Computed Tomography-Guided Percutaneous Acetic Acid Injection ...

0021-972X/03/$15.00/0 Printed in U.S.A.

The Journal of Clinical Endocrinology & Metabolism 88(12):5814 –5817 Copyright © 2003 by The Endocrine Society doi: 10.1210/jc.2003-030530

Computed Tomography-Guided Percutaneous Acetic Acid Injection Therapy for Functioning Adrenocortical Adenoma SHIGERU MINOWADA, TETSUYA FUJIMURA, NAOKI TAKAHASHI, HIROICHI KISHI, KANEHIRO HASUO, AND MANABU MINAMI Departments of Urology (S.M., T.F., H.K.) and Radiology (N.T., K.H.), International Medical Center of Japan, Tokyo 1628655, Japan; and Department of Radiology (M.M.), Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan We reported the outcomes of computed tomography (CT)guided percutaneous acetic acid injection therapy for functioning adrenocortical adenomas. With the patient in a prone position, the puncture needle was inserted vertically downward into the adenoma with frequent CT scanning. After confirmation by pilot injection with contrast medium, a small aliquot of 40 –50% acetic acid was injected and repeated. Between 1997 and 2002, 18 sessions of CT-guided injection therapy, including one session of ethanol injection, were performed on 10 patients (five patients with primary aldosteron-

ism and five patients with Cushing’s or subclinical Cushing’s syndrome) without any complications except transient upper abdominal pain during the acetic acid injection. The follow-up period ranged from 5– 69 months. The treatment resulted in almost an extirpation of the adrenocortical hyperfunction in seven patients after one or two sessions. CT-guided percutaneous acetic acid injection might be a simple, cost-effective, and far less invasive treatment for small functioning adrenocortical adenomas. (J Clin Endocrinol Metab 88: 5814 –5817, 2003)

P

[131I]Adosterol scintigrams showed unilaterally increased uptake at the tumor sites. Hypertension and hypopotassemia were normalized before the treatment sessions by the administration of spironolactone, 50 –100 mg a day. The five patients with Cushing’s syndrome or subclinical Cushing’s syndrome were confirmed by findings of increased serum cortisol on circadian changes, suppressed ACTH, and clinical features (Table 2). The cortisol levels remained above 3.0 ␮g/dl after overnight suppression with 1 mg dexamethasone. [131I]Adosterol scintigrams showed unilateral uptake, and CT scans showed adrenal tumors ranging from 16 –38 mm in diameter. A dosage of hydrocortisone, 10 mg a day, was administrated for 2– 4 wk after the injections.

ERCUTANEOUS ETHANOL INJECTION (PEI) has been commonly used as a simple and effective treatment for hepatocellular carcinomas measuring 3 cm or less in diameter (1, 2). In addition, PEI has also been employed for the treatment of endocrine tumors of the thyroid and parathyroid (3, 4). On the other hand, the use of a high concentration of acetic acid instead of ethanol has achieved safer and stronger cytotoxic effects in both animal studies and the clinical treatment of hepatocellular carcinomas (5, 6). Acetic acid induces swelling of the fibers and promotes dissociation of collagen in the tumor tissue owing to its low pH. With respect to therapy for the adrenal gland, only a small number of patients with adrenocortical solid tumors have been successfully treated by percutaneous injection treatment (7, 8). In a previous paper published in 2000 we reported the preliminary results of three cases treated with computed tomography (CT)-guided acetic acid injection therapy (9). Here we present 10 cases with adrenal functioning adenoma, including five cases with primary aldosteronism and five with Cushing’s syndrome, who underwent CTguided percutaneous acetic acid injection (PAI) therapy between 1997 and 2002. Patients and Methods Patients The PAI treatment was performed on 10 patients aged a mean of 50 yr (range 32– 67 yr) who presented with hormonally functioning adrenocortical adenomas. Five hypertensive patients showed the following biochemical data: hypopotassemia, high serum aldosterone levels, and low plasma renin concentration (Table 1). CT scans revealed tumors of the adrenal gland with tumor diameters ranging from 10 –20 mm. Abbreviations: CT, Computed tomography; PAI, percutaneous acetic acid injection; PEI, percutaneous ethanol injection.

Methods The patient was placed prone on the bed of a CT scanner. The scout scan confirmed the location of tumor, the appropriate puncture point on the skin vertically above the tumor, and the distance from the puncture point to the tumor (Fig. 1A). We used the same type of needle used for treatment of hepatocellular carcinoma, a 21-gauge PEI puncture needle with three pores 4 mm from the tip (Hakko Shoji Co., Tokyo, Japan). The needle was inserted along the puncture line toward the adenoma with frequent CT scanning. The monitoring was repeated four to six times until we delivered the needle tip precisely inside the tumor (Fig. 1B). After confirmation by pilot injection of 1% lidocaine hydrochloride mixed with approximately 10% contrast medium, an aliquot of 0.5 ml of 40 –50% acetic acid with 10% contrast medium was injected and repeated with repetitive CT imaging (Fig. 1C). When the injection fluid leaked outside the tumor, the treatment session was stopped. The patient was monitored carefully during and after the treatment procedures. All patients were followed by regular hormonal examinations and CT scans. If the first PAI treatment did not achieve success, subsequent PAI sessions were planned at intervals of 4 – 8 months. This study was approved by the local ethical committee and conducted in accordance with the Helsinki Declaration. Informed written consent was obtained from the patients.

Results

Eighteen sessions of CT-guided injection therapy (17 PAIs and one PEI) were performed on five patients with primary

5814

Minowada et al. • PAI for Functioning Adrenal Adenoma

J Clin Endocrinol Metab, December 2003, 88(12):5814 –5817 5815

TABLE 1. Patient characteristics, PAI treatment, and clinical outcome in primary aldosteronism Case no.

Age (yr)

Sex

1 2 3 4 5

56 37 45 32 67

F M M M F

Plasma aldosterone (pg/ml)

Plasma renin (pg/ml)

Tumor diameter (mm)

630 770 480 490 660

2.4 ⬍2.0 2.1 2.5 2.0

20 19 20 17 10

PAI treatment (injection volume in ml) 1st

2nd

3rd

1.2 2.0 2.0 1.5 0.5

3.0a 1.2

1.2

1.5 1.0

Follow-up (months)

Plasma aldosterone (pg/ml)

Tumor diameter (mm)

69 55 45 35 8

78 234 90 98 125

6 11 6 8 7

Normal range for plasma aldosterone, 30 –200 pg/ml; for plasma renin, 2.5–21.4 pg/ml. PEI.

a

TABLE 2. Patient characteristics, PAI treatment, and clinical outcome in Cushing’s syndrome

Case no.

1 2 3 4 5

Age (yr)

62 53 45 59 43

Sex

F F M M M

Hypertension

⫹ ⫹ ⫹⫹ ⫹⫺ ⫹⫺

Central obesity

⫹ ⫹ ⫺ ⫺ ⫺

Plasma ACTH (pg/ml)

10.0 ⬍5.0 8.6 12.9 5.9

Tumor diameter (mm)

Serum cortisol (␮g/dl) Basal

1 mg DST

13.9 14.9 19.2 16.9 25.2

5.1 14 5.6 8.6 10.7

16 27 38 30 18

PAI treatment (injection volume in ml) 1st

2nd

1.0 5.0 8.0 3.5 2.5

2.0 4.5 2.5

Follow-up (months)

22 18 14 13 5

Serum cortisol (␮g/dl) Basal

1 mg DST

16.5 10.9 6.8 9.1 11.9

7 1.4 1.5 1.5

Tumor diameter (mm)

13 21 29 25 16

Normal range for plasma ACTH, 9 –52 pg/ml; for serum cortisol, 3.8 –18.4 ␮g/dl; for serum cortisol after 1 mg dexamethasone overnight suppression test (DST), ⬍3.0 ␮g/dl.

FIG. 1. CT scan images during the PAI with the patient in a prone position. A, The appropriate skin point was selected. B, The needle was inserted and placed precisely within the tumor after repetitive CT monitoring. C, Acetic acid solution containing contrast medium was injected.

aldosteronism and five patients with Cushing’s syndrome without any serious complications except transient upper abdominal pain between 1997 and 2002. The duration of the puncture procedure varied from 45–120 min. Hospitalization had been 6 – 8 d in primary aldosteronism and 10 –14 d in Cushing’s syndrome, respectively. The follow-up period ranged from 5– 69 months. Follow-up CT scans revealed regression of the tumor size in all cases (Tables 1 and 2). One or two PAI sessions brought about a good outcome in four of the five patients with primary aldosteronism at a mean follow-up period of 42.4 months (Table 1). Plasma aldosterone levels fell to within normal range, and blood pressures returned to normotensive. In case 1 the CT image at 69 months showed a cystic degenerative tumor with marked regression of tumor size in contrast to before treatment (Fig. 2). The levels of plasma aldosterone have been kept normal over 5 yr. The remaining patient, case 2, with plasma aldosterone of 234 pg/ml, required a prescription of spironolactone, 25 mg a day, after three PAI sessions.

The clinical outcomes of the five patients with Cushing’s syndrome or subclinical Cushing’s syndrome are presented in Table 2. Case 1 could not undergo surgery using general anesthesia due to chronic heart failure and severe diabetes mellitus. The serum cortisol levels were normalized a few months after the two PAIs, but cortisol levels and blood pressure had soon risen. The hyperproduction of cortisol was almost extirpated by one or two sessions in cases 3, 4, and 5. The cortisol levels after overnight suppression with 1 mg dexamethasone were reduced to ⬍2.0 ␮g/dl. Follow-up CT images in case 3 obtained at 5 and 11 months showed cystic degenerative change with tumor regression (Fig. 3). The basal cortisol levels slightly increased for a few days after PAI and then reduced into the normal range. All the patients experienced transient upper abdominal pain associated with elevation in blood pressure during the acetic acid injection. Most of the patients needed one iv injection of 15 mg pentazocine for pain relief. One patient, case 4 with Cushing’s syndrome, experienced severe pain in

5816

J Clin Endocrinol Metab, December 2003, 88(12):5814 –5817


FIG. 2. Follow-up CT images showed cystic change with marked regression of tumor size and changes of plasma aldosterone in case 1 in the primary aldosteronism group. A, Before treatment. B, CT image with oil contrast medium 12 months after PAI. C, CT image 69 months after PAI. D, The basal levels of plasma aldosterone have been kept normal over 5 yr.

FIG. 3. Follow-up CT scans showed cystic change with tumor regression and changes of serum cortisol in case 3 in the Cushing’s syndrome group. A, Before treatment. B, CT image 5 months after PAI. C, CT image 11 months after PAI. D, Slight elevation of basal cortisol levels was temporarily observed after PAI, and then cortisol levels were reduced into normal range.

the upper abdomen and marked hypertension at the initial injection of a small amount of acetic acid, prompting us to discontinue the PAI session immediately. In the second PAI procedure, the use of epidural local anesthesia eliminated all pain and other complaints in this case.

Discussion

Laparoscopic adrenalectomy has been widely employed for various adrenal lesions as a less invasive therapy in recent years (10 –12). However, some complications involving major vascular injuries have been known to occur, mostly at the


beginning of the learning curve (11, 12). In our study, 18 percutaneous injection procedures were performed in 10 cases with adrenocortical adenoma without any adverse complications. Excellent clinical outcomes were obtained in seven of those patients after one or two injections. The most important practical point of acetic acid injection is to minimize the injection volume per shot. An excess of injection volume in a single session to achieve complete tumor ablation should be avoided, because the PAI treatment can be repeated at appropriate intervals. Because we became used to achieving PAI, we believe that a small aldosteronoma can be treated with single session with one night of hospitalization. Compared with laparoscopic adrenalectomy, CTguided PAI or PEI is a simpler, more cost-effective, and far less invasive treatment for small, hyperfunctioning adrenocortical tumors. CT-guided adrenal intervention at the posterior approach is considered a safe procedure. In most cases, the procedure can be performed very easily and reliably to insert the puncture needle into the adrenal tumor vertically. On the other hand, the puncture involves the risk of pneumothorax when the lower edge of the lung extends downward over the adrenal gland. In these cases we should employ the angled CT gantry method (13). However, the angled gantry procedure to avoid pneumothorax could not achieve tumor ablation in cases 1 and 2 of the Cushing’s syndrome group. A disadvantage of the injection therapy is the lack of histological confirmation of the lesions. However, we have so far experienced a large number of adrenocortical lesions, including primary aldosteronism, Cushing’s syndrome, and incidentally discovered adrenal tumors (14 –17). Owing to the various advanced diagnostic examinations such as endocrinological survey, CT scan, magnetic resonance imaging, and scintigraphy, accurate pretreatment diagnosis is now feasible in almost all cases. Tumor malignancy should be considered when the following findings are encountered: larger than 4 cm in diameter, faster velocity of tumor growth, irregular tumor shape, and heterogeneity of tumor contents (14 –17). We propose that PAI may be a good alternative for the treatment of functioning adrenocortical adenomas, especially in high-risk patients for surgical treatment. Furthermore, with the recent amazing advances in medical technologies such as radiofrequency ablation and robotic surgeries (18 –20), the development of a novel interventional treatment can be anticipated in the near future. Acknowledgments Received March 26, 2003. Accepted August 24, 2003.

J Clin Endocrinol Metab, December 2003, 88(12):5814 –5817 5817

Address all correspondence and requests for reprints to: Shigeru Minowada, Department of Urology, International Medical Center of Japan, 1-21-1, Toyama, Shinjuku-ku Tokyo, 162-8655, Japan. E-mail: [email protected].

References 1. Ebara M, Ohto M, Sugihara N, Okuda K, Kondo F, Kondo K 1990 Percutaneous ethanol injection for the treatment of small hepatocellular carcinoma: study of 95 patients. J Gastroenterol Hepatol 5:616 – 626 2. Livraghi T, Giorgio A, Marin G, Salmi A, Siode I, Bolondi L, Pompili M 1995 Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 197:101–108 3. Bennedbc´k FN, Karstrup S, Hegedu¨s L 1997 Percutaneous ethanol injection therapy in the treatment of thyroid and parathyroid diseases. Eur J Endocrinol 136:240 –250 4. Zingrillo M, Collura D, Ghiggi MR, Nirchio VN, Trischitta V 1998 Treatment of large cold benign thyroid nodules not eligible for surgery with percutaneous ethanol injection. J Clin Endocrinol Metab 83:3905–3907 5. Ohnishi K, Yoshioka H, Ito S, Fujiwara K 1998 Prospective randomized controlled trial comparing percutaneous acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma. Hepatology 27:67–72 6. Lau WY, Leung TWT, Yu SCH, Ho SKW 2002 Percutaneous local ablative therapy for hepatocellular carcinoma. A review and look into the future. Ann Surg 237:171–179 7. Rossi R, Savastano S, Tommaselli AP, Valentino R, Iaccarino V, Tauchmanova L, Gigante M, Luciano A, Lombardi G 1995 Percutaneous computed tomography-guided ethanol injection in aldosterone-producing adrenocortical adenoma. Eur J Endocrinol 132:302–305 8. Liang H-L, Pan H-B, Lee Y-H, Huang J-S, Wu TDL, Chang C-T, Liang H-L, Yang T-L, Yang C-F 1999 Small functional adrenal cortical adenoma: treatment with CT-guided percutaneous acetic acid injection: report of three cases. Radiology 213:612– 615 9. Minowada S, Enomoto Y, Korenaga T, Kamijo T, Homma Y, Kitamura T 2000 CT-guided acetic acid injection therapy for aldosterone-producing adrenocortical adenoma: a preliminary report of three cases. Endocr J 47:185–189 10. Higashihara E, Tanaka Y, Horie S, Aruga S, Nutahara K, Minowada S, Aso Y 1993 Laparoscopic adrenalectomy: the initial 3 cases. J Urol 149:973–976 11. Gagner M 1996 Laparoscopic adrenalectomy. Surg Clin N Am 76:523–537 12. Meria P, Kempf BF, Hermieu JF, Plouin PF, Duclos JM 2003 Laparoscopic management of primary hyperaldosteronism: clinical experience with 212 cases. J Urol 169:32–35 13. Hussian S 1996 Gantry angulation in CT-guided percutaneous adrenal biopsy. Am J Roentgenol 166:537–539 14. Barzon L, Scaroni C, Sonino N, Fallo F, Gregianin M, Macri C, Boscaro M 1998 Incidentally discovered adrenal tumors: endocrine and scintigraphic correlates. J Clin Endocrinol Metab 83:55– 62 15. Mantero F, Terzolo M, Arnaldi G, Osella G, Masini M, Ali A, Giovagnetti M, Opocher G, Angeli A 2000 A survey on adrenal incidentaloma in Italy. J Clin Endocrinol Metab 85:637– 644 16. Bulow B, Ahren B 2002 Adrenal incidentaloma: experience of a standardized diagnostic programme in the Swedish prospective study. J Intern Med 252: 239 –246 17. Ng L, Libertuno JM 2003 Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol 169:5–11 18. Wood BJ, Abraham J, Hvizda JL, Alexander HR, Fojo T 2003 Radiofrequency ablation of adrenal tumors and adrenocortical carcinoma metastases. Cancer 97:554 –560 19. Desai MM, Gill IS, Kaouk JH, Matin SF, Sung GT, Bravo EL 2002 Roboticassisted laparoscopic adrenalectomy. Urology 60:1104 –1107 20. Bentas W, wolfram M, Brautigam R, Binder J 2002 Laparoscopic transperitoneal adrenalectomy using a remote-controlled robotic surgical system. J Endourol 16:373–376