1,161 patients with adrenal incidentalomas: indications for surgery
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Background and aims
The aim of this study is to analyze the clinical data and criteria for surgery in a group of over 1,100 patients with adrenal incidentalomas (AI) observed at the Department of Endocrinology.
Patients and methods
The material consisted of 1,161 patients (842 women and 319 men, 10–87 years old) with AI ranging in size from 1.0 to 23.0 cm. The methods included clinical examination, imaging studies, hormonal determinations in the blood and in the urine as well as histological and immunocytochemical investigations in 390 patients treated by surgery.
Basing on these studies, we diagnosed 112 patients with primary malignant adrenal tumors (100 with carcinoma), 45 with metastatic infiltrations, and 1,004 with probable benign AI. Imaging phenotypes (especially high density on computed tomography, CT) were characteristic of malignant and chromaffin tumors. Subclinical adrenal hyperactivity was found in 8% of the patients with pre-Cushing’s syndrome as the most frequent form (6.5%). Chromaffin tumors were detected in 3%.
(1) Indications for surgery include malignant tumors (both primary and metastatic), tumors with subclinical hyperfunction, and chromaffin tumors. High density on CT, >20 HU, appeared to be an important indication for surgery. (2) A slight prevalence of oncological indications over endocrinological indications (14 vs. 11%) was found.
KeywordsAdrenal tumor Adrenal incidentaloma Adrenal cancer Chromaffin tumors
The number of incidentally found adrenal tumors is still growing. In 1992 we presented our first series of 64 patients with adrenal incidentalomas (AI)  and in 1997 we summarized our experience with 208 patients having these tumors . During the last 8 years, the number of patients with incidentally detected adrenal tumors increased by 550%. Many series of such patients were also reported by other authors [3, 5]. It has been a challenge how to manage them and to decide which patients have to be treated by surgery. The present study aimed at summarizing our experience in this matter, basing on observation of a group of over 1,100 patients referred to the Department of Endocrinology (Warsaw, Poland) during the last 16 years.
Materials and methods
The materials included 1,161 patients with incidentally found adrenal tumors, 842 women and 319 men [female (F)–male (M) ratio 2.6], aged 10–87 years (only three patients below 18 years old). There were 444 patients (38%) over 60 years old, while only 50 patients (4%) were 30 years old or younger. The diameter of the tumors ranged from 1.0 to 23.0 cm; 736 of them (63%) were up to 3.0 cm in size. In 557 cases (50%), the tumor was right-sided, in 335 (32%)–left-sided, while in 209 patients (18%) bilateral tumors were detected. In 996 patients, the tumor was found on ultrasound scans and confirmed by computed tomography (CT); in 163 patients it was detected on CT and in two patients on magnetic resonance imaging (MRI). Common reasons for imaging examination included abdominal or lumbar discomfort, nephrolithiasis, cholelithiasis, hematuria, urinary tract infection, and postoperative or general control.
The methods of evaluation included clinical examination, imaging studies, hormonal determinations as well as histological and immunocytochemical investigations in 390 patients treated by surgery. Our analysis of the clinical data accounted for the incidence of obesity, hypertension, diabetes mellitus, and other signs of Cushing’s syndrome. In biochemical investigations, we searched for hypokalemia in the hypertensive patients. In the female patients presenting with hirsutism, the procedures for diagnosis of polycystic ovary syndrome were introduced.
Imaging techniques included CT and MRI, which were used mainly to differentiate adenomas from non-adenomas. Ultrasonography, as a non-invasive and inexpensive method, has been used for long-term observation of the patients not qualified for surgical treatment. Computed tomography was the most frequently used method to evaluate the size, shape, structure (homogeneous or inhomogeneous), borders, unenhanced attenuation values (density), and enhancement with intravenous contrast medium and its washout. On MRI, the signal intensity on T2-weighted scans was evaluated to reveal tissue without lipid content (chromaffin tumor, metastatic infiltration, or some cases of adrenal cancer). The size and imaging phenotypes on CT and MRI were used to describe the malignant potential of the adrenal incidentalomas.
For the initial screening and hormonal examinations (in all patients referred for the first time), we measured cortisol in the blood to search for subclinical Cushing’s syndrome, as well as dehydroepiandrosterone sulphate (DHEA-S) and androstendione as predictors of adrenal cancer. More precise investigation was applied in patients with adrenal tumors exceeding 3.0 cm in diameter and those with increased density on CT, as well as in patients suspected for adrenal hyperactivity and included determinations of adrenocorticotropic hormone (ACTH), 17 OH-progesterone, aldosterone, plasma renin activity (PRA), circadian rhythm of cortisol, metanephrines (in 54 patients, in National Institutes of Health, Bethesda, MD, USA) in the blood, and 17-hydroxycorticosteroids (17-OHCS), 17-ketosteroids (17-KS), and metanephrines in daily urinary excretion. In patients with high normal cortisol levels and in obese, hypertensive patients, an overnight, low-dose (1 mg) dexamethasone test was performed. A 2-day dexamethasone test (8 mg by day) was done in patients with adrenal tumors of 4.0 cm or more in search for an autonomic function (as an important criterion for surgery). We avoided performing this test in the patients in whom a possibility of chromaffin tumor has not been excluded. Cortisol levels were measured by radioimmunoassay (RIA) and Delfia, and during the last 7 years by luminescence immunometric assay (Immulite 2000-DPC), androstendione, DHEA-S, and 17-OH progesterone by RIA and ACTH levels by a radioimmunometric method. Urinary 17-OHCS and 17-KS excretion was determined by routine assays (Silber and Porter and Zimmerman method, respectively) and metanephrines by routine Lender’s procedure.
390 patients were treated by surgery for oncological or endocrinological purposes.
165 patients with probable benign tumors, not exceeding 5.0–6.0 cm in diameter and 20 HU of density on unenhanced CT were treated by laparoscopic surgery. Open surgery by laparotomy or lumbotomy was a method of choice in 155 patients with probable malignant tumors and in a group of patients with some other indications especially in the early phase of our study. Histological and immunocytochemical investigations of the removed tumors were performed after surgery.
In the clinical examination, arterial hypertension was the most frequent finding observed in 286 patients (25%) followed by obesity present in 174 patients (15%). Diabetes mellitus, mainly type II, was present in 58 patients (5%). Supraclavicular fat pads were an early sign of subclinical Cushing’s syndrome.
The size of the adrenal tumors in our study ranged from 1.0 to 23.0 cm; the largest ones were adrenal cancers and myelolipomas (up to 21 cm). There were 731 of the tumors with imaging phenotype of an adenoma (63%) that did not exceed 3.0 cm in diameter; however, the largest one had a diameter of 11 cm. The size of adrenal cancer exceeded 5.0 cm in 87 cases; however, in 13 cases, it varied between 3.0 and 5.0 cm. The most important feature of adrenal cancers on CT, present in all but two patients, was high density, over 20 HU, on the unenhanced scans. Similarly, poor lipid content or lack of the lipids was a characteristic finding in MRI in all but two cases of adrenal cancer. Both the adrenal cancers and pheochromocytomas were frequently inhomogeneous. A total of 66 patients with adrenal cancer (66%) were admitted with regional and/or metastatic infiltrations of other tissues (III/IV stage of MacFarlane’s classification); in ten other patients, regional or distant invasion has been revealed during further observation.
In the hormonal examinations, the most frequent abnormalities were observed in cortisol secretion, i.e., insufficient decrease in evening cortisol levels and in the dexamethasone suppression test. These changes were defined as preclinical Cushing’s syndrome or pre-Cushing’s syndrome, which was diagnosed in 75 patients (6.5%) including postoperatively revealed cases. Slightly abnormal aldosterone urinary excretion as well as PRA and aldosterone concentrations were rather rare finding (0.5%) in some hypertensive patients (pre-Conn’s syndrome). Subclinical androgens excess was detected in 12 patients (1%) in the group under study.
The imaging phenotype (high density on the unenhanced scans, inhomogenous structure, and delayed washout of the contrast medium) was useful in the diagnosis of chromaffin tumors in 45 patients (3%); elevated urinary metanephrine excretion was found in 77% of them. In this group, 53% of the patients were hypertensive.
On the basis of the results of the above-described studies, we divided our material into three groups: (1) probable benign adrenal tumors—1,004 patients, (2) primary malignant adrenal tumors—112 patients, and (3) metastatic tumors—45 patients. The histological and immunocytochemical examinations revealed that in the group of patients with primary malignant adrenal tumors there were 100 patients with adrenal carcinoma, four patients with malignant pheochromocytoma (metastases present), five with lymphoma, two with sarcoma, and a 20-year-old woman with ganglioneuroblastoma.
Recommended to surgery were 390 patients (34%), including all but two cases of malignancy (with massive invasion of vena cava), both primary and metastatic (14% of the entire group), as well as all the patients with probable chromaffin tumors and those with subclinical hormonal hyperactivity (in sum, 11%). In 18 patients with adrenal cancer, more than one abdominal operation was performed (two to five); five patients were submitted to partial hepatectomy and three to nephrectomy.
Additionally, metastatic pulmonary lesions were removed in two patients. Mitotane has been administered following surgery in all cases of histologically proved adrenal cancer. Chemotherapy was used if necessary. From the observations made, a histological profile of the removed tumors (apart of the above mentioned primary malignant tumors) was derived: adenoma—139, chromaffin tumor—41, cyst and pseudocyst—19, myelolipoma—17, adrenal hyperplasia—14, hemangioma—3, neurofibroma—2. The medulla-derived tumors were classified as follows: pheochromocytoma—34, ganglioneuroma—3, medullar hyperplasia—2, schwannoma—2. The metastatic tumors derived from carcinoma were of the lung—18, kidney—17, colon—5, stomach–3, and breast–2. In 12 patients with bilateral adrenal metastatic tumors, pre-Addison’s or Addison’s disease was present, similarly as in three patients with bilateral lymphomas of the adrenals.
The control ultrasound scans have been performed within 3 months and 1 year following the surgery. In three cases with adrenal hyperplasia, a recurrence of the tumor was discovered and treated by surgery. A long-term follow-up revealed good results of surgery in all patients with benign adrenal tumors. In four patients with a rapid enlargement of the adrenal tumor during follow-up studies, surgical treatment seemed to be necessary; benign tumors were diagnosed microscopically in all of them. In the patients with invasive adrenal cancer, the prognosis was poor; however, the survival of 11 years has been observed in one of them and survival of more than 5 years in ten other patients.
To the best of our knowledge, this is the largest series of patients with incidentally found adrenal tumors observed at a single endocrinological center reported in the literature. Thus, all of the patients were diagnosed and managed in the same manner. Mantero et al.  summarized in 2000 a group of 1,004 patients with AI, in a multicentric, retrospective survey under the auspices of the Italian Society of Endocrinology; however, 26 referral centers for adrenal diseases participated in this study.
Facing such a great number of patients, we had to choose the most effective and inexpensive diagnostic methods and to define strict indications for surgery. By definition, the patients with AI should not present any signs of hormone excess; however, detailed clinical, biochemical, and hormonal examinations could reveal some subtle abnormalities, named subclinical adrenal hyperfunction . The aim of our clinical and endocrine studies was to detect early features of malignancy and those of slightly increased hormone secretion.
The indications for surgery were defined basing on oncological and endocrinological findings. Oncological indications included tumors with high malignant potential  in the imaging examinations as described above: 4.0–5.0 cm or more in diameter, high density on the unenhanced scans, and delayed washout of the contrast medium or a significant growth of the tumor in a series of imaging studies. In our previous paper  published in 1997, we suggested surgery in all patients with tumor size 4.0 cm or more; however, a group of nine patients with tumors ranging in size from 4.0 to 4.9 cm refused to be treated by surgery and no progression has been observed in them during long-term follow-up. In our experience, high, unenhanced CT attenuation was the most important criterion for surgery, even in small adrenal tumors. In the majority of patients, it was characteristic for carcinoma, metastatic infiltration, or chromaffin tumor, apart from hemangioma and very rare cases of extraadrenal tissues like additional lien or kidney.
Endocrinological indications included the cases with signs of subclinical hyperfunction and all patients with possible chromaffin tumors (to avoid hypertensive crisis). Screening hormonal examinations, performed in all patients referred to our department, aimed at finding the group for further studies because of oncological or endocrinological suggestions. More precise investigations were performed in the patients with adrenal tumor exceeding 3.0 cm in size because in such cases more frequently subclinical hypersecretion of cortisol could be revealed. Incidence of the pre-Cushing’s syndrome in our material (6.5%) did not differ from other reports  with their 5–8%. Difficult decisions were necessary in patients with preclinical Cushing’s syndrome and bilateral adrenal tumors: which tumor to remove. In such situations, we decided to remove a tumor greater in diameter, quickly growing, or presenting higher density on CT. Subclinical hyperaldosteronism was a rare event in our group of patients (0.5%) compared to other authors citing 1–5% [8, 10]. The frequency of subclinical androgens excess (1%) has been our original observation because there are no such reports in the literature. Interestingly, no signs or only poor signs of virilization were observed in these patients, which may be due to an androgen receptor defect. We found 3% of chromaffin tumors in our material, while other authors reported only pheochromocytomas (3–5%) .
One had to remember rare cases of hemorrhage to the adrenal tumor, with urgent indications for surgery. We observed three such life-threatening incidents, in the patients with adrenal carcinoma, but we did not include them here because no imaging studies were performed prior to the hemorrhage.
Laparoscopic approach appeared to be a method of choice in most AI; however, open adrenalectomy has been necessary for diagnosed or suspected adrenal cancer and metastatic tumors.
After surgery, a temporary, secondary adrenal hypofunction appeared in patients with pre-Cushing’s syndrome and in a scarce group of patients without such a preoperative suggestion (also qualified ex post as subclinical cortisol hypersecretion resulting in suppression of the hypothalamo–pituitary–adrenal axis). A transient replacement therapy with hydrocortisone in gradually diminished daily doses was introduced in such cases. In rare cases, a long-term postoperative adrenal insufficiency was observed . In the entire group of patients treated by surgery, the control ultrasound scans were done within 3 months and 1 year after the operation. Postoperative hematomas were sometimes found in the early period of our study. In the long-term observation, a recurrent adrenal tumor was discovered in three patients with previously found adrenocortical hyperplasia, probably due to the presence of an additional adrenal gland.
Recommendations concerning management of patients with adrenal cancer were published recently as a result of an international consensus conference . They include frequent postoperative imaging and hormonal examinations as well as therapeutical indications. In our experience, early administration of mitotane after surgery appeared to be a good prognostic factor in the course of adrenal cancer .
The patients not qualified for surgery with tumors up to 4.0 cm in diameter and density not exceeding 10 HU should be examined by ultrasonography every 6 months during the first 2 years and, next, every 12 months, for 2 years or longer, if necessary. A search for pre-Cushing’s syndrome and carcinoma (cortisol and DHEA-S determinations) has to be continued every year. Significant growth of the tumor in a series of imaging studies and/or increase in cortisol or androgens levels could be an additional indication for surgery.
More than one third of our patients were over 60 years old; such an observation has been a common one. This tendency is probably due to arteriopathy observed in the ageing adrenals, which results in nodular hyperplasia, adenoma, or myelolipoma development . In such a population, the criteria for surgery have to be strictly defined, to avoid perioperative complications; however, in the case of life-threatening tumors such as cancer, metastatic lesion, or pheochromocytoma, only individual contraindications to surgical treatment could be taken into account.
The adrenal incidentalomas present a true challenge for the practitioners but we do not agree with George Griffing’s suggestion of “avoiding unnecessary abdominal imaging procedures” . Growing number of incidentally found adrenal cancers, mainly on ultrasound scans, prove the utility of imaging studies.
In summary, in our material consisting of 1,161 patients with AI, indications for surgery were found in about one third of the patients, including malignant tumors, both primary and metastatic, as well as chromaffin tumors and hormonally hyperactive AI. High, unenhanced CT attenuation appeared to be a very important indication for surgery. A slight prevalence of oncological over endocrinological indications (14% vs. 11%) was found.
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