C. Proye . M. Jafari Manjili . F. Combemale F. Pattou . O. Ernst . B. Carnaille . J. L. Wemeau
Experience gained from operation of 103 adrenal incidentalomas
Received: 28 January 1998 / Accepted: 16 June 1998
Abstract Background: Adrenal incidentaloma poses a perplexing problem for physicians. The challenge is to identify the rare functioning or malignant adrenal tumor that should be removed. Patients and methods: From 1970 until December 1996, we managed 579 patients with ad- renal hyperplasia or neoplasm. Of these, 110 were fol- lowed without any operation and 469 were operated on. The histology from the operated patients revealed 145 phe- ochromocytomas, 72 Cushing’s syndrome, 98 aldosteron- omas, 21 virilizing tumors, 3 feminizing tumors, 98 non- functioning adrenalomas, 17 metastases, 7 cysts, and 15 miscellaneous tumors. Results: Among the 98 non-func- tioning adrenal tumors, 79 were incidentalomas. Histolog- ical examination of 103 operated incidentalomas found 55 adenomas (5 functioning = aldosteronomas), 12 benign pheochromocytomas, 3 malignant or suspicious pheoch- romocytomas, 8 cystic lymphangiomas, 4 metastases, 4 an- giomas, 3 ganglioneuromas, 4 myelolipomas, 1 hyperpla- sia, 2 hematomas, 2 cysts, and 5 adreno-cortical carcino- mas. Among the non-operated incidentalomas, the most frequent findings were adenomas, metastases, hematomas, cysts and pseudotumoral hyperplasia; three disappeared spontaneously. No patients died of unrecognized adreno- cortical carcinoma. Conclusion: Our experience confirms that in case of incidentaloma, the first concern is a non- functional pheochromocytoma (15%), and the less com- mon occurrence is adreno-cortical carcinoma (2%). We recommend a restrictive surgical approach in the setting of adrenal incidentalomas.
C. Proye () . M. Jafari Manjili . F. Combemale . F. Pattou
B. Carnaille
Clinique Chirurgicale Adulte Est, Service de Chirurgie Générale et Endocrinienne, Hôpital Huriez, CHU de Lille, Place de Verdun, F-59037 Lille Cedex, France
Tel .: +33 03 20 44 51 32; Fax: +33 03 20 44 47 58
O. Ernst
Service de Radiologie (Pr C. L’HERMINE),
CHU de Lille, Place de Verdun, F-59037 Lille Cedex, France
J. L. Wemeau
Clinique Endocrinologique Marc Linquette, U. S. N.A,
6 Rue de Pr Laguesse, CHU de Lille, F 59037 Lille Cedex, France
Key words Adrenal incidentalomas . Non-functioning adenomas · Pheochromocytomas . Urinary levels of catecholamines · NP-59 scan
Introduction
The adrenal incidentaloma is a mass lesion, serendipitously discovered by radiologic examination, in the absence of symptoms or clinical findings suggestive of adrenal dis- ease. The appropriate evaluation and management of an adrenal incidentaloma are controversial, with recommen- dations ranging from routine excision regardless of size or function to exhaustive biochemical screening and radio- graphic studies prior to consideration for surgery.
It is estimated that 0.5-1.3% of patients studied with ultrasonography, computed tomography (CT), and/or mag- netic resonance imaging (MRI) will be found to have an incidentally discovered adrenal mass [1, 6, 7]. Increasing sensitivity of imaging studies may still increase those num- bers. It poses a perplexing problem for physicians. The challenge is to identify the rare functioning or malignant adrenal tumor that should be removed.
Incidence of adrenal cortical tumors with clinical signs or symptoms of hypersecretion is estimated to be four cases per million, two adenomas and two carcinomas [15]. Inci- dence of adrenal cortical carcinomas, as suggested by ne- cropsy studies, should be 2.5 cases per million [2]. Hence, the suggested incidence of non-functioning adrenal corti- cal carcinomas could be 0.6-1.7 cases per million [7, 8].
If those figures are matched with the prevalence of ad- renal incidentalomas, i.e., 0.6-1.3% of the ambulatory population, it becomes immediately obvious that, when faced with an adrenal incidentaloma, the non-functioning adrenal cortical carcinomas are the last concern for the cli- nician; 4 of 342, i.e., 1.2% of overall incidentalomas for van Heeden [13]. Conversely, depending on the patient’s profile, pheochromocytoma(s) and/or metastasis are the first concerns, as they occur in 1-5% and 22%, respectively [19].
| Hyper- plasia | Benign tumor | Malignantª tumor | Total | |
|---|---|---|---|---|
| Pheochromocytoma | 0 | 108 | 37 | 145 |
| Cushing's syndrome | 34 | 25 | 13 | 72 |
| Conn's syndrome | 0 | 98 | 0 | 98 |
| Virilizing tumor | 0 | 10 | 11 | 21 |
| Feminizing tumor | 0 | 0 | 3 | 3 |
| Non-functional tumor | 1 | 72 | 25 | 98 |
| Metastasis | 0 | 0 | 17 | 17 |
| Other lesions | 8 | 7 | 0 | 15 |
| Total | 43 | 320 | 106 | 469 |
a Malignant primary intra-adrenal tumors: 45 adrenocortical carci- nomas; 7 non-adrenal tissue carcinomas
| Adreno-cortical adenomas | 55 (5 functional= Conn's syndrome) | |
|---|---|---|
| Hyperplasia | 1 | |
| Benign pheochromocytomas | 12 | |
| Malignant or suspicious | 3 | |
| pheochromocytomas | ||
| Cystic lymphangiomas | 8 | |
| Metastasis | 4 | |
| Angiomas | 4 | |
| Myelolipomas | 4 | |
| Ganglioneuromas | 3 | |
| Hematomas | 2 | |
| Cysts | 2 | |
| Adreno-cortical carcinomas | 5 | |
| Mortality | 2 (1.9%) |
| Septical shock (catheter) | 1 |
| Disseminated melanoma | 1 |
| Morbidity | 11 (10.6%) |
| Cardiac arrest | 1 |
| Cerebral infarction | 1 |
| Intra-abdominal hematoma | 1 |
| Phlebitis | 1 |
| Pneumothorax | 1 |
| Wound abscess | 6 |
Personal experience
From 1970 until December 1996, we managed 579 patients with adrenal hyperplasia or neoplasm at our institution; 110 patients were followed without any operation and 469 were operated on. The histology results from the op- erated patients revealed pheochromocytomas (145 cases), Cushing’s syndrome or Cushing’s disease (72 cases), Conn’s syndrome (98 cases), virilizing tumors (21 cases), feminizing tumors (3 cases), non-functioning adreno-cor- tical tumors (98 cases), metastasis (17 cases), cysts (7 cases), and miscellaneous tumors (15 cases) (Table 1). Among the 98 non-functioning adrenal tumors, 79 were in- cidentalomas.
| Carcinoma | Number |
|---|---|
| Symptomatic functioning adreno-cortical carcinomas | 27 |
| Cushing's syndrome | 13 |
| Feminizing tumors | 3 |
| Virilizing tumors | 11 |
| Symptomatic non-functioning adreno-cortical carcinomas | 13 |
| Adreno-cortical carcinomas incidentally discovered | 5 |
| Non-adrenal tissue malignant lesions developed in the adrenal fossa | 7 |
| Histiocyto-sarcoma | 2 |
| Lymphoma | 1 |
| Germinal tumor | 1 |
| Leiomyosarcoma | 2 |
| Kidney adeno-carcinoma | 1 |
Histological examination of a total of 103 incidentalo- mas that were operated on found 50 non-functioning adreno-cortical adenomas, 5 functioning adreno-cortical adenomas (aldosteronomas), 12 benign pheochromocyto- mas, 3 malignant or suspicious pheochromocytomas, 8 cys- tic lymphangiomas, 4 metastases, 4 angiomas, 3 ganglio- neuromas, 4 myelolipomas, 1 hyperplasia, 2 hematomas, 2 cysts, and 5 adreno-cortical carcinomas (Table 2). Mor- tality was 1.9% and morbidity was 10.6% (Table 3).
Adreno-cortical carcinomas were defined as large tu- mors with a weight ranging from 100 g to 2000 g, found during follow-up for gallbladder stones and leukemia in two patients. The other three were symptomatic in retro- spect (hematuria, abdominal pain, and malaise).
If we sum up, adreno-cortical carcinomas or rather ma- lignancies of the adrenal fossa, in our experience, inciden- talomas accounted for only 5 of 52 (Table 4). Among the non-operated incidentalomas, in which the diagnostics was established by follow-up, the most frequent findings were adenomas, metastases, hematomas, cysts and pseudotumo- ral hyperplasia; three disappeared spontaneously. None of the patients of this group died of unrecognized adreno-cor- tical carcinoma, to the best of our knowledge.
Discussion
Laboratory evaluation of an adrenal incidentaloma
In the asymptomatic patient, the minimal screening for hor- monal activity needs only to consist of: (1) measurements of serum potassium levels to rule out an aldosteronoma, (2) measurements of morning and afternoon cortisol, and ACTH levels to rule out a subclinical Cushing’s syndrome, and (3) determination of 24-h urinary levels of catechola- mines, which include norepinephrine, epinephrine, nor- metanephrine, metanephrine, and methoxyderivatives or plasma methoxyderivatives to rule out a pheochromocy- toma [19].
The incidence of incidentaloma among operated phe- ochromocytomas was 10% in our experience. When fac- ing an incidentally discovered adrenal mass in a normo- tensive or hypertensive patient, elevated urinary levels of catecholamines or their metabolic products are sufficient to make the diagnosis of a pheochromocytoma [21]. The glucagon test does not appear to offer additional advan- tages in the diagnosis of incidentally discovered pheo- chromocytomas [5]. In the patient whose screening stud- ies demonstrate hypokalemia, particularly when associated with hypertension, the diagnosis of aldosteronoma will be confirmed by finding an elevation of serum aldosterone with depressed serum renin levels.
The incidence of incidentaloma in operated Conn’s syn- drome was 5% in our experience. These were found dur- ing follow-up of a hypertensive patient (one case), work- up of lumbar pain (two cases), follow-up of hepatic an- gioma (one case), and abdominal ultrasonography for vas- cular murmur (one case). Some authors reported cases of pre-Cushing’s syndrome presenting as incidentaloma [6, 9, 15], which is defined as an overproduction of corti- sol by an adrenal adenoma, without physical changes on clinical examination [9]. The incidence of pre-Cushing’s syndrome or subclinical Cushing’s syndrome is 5% in cases of asymptomatic adrenal masses [15]. Progression from an asymptomatic state to clinical syndrome, i.e., Cushing’s, has been reported [16].
The best indicators of subclinical hypercortisolism are loss of the normal diurnal variation of cortisol synthesis and also contralateral adrenal gland suppression [21], which may be documented by adrenal scanning with 131I-6-betaiodomethyl-19-nor-cholesterol (NP-59). This agent is taken up by functioning adrenal tumors, including at a subclinical level, but is not taken up in the suppressed contralateral gland [3, 12].
Imaging studies of an incidental adrenal mass
Both CT scan and MRI, theoretically, are equally capable of demonstrating the adrenal masses 2 cm or larger [11]. CT scan is the preferred imaging modality for evaluation the adrenal gland because of its superior spatial resolu- tion, but its tissue specificity is relatively poor, except for most adrenal cysts and lipomas. In current practice, the CT-scan findings suggestive of a benign or a malignant process are too inconsistent to be the sole determinant for clinical decision making. However, CT scan does have a distinct role in follow-up of the unresected adrenal masses.
MRI offers poorer spatial resolution than CT scan, but demonstrates better contrast resolution. Quantitative MRI scanning has been reported to show some potential use for tissue characterization, especially in distinguishing benign from malignant adrenal cortical lesions. This modality has been reported to be able to distinguish adrenal metastases, carcinomas, and pheochromocytomas from adrenal aden- omas, myelolipomas, and cysts, by comparing signal-in- tensity ratios to reference organs [18].
T1-weighted images are used for anatomical definition, while T2-weighted images are used for tissue character- ization [11]. An increased signal intensity on T2-weighted images may be helpful in identifying a pheochromocytoma or a neuroblastoma [10]. However, the overlap in MRI find- ings with cortical adenomas, adreno-cortical carcinoma, and metastases is relatively similar to that seen with CT scanning
Ultrasonography (US) is not a dominant diagnostic technique in the evaluation of adrenal incidentalomas.
Adrenal scintigraphy
Adrenal scintigraphy utilizes a radiolabeled isotope of cho- lesterol: 131I-6-beta-iodomethyl-nor-cholesterol (NP-59) to image functioning adrenal cortical tissue. It is known that the percentage of total uptake of NP-59 is proportional to the amount of cortisol released by an adrenal tumor [20]. The NP-59 scan provides functional information comple- menting the morphological evaluation by CT scan [15]. If the radiopharmaceutical is taken up by the adrenal mass, it assesses its cortical origin and its benignity. If the con- tralateral adrenal is suppressed, it assesses its hyperfunc- tioning state (concordant CT and NP-59 scans). If the ra- diopharmaceutical is not taken up by the adrenal mass, it assesses its malignancy (discordant CT and NP-59 scans). Exceptions to this rule are highly differentiated hypersec- retory adreno-cortical carcinomas with positive uptake, that actually are never diagnosed as incidentalomas [12], and intra-adrenal malignancies of non-adrenal tissues with negative uptake.
A benign non-hyperfunctioning adrenal tumor should not be operated on, and this condition accounts for the vast majority of incidentalomas. In contrast, the other patterns of NP-59 scanning are indications for surgery. In our ex- perience of operated pheochromocytomas, 30% of the pa- tients were not obviously hypertensive [17]. In order to rule out a non-functioning and non-hypertensive pheoch- romocytoma, adrenal scanning with 131I-metaiodo-benzyl- guanidine (MIBG) is useful.
Surgical management and size of tumors
Clinical reviews of incidentally discovered adrenal masses have emphasized a positive relationship between the size of the adrenal mass and the likelihood of malignancy. It has been reported that for adrenal lesions 6 cm in diameter or larger, the incidence of adreno-cortical carcinoma is 1 in 60 (1.7%). Whereas, for adrenal lesions between 1.5 cm and 6 cm, the incidence of adreno-cortical carcinoma is 1 in 4000 (0.03%) [15]. However, it should be emphasized that size itself is unreliable and a poor discriminator of malig- nancy. In a reported experience of 45 patients with adrenal masses equal to or larger than 5 cm in size, it was demon- strated that 67% proved to be benign masses [14].
In patients with a history of malignant disease, metas- tases are the most common cause of an incidental adrenal
mass, whatever might be its size [4]. The tumors that most commonly metastasize to the adrenals are melanoma, hy- pernephroma, and carcinomas of the lung, breast, and stomach [8]. Although adrenal metastases are generally bilateral and greater than 3 cm in size, they may be unilat- eral and rather small [21].
In our experience four metastases were discovered in- cidentally: one melanoma, two carcinomas of the lung, and one esophageal adenocarcinoma; the diameter measured by means of CT scan was less than 3 cm in one case (eso- phageal adenocarcinoma: 1 cm in diameter).
Conclusion
Among incidentalomas, whether operated or not, adreno- cortical carcinomas are very rare. The perioperative risk is nearly the same as that of developing a malignant lesion. In the future, technical advances in MRI should allow phy- sicians to base the indication for operation on criteria other than size alone. We do not recommend fine-needle aspira- tion in incidentalomas, because there is a risk of tumor spread by violation of the capsule. Moreover, histological examinations of the smears are difficult and often non- diagnostic.
Our experience confirms that in the case of incidental- oma, the first concern is a non-functional pheochromocy- toma (15%), and the less-common occurrence is adreno- cortical carcinoma (2%). Our experience causes us to be in favor of a restrictive surgical approach in the setting of adrenal incidentalomas. Increasing popularity of laparos- copic adrenalectomy should not alter this policy and lead to increasing removal of benign adrenal masses.
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