Endosonographic Imaging of Benign and Malignant ...

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The Journal of Clinical Endocrinology & Metabolism 89(4):1694 –1697 Copyright © 2004 by The Endocrine Society doi: 10.1210/jc.2003-031709

Endosonographic Imaging of Benign and Malignant Pheochromocytomas P. H. KANN, B. WIRKUS, T. BEHR, K.-J. KLOSE,

AND

S. MEYER

Division of Endocrinology & Diabetology (P.H.K., B.W., S.M.), Department of Nuclear Medicine (T.B.), and Department of Radiology (K.-J.K.), Philipps University Hospital, D-35033 Marburg, Germany Endosonography enables imaging of the adrenal glands, the mediastinum, and the epigastric retroperitoneal area. In this study, the diagnostic power of endosonography regarding the detection and localization of pheochromocytomas and the differentiation between benign and malignant lesions and their metastases and recurrences was investigated. Endosonography was performed using a Pentax FG 32 UA endosonoscope with a longitudinal 7.5-MHz sector array from the esophagus, stomach, and duodenum. A total of 22 pheochromocytomas in 11 patients were studied. All these tumors, recurrences, and metastases were histologically proven except in one single patient where pheochromocytoma had been diagnosed histologically in the past, and actual findings were obvious local recurrence and four metastases. Malignant pheochromocytoma (n ⴝ 10) tended to be larger at the time of examination

E

NDOSONOGRAPHY WITH A LONGITUDINAL sector scan performed from the esophagus, the stomach, and the duodenum enables imaging of the mediastinum, both adrenal glands, and the epigastric retroperitoneal area (1–11). We have previously reported endosonographic imaging to yield higher resolution of the adrenal glands than computed tomography (CT) and magnetic resonance imaging (MRI), with reference to postoperative histology as the gold standard (3), and to be well tolerated by the patients (12). In this study, we addressed the diagnostic power of endosonography in detecting and localizing pheochromocytomas and differentiating between benign and malignant lesions and their metastases and recurrences, taking into account diameter, echogeneity, and echostructure of the tumors. Patients and Methods Endosonography was performed using a Pentax FG 32 UA endosonoscope (Pentax Corporation, Tokyo, Japan) with a longitudinal 7.5 MHz sector array in combination with Hitachi EUB 420 or Hitachi EUB 525 ultrasound computers (Hitachi Medical Corporation, Tokyo, Japan). Clinical indications for performing endosonography were: 1) detection and localization of pheochromocytomas; 2) screening for multiloculated pheochromocytomas/multiple lesions; 3) screening for recurrent and/or metastatic disease; 4) identification of morphologically normal sections of the adrenals in patients with biadrenal pheochromocytomas (planning of surgical strategy); and 5) characterization of adrenal masses in patients presenting with incidentaloma, especially concerning criteria Abbreviations: CT, Computed tomography; MEN, multiple endocrine neoplasia; MIBG, meta-iodobenzylguanidine; MRI, magnetic resonance imaging. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.

than benign pheochromocytoma (n ⴝ 12; P ⴝ 0.069). No significant differences between benign and malignant pheochromocytomas regarding echogeneity and echostructure could be detected. However, hyperechoic echogeneity was seen only in benign lesions, which, however, had variable echogeneity. If confirmed by future observations, hyperechoic echogeneity may be considered to be suggestive of a benign nature. In several cases, endosonography detected small lesions that had been missed by routine diagnostic procedures and yielded helpful information for planning surgical strategy. In conclusion, endosonography is considered to be useful in early detection of pheochromocytomas, and in malignant disease of recurrence and metastases. (J Clin Endocrinol Metab 89: 1694 –1697, 2004)

of malignancy such as local lymph node metastases, angioinvasion, and infiltration of neighboring structures/organs. Informed consent was obtained from each patient. Premedication was performed with 30 mg pentazocine, 10 –30 mg diazepam, and 0.25– 0.5 mg atropine. Examination time was approximately 45 min. The left adrenal gland was imaged from the proximal corpus region of the stomach, and the right adrenal gland from the antrum or the duodenal bulb. Extraadrenal locations were observed from the proximal esophagus down to the horizontal part of the duodenum. A total of 22 tumors (adrenal pheochromocytomas/paragangliomas/ metastatic pheochromocytomas) in 11 patients were studied (Table 1). All these tumors, recurrences, and metastases were histologically proven except for metastases in a single patient where pheochromocytoma had been diagnosed histologically in the past, and meta-iodobenzylguanidine (MIBG) scanning demonstrated local recurrence and four metastases. Pheochromocytomas were characterized endosonographically with regard to: 1) tumor diameter; 2) echogeneity classified as hypoechoic, isoechoic, hyperechoic, or echocomplex (based on visual comparison with the adjacent nontumorous adrenal gland and the kidney); and 3) echostructure classified as homogenous, slightly heterogenous, strongly heterogenous (including cystic/necrotic lesions and calcifications). Ability to discriminate between benign and malignant lesions was analyzed by correlating endosonographic findings with histology and presence or absence of recurrence or metastases on clinical follow-up of the patients (mean ⫾ sd follow-up time, 34 ⫾ 21 months; median, 32 months; range, 7–73 months). Diagnostic value of endosonographic imaging was analyzed by comparing it to findings on CT, MRI, and MIBG scanning for each single tumor. Statistical analysis of the results was performed by using the calculating program SPSS. A P-value in the Mann-Whitney U test of less than 0.05 was considered to be significant.

Results

Malignant pheochromocytomas (n ⫽ 10; 33 ⫾ 17 mm; median, 32 mm; range, 13–70 mm) tended to be larger at the

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TABLE 1. Descriptive data: 22 pheochromocytomas in 11 patients Geneticsa (age and genderb)

Sporadic n ⫽ 6 (28f, 64f, 24m, 51m, 61m, 72m)

Benign or malignantc

Benign Malignant (local recurrence) Malignant (metastasis)

MEN-2a disease, n ⫽ 3 (29f, 36f, 34m)

Benign

vHL disease, n ⫽ 2 (25f, 35f)

Benign Malignant (metastasis)

Localizationc

n

Left adrenal Right paraadrenal region Cardial Left adrenal region (after adrenalectomy)

1 1 1 2

Right adrenal region (after adrenalactomy) Paraaortal Mediastinal Left kidney Right adrenal Left adrenal Right adrenal Left paraadrenal region Paraaortic

1 2 2 1 1 5 3 1 1

Tumor diameter: 6 –20 mm (n ⫽ 11); 21– 40 mm (n ⫽ 8); 41– 60 mm (n ⫽ 2); ⬎60 mm (n ⫽ 1). vHL, von Hippel-Lindau. a Given numbers referring to patients. b f, Female; m, male. c Given numbers referring to tumors.

time of examination than benign pheochromocytomas (n ⫽ 12; 20 ⫾ 10 mm; median, 17 mm; range, 8 –30 mm; P ⫽ 0.069), but the difference did not reach statistical significance. No significant differences between benign and malignant pheochromocytomas could be detected regarding echogeneity and echostructure (Table 2). However, only benign lesions (four of 12) demonstrated hyperechoic echogeneity. In no case of our cohort could angioinvasion or infiltration of neighboring structures be identified. In the following cases, endosonography was diagnostic; whereas conventional imaging techniques were negative, yielded unclear results, or were misleading. 1. In a 64-yr-old female with a history of hypertensive crises over more than 5 yr and several unsuccessful diagnostic attempts elsewhere, a 33-mm intracardial pheochromocytoma was detected in the wall of the right atrium by endosonographic imaging. This patient was the only case where a hypertensive crisis occurred during examination, which happened while passing the esophagus with the endosonoscope. The hypertensive crisis was successfully treated with ␣-adrenergic blockade, and the examination was continued with special attention to the mediastinum. Prior CT of thorax and abdomen and whole-body MIBG scanning were negative. Even knowing the endosonographic finding, it was not easy to confirm the cardiac tumor by reviewing the CT films. During a 19-month period of followup, there has been no evidence of malignancy of this tumor. 2. In a 29-yr-old asymptomatic female with genetically confirmed multiple endocrine neoplasia (MEN)-2a, CT revealed a slight enlargement of the right adrenal gland without clear enhancement, and further evaluation by endosonography was recommended. Endosonography detected a 17-mm adrenal tumor, which appeared typical for pheochromocytoma on MIBG scanning. During a 32-month follow-up period, there has been no evidence of malignancy of this tumor. 3. In a 34-yr-old male without specific symptoms, but with genetically confirmed MEN-2a and histologically proven bilateral pheochromocytomas, MRI (performed elsewhere) revealed two left adrenal tumors, but no abnormality was described for the right adrenal. Endosonography identified a 35-mm tumor within the right adrenal, which was con-

TABLE 2. Echogeneity and echostructure of 10 malignant and 12 benign pheochromocytomas

Echogeneity Hypoechoic Isoechoic Hyperechoic Echocomplex Echostructure Homogenous Slightly heterogenous Strongly heterogenous

Malignant

Benign

6 (60%) 4 (40%)

4 (33%) 2 (17%) 4 (33%) 2 (17%)

2 (20%) 4 (40%) 4 (40%)

2 (17%) 7 (58%) 3 (25%)

firmed by repeated MRI; bilateral adrenal masses were found by CT. MIBG scanning was positive only for the left adrenal, octreotide scanning for the right adrenal. During a 40-month follow-up period, there has been no evidence of malignancy (follow-up time, 40 months). 4. In a 34-yr-old female without specific symptoms, but with genetically confirmed MEN-2a, CT detected two nodules (10and 11-mm diameter, respectively) in the left adrenal, and a possible 6-mm nodule in the right. Endosonography showed three tumors in the left adrenal (16-, 15-, and 8-mm in diameter; Fig. 1), and an 8-mm diameter tumor in the medial part of the right adrenal. The lateral part of the right adrenal appeared normal. The findings on MIBG scanning were compatible with pheochromocytoma in the left adrenal and possible pheochromocytoma in the right adrenal. The patient underwent total left-sided adrenalectomy and subtotal right-sided adrenalectomy, leaving the lateral part of the right adrenal in situ. The patient needed substitution of hydrocortisone for 6 months and, since then, has not required medical treatment for adrenal insufficiency. During 31 months of follow-up, there has been no evidence of malignancy. 5. In a 24-yr-old male with recurrent and metastatic malignant pheochromocytoma of the left adrenal (Fig. 2), after normal MRI and CT of the right adrenal, endosonography detected a 15-mm diameter tumor strongly suspected of being a pheochromocytoma within the right adrenal, which was also suspected after reviewing the original MRI. MIBG scanning was negative. The diagnosis was proven by histology.

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FIG. 1. Enlarged left adrenal gland in a 34-yr-old female with MEN2a; endosonographic imaging shows three pheochromocytomas (8 –13 mm in diameter) with slightly different echogeneity (diagnosis proven by histology).

For endosonographic imaging, ␣-adrenergic blockade was not performed as a premedication. Blood pressure was assessed continuously during the whole examination and for a 30-min period thereafter. Besides one hypertensive crisis in a case of cardiac pheochromocytoma (case 1), which was successfully treated with ␣-adrenergic blockade and was no reason for termination of the examination, no other adverse events were observed. No tumors located in the diagnostic range (lung and bone metastases are outside the diagnostic range) were missed by endosonography but detected by other means. Discussion

It is not always easy to distinguish benign from malignant pheochromocytoma, even if a tumor has been surgically removed and is completely accessible for histopathological examination. Clear criteria of malignancy are metastases, invasive growth, and vascular invasion (13, 14), but the absence of these features does not confirm benignancy (15–17). Thus, efforts have been made to identify clinical characteristics (14, 18, 19) and, in particular, histopathological markers capable of predicting prognosis in patients with pheochromocytoma (14, 20 –26). Pheochromocytomas can be localized using MIBG scanning (27, 28). If MIBG uptake of a pheochromocytoma is low or absent, this is highly suggestive for malignancy. However, positive tumors can be benign or malignant. The ability of MIBG scanning to detect pheochromocytomas depends on tumor size and its differentiation, which is correlated to its ability to accumulate the tracer (29, 30). A subgroup of pheochromocytomas can be visualized by octreotide scintigraphy, in some cases of malignant disease tumors that are negative by MIBG scanning (30 –33). For both CT and MRI, criteria exist for differentiating pheochromocytoma from other adrenal masses (34 –39). However, a considerable overlap between the MRI appearance of pheochromocytoma and other adrenal lesions has been reported (40). Even these techniques are unable to differentiate benign from malignant tumors, if neither invasive

Kann et al. • Endosonographic Imaging of Pheochromocytomas

FIG. 2. Paraaortic metastasis (8-mm diameter) of a malignant pheochromocytoma in a 24-yr-old male with sporadic disease; endosonography shows a hypoechoic paraaortic node with slight hyperperfusion, in color-coded duplex imaging, considered as local metastasis (diagnosis highly likely, given known histology of the primary, local recurrence, other metastases, and clinical follow-up).

growth nor metastases can be shown (41). Small adrenal tumors can be missed by these diagnostic procedures, which may be detected by endosonography (3). Our data show that, in some cases, endosonography can detect pheochromocytomas that have been missed by other diagnostic procedures, and can provide relevant data for planning surgical strategy. Endosonography was unable to differentiate between benign and malignant tumors in this study. In contrast to other studies published earlier and using other methods (42, 43), in our cohort, malignant tumors were not significantly larger than benign tumors. This is probably due to the fact that endosonography, which was used in the follow-up of patients with malignant pheochromocytomas, was able to detect small recurrences and metastases. Besides one hypertensive crisis (case 1), which was successfully treated with iv ␣-adrenergic blockade and was no reason for termination of the examination, no other adverse events were observed. However, when performing endosonography for suspected pheochromocytoma, premedication with ␣- and ␤-blockers should be considered, especially in patients with elevated urinary catecholamine levels (especially when there is not much experience with this diagnostic procedure in pheochromocytomas) until more experience with this technique and in this clinical setting has been accumulated. Availability of an ␣-blocker for iv use is mandatory. In conclusion, endosonography appears capable of detecting small pheochromocytomas that are missed by routine diagnostic procedures and may provide helpful information for planning surgical strategy. Not unexpectedly, endosonographic imaging of pheochromocytoma is of limited value in differentiating benign from malignant tumors. As observed by conventional sonography (44), pheochromocytomas demonstrate a broad spectrum of sonographic features also in endosonographic imaging. Based on our data, hyperechogeneity favors a benign lesion, because we have not, so far, seen it in a proven malignant one. Benign tumors were more often heterogenous than homogenous. Endosonography may be especially useful in early detection of pheochromocytoma in sub-

Kann et al. • Endosonographic Imaging of Pheochromocytomas

jects with genetic disorders predisposing to the development of pheochromocytoma, such as MEN-2a/b-disease, von-HippelLindau disease, and neurofibromatosis type 1. In malignant disease, some recurrences and metastases might be detected earlier by this technique than by other diagnostic approaches. Received October 1, 2003. Accepted January 13, 2004. Address all correspondence and requests for reprints to: Peter Herbert Kann, M.D., Professor of Endocrinology, Head, Division of Endocrinology and Diabetology, Philipps University Hospital, D-35033 Marburg, Germany (EU). E-mail: [email protected].

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JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.