Incidentally discovered adrenal mass (incidentaloma): investigation and management of 208 patients
A. A. Kasperlik-Załuska, E. Rosłonowska,
J. Słowińska-Srzednicka, B. Migdalska, W. Jeske, A. Makowska and H. Snochowska Department of Endocrinology, Centre of Postgraduate Medical Education, Warsaw, Poland
(Received 6 December 1996; returned for revision 31 January 1996; finally revised 28 June 1996; accepted 15 October 1996)
Summary
OBJECTIVE Incidentally discovered adrenal masses are fairly common, although there are some contro- versies concerning the results of hormonal investiga- tion (especially DHEAS values) and the methods of management. We summarize our experience in diag- nosis, pathological findings and treatment of a large group of patients with incidentally found adrenal tumours.
DESIGN AND PATIENTS Our study included patients referred to the Department of Endocrinology of the Centre of Post-graduate Medical Education (Warsaw, Poland) during the last 10 years because of an adrenal tumour incidentally found on ultrasound scan. In all cases this was confirmed by computed tomography. There were 208 patients (148 female and 60 male), 14- 76 years old. Unilateral adrenal masses were found in 172 patients (right 106, left 66), while bilateral masses were demonstrated in 36 patients. The size of the tumours ranged between 0-8 and 21-0 cm. The most common clinical abnormalities were hypertension (36 cases), obesity (23 cases), diabetes (8 cases), Addison’s disease (6 cases).
MEASUREMENTS Endocrine tests evaluating pituitary-adrenal function (urinary excretion of 17- hydroxycorticosteroids, 17- ketosteroids and catecho- lamines, plasma concentrations of ACTH, cortisol, DHEAS, androstendione and testosterone, dexametha- sone suppression test and corticotrophin-releasing hormone stimulation test).
RESULTS Cortisol hypersecretion was noted in two patients with coexisting Cushing’s disease and high normal 17-OHCS values with lack of dexamethasone suppressibility were found in six other patients
with pre-clinical Cushing’s syndrome. More common were subtle hormonal abnormalities: low ACTH levels (in 33 out of 98 investigated patients), diminished dexamethasone suppressibility and lack of ACTH response in the CRH test (in two out of 12 patients). Urinary catecholamine excretion was elevated in nine patients. In the group of 85 patients treated by surgery the most frequent pathological findings were: adreno- cortical adenoma (21), carcinoma (17), phaeochromo- cytoma (13), metastatic masses (12) and myelolipoma (10). The size of carcinomas ranged from 3-2 to 20-0 cm, while the size of non-malignant tumours ranged from 1-5 to 21-0 cm.
CONCLUSIONS Every patient with an incidentally dis- covered adrenal mass has to be investigated to detect malignancy and subtle hormonal overproduction, to select the cases for surgical treatment. Most of the adrenocortical carcinomas were >7.0 cm in diameter. For prophylactic purposes, adrenal incidentalomas >4.0 cm should be treated by surgery, while the smaller ones could be followed-up (with especial care for those between 3-0 and 4.0 cm).
The incidentally discovered adrenal mass (incidentaloma), a new clinical entity discovered due to the advent of non-invasive methods of imaging the abdomen (Glazer et al., 1982; Copeland, 1983; Abecassis et al., 1985; Herrera et al., 1991) still demands determination of a specific management approach, both diag- nostic and therapeutic. Within the last 10 years 208 patients with incidentally detected adrenal tumours have been referred to the Department of Endocrinology at the Centre of Post- graduate Medical Education (Warsaw, Poland). This paper describes the clinical and endocrine features, management, pathological findings and outcome in this group of patients.
Patients
A total of 220 patients were referred to our department with an incidentally discovered adrenal tumour; however, in ten of them the diagnosis was not confirmed by computed tomography (CT). Two other female patients with bilateral adrenal masses, 27 and 39 years old, were excluded because we diagnosed congenital adrenal hyperplasia. In the series of 208 patients there were 148 women and 60 men (F/M ratio 2-47) aged between 14 and 76 years (mean 51-8). Adrenal nodules were
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discovered on CT in only three while in all the remaining patients ultrasonography was the first diagnostic procedure, followed by CT. Unilateral adrenal masses were found in 172 patients, right-sided in 106 and left-sided in 66. In 36 patients bilateral tumours were diagnosed. In four patients, 3 or 4 nodules were found. The diameter of the adrenal tumours ranged from 0-8 to 21.0cm. There were 119 tumours with diameter <3.0 cm, 38 tumours ranging from 3-1 to 4.0 cm, 40 ranging from 4.1 to 9.9 cm and 18 tumours >10-0 cm. Figure 1 shows the distribution of individual tumour sizes, grouping the patients as ‘adrenal adenoma’, ‘adrenal carcinoma’, ‘phaeo- chromocytoma’, ‘others’ (operated, excluding metastatic tumours since they form a distinct group of patients) and ‘unoperated’.
The most frequent clinical features at presentation were hypertension (36 cases), obesity (23 cases) and diabetes mellitus (8 cases). Addisonian signs were noted in six patients and hypertrichosis in four others. The most common reasons for ultrasound examination were abdominal or lumbar pain or
discomfort, nephrolithiasis, urinary infection, haematuria and erythrocytosis.
Methods
Oncological screening tests
In all patients, chest radiograph, investigation of the breast and prostate, gynaecological examination, full blood count and erythrocyte sedimentation rate were done. In cases of suspected metastatic tumours further gastrointestinal, thyroid and other examinations were performed.
Urinary hormone assays
These determinations included 24-hour urinary excretion of 17- hydroxycorticosteroids (17-OHCS) by the Silber and Porter method (normal range 6-1-19.3 umol/24 hours), 17-ketosteroids (17-KS) by the Zimmerman method (normal range, women
10-0-56-0 pmol/24 hours, men 14-0-87-0 pmol/24 hours) and catecholamines (in the patients with hypertension or arrhyth- mia), adrenaline and noradrenaline, by a fluorimetric method (normal ranges, adrenaline, 7-6-81-3 nmol/24 hours; noradre- naline 66-8-284-3 nmol/24 hours).
Plasma hormone assays
Standard immunoassays have been used for determination of cortisol (Delfia, Turku, Finland), dehydroepiandrosterone sulphate (DHEAS) (Immunotech, Marseille Cedex, France), androstenedione (Immunotech, France) and testosterone (Orion Diagnostica, Finland). Plasma ACTH concentration was determined by a radioimmunometric assay (Hodgkinson et al., 1984) (Cis-France). Normal basal values were: cortisol 209- 692 nmol/l at 0900 h and 110-390 nmol/l at 2200 h; DHEAS, women before menopause 1.89-10-53 pmol/l; after menopause 0.3-1.65 mmol/l; men 5-4-10-12 umol/l; androstendione, women 0-73-10-75 nmol/l; men 1-05-10-82 nmol/l; testos- terone, women 0-3-3-0 nmol/l; men 8-2-34-6 nmol/l; ACTH 20-60 ng/1 (4-4-13-6 pmol/l) at 0900h and 12-5-29-0 ng/1 (2-3-6-4 pmol/l) at 2200 h.
Dynamic endocrine tests
Circadian rhythm of cortisol and ACTH. Blood samples were taken at 0900 and 2200 h in 89 patients (resting but awake). In the remaining group (out-patients) blood for examination was drawn only at 0900 h, after a 30-minute rest. Normal circadian rhythm for both cortisol and ACTH levels was defined when the hormonal values in the evening decreased by 50% when compared to the morning values.
Dexamethasone suppression test. Dexamethasone was adminis- tered in a dose of 0-5 mg every 6 hours during first 2 days and 2 mg every 6 hours during a further 2 days. Twenty-four hour urine collection was performed on the second day of the low and the high dexamethasone dose. In normal subjects the urinary 17-OHCS excretion should be suppressed to 5-5 pmol/ 24 hours. This test was performed in 48 patients, mainly in those with some clinical features suggestive of Cushing’s syndrome (obesity, hypertension, diabetes mellitus) and in the patients with high normal 17-OHCS values.
Corticotrophin-releasing factor (CRH) test. A 100-µg dose of synthetic ovine CRH was given by an intravenous bolus injection at 0900 h, after an overnight fast. Blood samples for ACTH and cortisol determinations were taken at -15, 0, 15, 30, 60, 90 and 120 minutes. A rise in ACTH and cortisol concentration >100% was defined as a normal response.
ACTH (1-24) stimulation test. This test was performed only in the patients with clinical features of adrenal insufficiency or urinary 17-OHCS excretion below the normal limit.
Synacthen-depot was given intramuscularly in a dose of 0.5 mg every 12 hours for 2 days and daily urinary 17-OHCS excretion was determined during the test.
Informed consent for the investigation was obtained from all patients.
Management, surgical treatment
All the patients with an adrenal tumour >4.0 cm in diameter were advised to undergo a surgical operation and 59 of them gave informed consent. Surgery was also advised for the patients with a known neoplasm, or clinical and CT features suggestive of metastatic disease (Reznek & Armstrong, 1994). The third group of patients referred for surgery were those with hormonal overproduction of catecholamines and aldosterone or lack of dexamethasone suppressibility. A total of 85 patients underwent surgical treatment. Patients with tumours <4-0 cm and those with larger adrenal masses, who did not give consent to surgery, were carefully observed. The first ultrasound scan was performed a month after the adrenal tumour had been found, and the next 3 months later if the incidentaloma had not increased in size. If a stable image and size were demonstrated, further visualization was performed every 6 months. Basal hormonal examinations were repeated every 6-12 months, if necessary.
Results
Hormonal investigations
Urinary 17-OHCS excretion (Fig. 2). 17-OHCS values were elevated in two patients, diagnosed as Cushing’s disease coexisting with adrenal incidentalomas. In five patients high normal 17-OHCS were noted at presentation and in one patient, a 47-year-old woman, 17-OHCS values in the low normal range at presentation rose during a 5-month period to the upper limit of normal (pre-clinical Cushing’s syndrome). In three patients diagnosed on further investigation as adrenal carcinoma, 17- OHCS or 17-KS urinary excretion (Fig. 3) was increased; however, mild signs of Cushing’s syndrome were present in only one of them. In the remaining patients urinary 17-KS excretion was normal. Urinary catecholamines excretion was increased in 9 cases.
Serum cortisol concentration. The circadian rhythm of cortisol is shown in Fig. 4. Evening cortisol values slightly higher than half of the corresponding morning values were observed in a significant number of patients.
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Plasma ACTH concentration (Fig. 5 a-d). Low ACTH levels, below the lower normal limit, were revealed in 33 out of 98 patients under investigation (the plasma ACTH levels measured in Cushing’s disease, Addison’s disease and ‘phaeochromo- cytoma’ group are not shown).
Serum DHEAS concentration. Results in 77 patients are shown in Fig. 6 a and b.
Androstendione and testosterone levels. Serum androstendione levels in 54 patients were within normal limits for sex and age. Serum testosterone concentration was elevated in four women in whom clinical studies revealed coexisting polycystic ovary syndrome.
Dexamethasone suppression test. Lack of suppression after both doses of dexamethasone was found in six patients (preclinical Cushing’s syndrome). They presented only subtle, and not typical, clinical features of hypercortisolism: hyperten- sion (3), facial telangiectasia (2), obesity (2) and diabetes
mellitus (1). Additionally, incomplete dexamethasone suppres- sion was revealed in 13 patients when tested with a low dose.
CRH test. In two out of 12 patients the ACTH and cortisol values did not change during the test and in one patient cortisol level rose only slightly. In the remaining patients a normal response was observed.
ACTH stimulation test. In all patients under investigation the diagnosis of adrenal insufficiency was confirmed.
Management, surgical treatment and pathological findings
During long-term observation in three patients significant tumour enlargement was observed: (1) from 2-0 to 3-2 cm within 14 months, (2) from 3-0 to 4-2 cm within 2 years and (3) from 3-0 to 7.0 cm within 5 months. In the last case an adrenal haemorrhage was diagnosed on the basis of acute lumbar pain
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and ultrasound scan. All three patients underwent surgery; pathological examination revealed an adenoma, a myelolipoma and a haemorrhagic pseudo-cyst with remnants of adreno- cortical tissue, respectively (all three cases are included in the Table 1).
The pathological findings in the group of patients treated by surgery are summarized in Table 1.
The diagnosis of adrenocortical carcinoma was based on histological criteria (Hough et al., 1979). The diameter of the carcinomas ranged from 3-2 to 20-0 cm. In the group of patients with cysts two were pseudo-cysts, one deriving from an adenoma and the other from a phaeochromocytoma; in one case a cyst of embryonic origin was diagnosed and the origin of the fourth was uncertain.
Long-term outcome
On the basis of clinical studies and pathological examinations (both post-operatively and post mortem) we divided our cases into three groups: non-malignant adrenal tumours, adreno- cortical carcinoma and metastatic tumours. The details are summarized in Table 2.
In six patients presenting with mild Cushing’s syndrome very low 17-OHCS values were found following tumour excision and replacement therapy was necessary. The same observation was found in two other patients with hormonally silent tumours, one of them having a myelolipoma and the other an adenoma. Replacement therapy was also administered following subtotal adrenalectomy in two patients with bilateral multiple adrenal nodules. In the remaining patients hydrocortisone was adminis- tered only during the operation and 2-5 days post-operatively.
Diagnosis of adrenocortical carcinoma was established in 17
patients on surgical histology and in one at post-mortem examination. Ten patients were classified as metastatic stage, three regional stage and five as local stage according to the Summary Staging Guide for Cancer Surveillance, Epidemi- ology and End Result Reporting Program, 1977. In four patients a partial hepatectomy was performed and in one patient unilateral nephrectomy. Following surgery, all patients were treated with mitotane, as recently described (Kasperlik-Załuska et al., 1995). Replacement therapy with hydrocortisone and fludrocortisone was given during mitotane therapy. Ten patients from this group are still alive (the time of observation ranging between 0-5 and 6 years).
In 10 out of 19 patients with metastatic adrenal lesions both adrenals were affected. In 17, the site of the primary neoplasm has been found. In six, the metastases derived from kidney, in four from a bronchogenic carcinoma, in three from the colon, in two from the stomach, and in two others from the breast. Four of them presented with adrenal insufficiency. At present, seven out of 12 patients treated by surgery are alive (survival time 2- 6 years).
Discussion
In 1992, we described the first series of 64 patients with incidentally detected adrenal tumours referred to our depart- ment from 1985 (Kasperlik-Załuska et al., 1992a). In the last 3 years we have had the opportunity to observe 144 new cases of such tumours. This rapid increase in the number of registered adrenal incidentalomas underlines their frequency (Griffing, 1994). In our cases we found a great prevalence of female patients. Only metastases in the adrenals were more frequent in male patients. In common with other reports (Osella et al., 1994; Bencsik et al., 1995) and the review by Kloos et al. (1995), adrenal adenoma was the most frequent tumour in 85 patients treated by surgery and diagnosed histologically. The prevalence of adrenocortical carcinoma in our series was surprisingly high: 21.1% among the patients submitted to surgery and 8-6% in the whole group of adrenal incidentalomas. One cannot exclude the possibility that ultrasound scan as our initial screening method may have missed smaller, benign lesions, thus increasing the percentage of the malignant tumours. In the entire group of 63 patients with adrenocortical carcinoma referred to our department till now, 28-5% were discovered incidentally. In most of them the greatest diameter was >7.0 cm; however, size alone has not been a completely reliable predictive factor of malignancy. The smallest malignant tumour had a diameter of 3.2 cm; invasion of blood vessels was observed on pathological examination. A local recurrence of the carcinoma occurred when the patient stopped mitotane. Addi- tionally, in the series of non-malignant incidentally discovered tumours there were two adrenal adenomas, 11-0 and 12-0 cm in
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diameter, and a myelolipoma of 21.0 cm. The characteristic features of adrenal metastatic tumours have been frequent bilateral localization and signs of adrenal insufficiency.
Our observations differ from other authors (Gross & Shapiro, 1993; Kloos et al., 1995) who found breast carcinoma as the most common neoplasm to metastasize to the adrenals. In our material the most frequent primary malignancy was of kidney or lung origin. Phaeochromocytoma was also frequently found on pathological examination; however, in four cases normal catecholamine excretion was noted (silent phaeochromo- cytomas). Such a type of tumour was the most frequent in the
autopsy series of Sutton et al. (1981). The prevalence of myelolipoma was unexpectedly high in our group of patients who underwent the surgery (11.7%). It is uncertain whether myelolipoma should be treated surgically; however, the size of all these tumours in our study was >4.0 cm.
The hormonal investigations revealed six patients with autonomous adrenal adenomas. The 4-day dexamethasone suppression and CRH tests have been the most valuable diag- nostic procedures, when plasma cortisol levels and 17-OHCS excretion did not exceed their upper normal limits. The terms preclinical or subclinical Cushing’s syndrome and pre-Cushing’s
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syndrome were introduced to characterize such patients (Bogner et al., 1986; Reincke et al., 1992). We do not use the overnight dexamethasone suppression test because false negative and false positive results are sometimes found; however, it is one of the most widely used screening tests. We were intrigued by a patient with a myelolipoma, with full dexamethasone suppression of cortisol, in whom surgery was followed by adrenal hypofunction. Urinary free cortisol determination would be more valuable in such cases since it is a very important parameter in the evaluation of adreno- cortical function. Sometimes endocrine abnormalities have been found in patients with myelolipoma (Oliva et al., 1988). In our group of 72 operated hormonally active adrenocortical tumours (Kasperlik-Załuska et al., 1992b) there was a case of adrenal myelolipoma with overt Cushing’s syndrome.
In the series reported previously (Kasperlik-Załuska et al., 1992a) we paid attention to a subgroup of ten patients with subnormal plasma ACTH levels (out of 20 patients submitted to this assay). We interpreted these results as a possible pituitary
suppression by periodically increased cortisol concentrations. One may speculate that insufficiently decreased evening corti- sol levels (but within normal limits), in comparison with the values determined at 0900 h, may in some cases be responsible for the ACTH suppression.
A review of the literature shows a controversy concerning the DHEAS levels in patients with adrenal incidentalomas. Osella et al. (1994) reported the reduction of DHEAS concentrations as the most frequent endocrine abnormality in their group of patients. Such an observation was not confirmed by Bencsik et al. (1995). In our material there were some cases with subnormal DHEAS levels in the female group. In the male group all DHEAS values were below the lower normal limit; however, the majority of the patients (10/19) were aged over 60 years. Decreased DHEAS values were not associated with low ACTH levels. An important diagnostic role of the CRH stimulation test has to be emphasized; however, in our experience this examina- tion has not been superior to the 4-day dexamethasone suppression test. In our group of patients, only two had an
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aldosteronoma, confirmed by aldosterone and plasma renin activity assays, because we excluded all patients examined by ultrasonography because of hypertension associated with, even slight, hypokalaemia. Among other diagnostic procedures two have to be mentioned. One is an examination of the cortisol and 17a-hydroxyprogesterone response to ACTH stimulation, to look for a late onset form of 21-hydroxylase deficiency or a steroidogenic enzymatic defect secondary to the adenomatous growth (Ambrosi et al., 1995; Del Monte et al., 1995). The other is an adrenal iodo or seleno-cholesterol scan which is an important morpho-functional study. We performed adrenal scintigraphy using 75 Se-selenocholesterol in some selected cases (Kasperlik-Załuska et al., 1992a); however, it has not been a routine investigation.
We chose surgery as the main method of treatment in the patient with large tumours, >4.0 cm, and with hormonal hypersecretion. Specific request by the patient or their family
| Pathological diagnosis | Number of tumours |
|---|---|
| Adenoma | 21 |
| Carcinoma | 17 |
| Phaeochromocytoma | 13 |
| Metastatic tumour | 12 |
| Myelolipoma | 10 |
| Cyst | 4 |
| Nodular hyperplasia | 3 |
| Aldosteronoma | 2 |
| Lipoma | 1 |
| Lymphoma (bilateral) | 1 |
| Neurilemmoma | 1 |
| Haematoma | 1 |
was the reason for operating on two tumours sized 1.5 and 3.2 cm. The remaining patients have been followed up as described above. The criterion for operation based on diameter of the adrenal tumours varies in the literature from 3-0 cm (Prinz et al., 1982) to 5-0 cm (Abecassis et al., 1985). We decided also to operate on 12 patients with secondary adrenal malignancy. The primary neoplasms were also treated by surgery and a bronchogenic carcinoma by chemotherapy.
In conclusion, in our series of 208 patients with adrenal incidentaloma the largest group (171) included probably non- malignant tumours (84%); however, adrenal carcinoma was a relatively frequent finding. All patients with incidentally dis- covered adrenal tumours have to be examined for malignancy, primary or metastatic, and subclinical endocrine hypersecre- tion, so that patients can be selected for surgery. The size of the tumour is not a certain predictive factor of malignancy; however, tumours >4-0 cm should be treated by surgery. The smaller adrenal masses have to be carefully followed up. In our experience, the most valuable hormonal assays in the investi- gation of adrenal incidentalomas function were 17-OHCS
| Number of patients | Age (years) | |||||
|---|---|---|---|---|---|---|
| Total | F | M | F/M ratio* | range | mean | |
| Non-malignant tumours | 171 | 132 | 39 | 3-38 | 23-76 | 51-7 |
| Adrenocortical carcinoma | 18 | 10 | 8 | 1.25 | 14-76 | 44-2 |
| Metastatic tumours | 19 | 6 | 13 | 0-46 | 45-73 | 59-6 |
* F/M ratio, Female/male ratio.
@ 1997 Blackwell Science Ltd, Clinical Endocrinology, 46, 29-37
excretion (patients with high normal values have to be further investigated), plasma ACTH determinations, 4-day dexametha- sone suppression test and CRH-test.
Acknowledgements
This work was supported by a grant from CMKP-S-6/94 and 6/95.
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