC metastases deserve a modified ablation protocol due to perfusion related cool- ing effects and to increase the efficacy of RFA.
received 29.02.2008 first decision 11.04.2008 accepted 20.08.2008
Bibliography DOI 10.1055/s-0028-1087178 Published online: December 3, 2008 Exp Clin Endocrinol Diabetes 2009; 117: 316-319
@ J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart . New York ISSN 0947-7349
Correspondence M. Quinkler, MD Internal Medicine
Center for Gastroenterology Hepatology and Endocrinology Charité Campus Mitte Charité University Medicine Berlin Charitéplatz 1 10117 Berlin Germany Tel .: +49/30/450 51 41 52
Fax: +49/30/450 51 49 52 marcus.quinkler@charite.de
Introduction &
Adrenocortical carcinoma (ACC) is a rare (1-2 per million and per year) and heterogeneous malig- nancy with incompletely understood pathogen- esis and poor prognosis (Wajchenberg et al., 2000; Abiven et al., 2006; Allolio and Fassnacht, 2006). Patients present with evidence of adrenal steroid hormone excess (Cushing’s syndrome, hyperandrogenemia, estrogen excess or hyper- mineralocorticolism) in approximately 60% of cases (Koschker et al., 2006). Surgery is the basis for the treatment since complete removal (R0 resection) of a localized tumor is the best chance for a cure (Schteingart et al., 2005). Local recur- rence is frequent, especially after a rip in the tumor capsule. Incomplete resection of the pri- mary tumor or metastatic disease not amenable to surgery is associated with a particulary poor prognosis. To date there is no medical treatment that has convincingly been shown to provide a definitive solution in locally invasive and/or met- astatic ACCs. However, patients with no surgical
approach should receive mitotane alone or in combination with cytotoxic drugs (Allolio and Fassnacht, 2006). Tumor debulking may help to control hormone excess and may in individual cases open the possibility of other therapeutic options (Allolio and Fassnacht, 2006). However, the drawback of a local or regional treatment is the occurrence of new metastases in the same or other organs.
Radiofrequency thermal ablation (RFA) has shown promising effects as a technique for treat- ing solid tumors involving the liver, kidney, bone and lung in selected patients (Solbiati et al., 2001; Livraghi et al., 1999; de Baere et al., 2006; Goetz et al., 2004). For liver tumors of different origin, the local efficacy of RFA was reported to lie between 60 and 96%, depending on tumor size, ablation devices/protocols and tumor location. Therefore this method has been suggested as an alternative to surgery in some patients with ACC. This article provides a review of RFA in ACC and reports a case, which highlights the need for spe- cific RFA protocols.
‘Both authors contributed equally to this work.
Case Report
& A 30 year old woman, who had been diagnosed a stage 4 corti- sol-producing ACC 18 months previously, was primarily oper- ated and received mitotane treatment in combination with etoposide, doxorubicin and cisplatin (EDP) chemotherapy (ini- tial tumor burden before chemotherapy: 70mm as sum of long- est diameter of all target lesions including one liver metastasis of 30 mm). After initial partial response, progression of disease occurred after six cycles of EDP, and therapy was switched to mitotane and streptozotocin. Eight weeks later, after two cycles of streptozotocin local recurrence in the right adrenal region, progression of the existing liver metastasis, and a new liver metastasis appeared. The patient was switched to a salvage ther- apy with gemcitabine (800 mg/m2 every 2 weeks) and erlotinib (100 mg/d). Mitotane was continued to control cortisol excess with mitotane serum levels between 16-19mg/l. In addition, the local recurrence was surgically removed and the two liver metastases (size 45mm [volume 41 ml] and 38mm [32 ml], respectively) were intraoperatively treated with RFA guided by intraoperative ultrasound by use of a 5cm LeVeen needle (umbrella design with multiple spikes) electrode RFA system (Boston Scientific, USA). The tumor burden before this second operation was 230mm (sum of longest diameter of target lesions). Treatment started at the smaller (38 mm) metastasis. After needle placement and full opening of the umbrella, abla- tion was initiated at 100 Watt (W) and increased in 10W incre- ments each 30s to a maximum of 150W. After roll-off was achieved after 3.5 min heating at 150W, a second burn was started at 80W. After 5 min energy was increased in 10W incre- ments each 30s to a maximum of 200W. Second roll-off was achieved after 2 min heating at 200W. The same procedure was performed with the larger (45 mm) metastasis. After full open- ing of the umbrella, ablation was initiated at 100 W and increased in 10-W increments each 30 s to a maximum of 150 W. After roll- off was achieved after 4.5 min heating at 150W, a second burn was started at 80W. After 5 min energy was increased in 10W
increments (each 30s) to a maximum of 200 W. Second roll-off was achieved after 4 min heating at 200 W. The whole procedure lasted for approximately 50 min. Upon needle removal the nee- dle track was cauterized to decrease the risk of needle track seeding and to prevent track bleeding.
To evaluate response we postoperatively performed conven- tional ultrasound and contrast-enhanced sonography after one and three weeks. One metastasis was completely ablated and remained free of tumor during further follow-up. Within the other lesion, first evaluation after one week showed the unusual finding of a coagulation necrosis with a stellar-like structure of vital tumor tissue within the ablated area (· Fig. 1A, · Fig. 3). Further follow-up demonstrated rapid invasion of tumor cells into the ablated region ( Fig. 1B). Another percutaneous RFA for reduction of tumor masses was performed 6 weeks later. Due to the insufficient previous ablation, an ablation protocol with prolonged ablation time with a mean heating temperature of 105°C was chosen to assure constant high temperatures within all tumor regions (RITA XL Le Veen-type needle device, RITA Medical Systems, USA). The needle was initially positioned in the posterior part of the tumor. Ablation started with 2 cm abla- tion diameter and stepwise (each step 1 cm) extension of abla- tion area to 5cm. In all 5 temperature-measuring spikes, a temperature of at least 95 ℃ was awaited until spikes were fur- ther extended. After extension to 4cm, heating was performed for 4min before further extension to 5cm. After spikes were fully expanded, all 5 temperature control tips indicated stable temperatures of >97℃ during ablation. After target tempera- ture at full 5 cm-extension was achieved, heating was performed for 12 min. After completion of the first ablation the needle was repositioned in a position 2.5 cm proximal of the initial position and ablation repeated. Control tips again indicated stable tem- peratures of >97℃ during ablation. The whole procedure lasted for 50 min ( Fig. 2A). Upon needle removal the needle track was ablated. After the procedure, the patient suffered from sub- febrile temperatures, showed elevated liver enzymes and needed pain medication. Despite of this intensified RFA procedure, a
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similar incomplete tumor necrosis, comparable to the initial ablation, was observed. Again, the unusual finding of a coagula- tion necrosis with a stellar-like structure of remaining vital tumor tissue within the ablated area was observed (· Fig. 2B). In both cases, the regrowth may have started from tumor cells adjacent to intact vessels in the center region of the tumor, which may have survived due to heat-sink effects caused by blood stream-induced cooling. This highlights a possible major prob- lem in highly arterial vascularized ACC metastases, which may increase the risk of tumor recurrence. The patient died five months after the second RFA procedure.
Discussion
&
There is no large randomized trial investigating the efficacy of RFA in patients with ACC against surgery. Recently de Baere et al. (de Baere et al., 2006) reported the first patients with metastatic ACC, who underwent RFA of the lung. In the follow-up local tumor recurrence appeared six months after treatment. Wood et al. (Wood et al., 2003) described RFA therapy in eight ACC patients. In these patients 15 lesions were ablated including 5 local recurrences in the adrenal region, 2 local recurrences invading the kidney, 2 paraspinal local recurrences, 5 liver metastases and 1 bone metastases. The follow-up was done for up to two years. They reported a decreased tumor size in 8 of the 15 ablated tumors, four tumors had no change in size, and three tumors showed continuous growth after RFA (Wood et al., 2003). The authors concluded that RFA seems to be safe and well toler- ated, and that better results were achieved with smaller lesions. However, Wood et al. did not provide any clinical or treatment data on their eight ACC patients, apart from stating that no patient had hypercortisolism. From the same group a previous report described RFA therapy in four patients including ablation of two liver, two adrenal bed, two renal hilum, one infrarenal and one paraspinal metastasis (Abraham et al., 2000). It is not clear if those patients were also included in the more recent
publication of the group (Wood et al., 2003). The four patients received RFA therapy 5-6 years after the date of original diagno- sis and were pretreated with mitotane and chemotherapy. No information on hormonal data was given. Regarding the long survival of the patients (Abraham et al., 2000), we hypothesize that these patients might have suffered from a less aggressive ACC subgroup.
However, these three small series suggest that RFA may be an alternative to surgery in some patients with metastatic ACC and smaller sized lesions, but the clinical data is to scarce to give any recommendation. In addition, its potential benefits have to be weighed against complications (Schteingart et al., 2005; Rhim et al., 2004; Brown, 2005). Percutaneous RFA is relatively easy to repeat, has a lower morbidity and lower cost than an operation. Generally, it is conceivable that repeated percutaneous RFA stresses the immune system less than repeated surgical resec- tions (Wood et al., 2003). However, tumors located at the liver capsule with close contact to other organs have been associated with an increased risk of complications (bleeding, gastrointesti- nal perforations and others), while locations near large vessels have been associated with a risk of incomplete ablation. In addi- tion, tissue around greater vessels is heat-protected by a perma- nent cooling effect of the bloodflow, which is speculated to increase the risk of tumor recurrence in regions adjacent to larger blood vessels (Wood et al., 2003; Lu et al., 2003; Gillams and Lees, 2000; Hori et al., 2003). However, other studies in patients with hepatocellular carcinoma or liver metastases did not find such an association (Curley et al., 1999; Komorizono et al., 2003). Generally, best results are achieved in lesions smaller than 3-4cm, however with new needle devices larger ablation areas of up to 7 cm were reported (Livraghi et al., 1999; Livraghi et al., 2000). For optimal efficacy, not only the lesion itself should be completely ablated, but also a surrounding mar- gin of 1 cm.
Insufficient tumor ablation due to cooling effects related to large vessels has been implicated in increased rates of tumor recur- rence (Lu et al., 2003). In our reported case, the stellar structures of remaining vital tumor tissue indicate that the tumor tissue located between the single spikes was not sufficiently heated. In contrast to liver metastases from colorectal cancer or other can- cers of epithelial origin, metastases of adrenocortical cancer are highly vascularized lesions, which may influence ablation char- acteristics. The insufficient perivascular ablation within the center of the tumor tissue in our patient raises the suspicion that standard ablation protocols may not always obtain sufficient results in highly vascularized lesions. Prolonged ablation or higher temperatures may be required for complete ablation of these tumors. Occlusion of portal or venous vessels by clamping or ballon dilatation, respectively, has been proposed to more suf- ficiently ablate perivascular tumor regions (de Baere et al., 2002; Chok et al., 2005; Yamasaki et al., 2002). However, the potential of additional vascular blockade, e.g. hepatic artery embolisation, has still to be evaluated.
It is important to emphasize that our patient had very advanced and aggressive ACC and was heavily pre-treated. We cannot exclude that RFA therapy may be more effective on ACC when it is used at an earlier stage of disease and on smaller liver lesions, as desribed in previous reports (Abraham et al., 2000; Wood et al., 2003; de Baere et al., 2006). In addition, the liver metasta- sis in our patient, which did not respond to RFA therapy, existed from the very beginning of the disease. Initially, this hepatic lesion responded to EDP chemotherapy, then progressed and
was not influenced by streptozotocin or by gemcitabine/erlotinib therapy. Therefore, this growth pattern and unresponsiveness to treatment suggests resistent and robust tumor cells and might explain the incomplete effect of RFA therapy.
In conclusion, this case reinforces the need for sufficient ablation time and temperature in highly-vascularized lesions. Investiga- tors should be aware of unexpected strong cooling effects and modify the ablation procedure accordingly. In general, RFA in ACC should be limited to patients in whom surgery is contrain- dicated. Generally, best results seem to be obtained in tumors smaller than 30-40 mm (Wood et al., 2003), however the effi- cacy in highly arterial vascularized ACC metastases and aggres- sive ACC disease needs to be proven (Wood et al., 2003; Lin et al., 2004). A randomised trial is needed to investigate the efficacy of RFA in metastatic ACC, and its impact on survival.
Conflict of interest: None.
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