HIGH RISK OF MALIGNANCY IN PATIENTS WITH INCIDENTALLY DISCOVERED ADRENAL MASSES: ACCURACY OF ADRENAL IMAGING AND IMAGE-GUIDED FINE-NEEDLE ASPIRATION CYTOLOGY
Franco Lumachi1, Simonetta Borsato2, Alberto Tregnaghi3, Filippo Marino4, Ambrogio Fassina2, Pietro Zucchetta5, Maria Cristina Marzola5, Diego Cecchin5, Franco Bui5, Maurizio lacobone1, and Gennaro Favia1
1Endocrine Surgery Unit, Department of Surgical & Gastroenterological Sciences, 2Section of Cytopathology, 3Section of Radiology, 4Department of Pathology, 5Nuclear Medicine Service, Department of Diagnostic Medical Sciences, University of Padua, School of Medicine, Padova, Italy
Aims and background: The incidental finding of nonfunctioning adrenal masses (incidentalomas) is common, but no reliable criteria in differentiating between benign and malignant adrenal masses have been defined. The aim of this prelimi- nary study was to assess the usefulness of adrenal imaging and image-guided fine-needle aspiration cytology in patients with nonfunctioning adrenal incidentalomas with the aim of excluding or confirming malignancy before surgery.
Methods: Forty-two consecutive patients (18 men and 24 women; median age, 54 years; range, 25-75 years) with inci- dentally discovered adrenal masses of 3 cm or more in the greatest diameter were prospectively enrolled in the study. All patients underwent helical computerized tomography scan and image-guided fine-needle aspiration cytology, 33 (78.6%) underwent magnetic resonance imaging, and 26 (61.9%) un- derwent norcholesterol scintigraphy before adrenalectomy. Results: The revised final pathology showed 30 (71.4%) benign (26 adrenocortical adenomas, of which 3 were atypical, 2 gan- glioneuromas, and 2 nonfunctioning benign pheochromocy- tomas) and 12 (28.6%, 95% CI = 15-42) adrenal malignancies
(8 adrenocortical carcinomas and 4 unsuspected adrenal metastases). The definitive diagnosis of adrenocortical carci- noma was made according to Weiss criteria and confirmed on the basis of local invasion at surgery or metastases. The sen- sitivity, specificity and accuracy were 75%, 67% and 83% for computerized tomography scan, 92%, 95% and 94% for mag- netic resonance imaging, 89%, 94% and 92% for norcholes- terol scintigraphy, and 92%, 100% and 98% for fine-needle as- piration cytology. The sensitivity and accuracy of image-guid- ed fine-needle aspiration cytology and magnetic resonance imaging together reached 100%. Immediate periprocedural complications of fine-needle aspiration cytology occurred in 2 (4.7%) patients: self-limited pneumothorax (n = 1), and severe pain (n = 1) requiring analgesic therapy. No postprocedural or late complications were observed.
Conclusions: With the aim of selecting for surgery patients with a non-functioning adrenal incidentaloma of 3 cm or more in diameter, the combination of magnetic resonance imaging and fine-needle aspiration cytology should be considered the strategy of choice.
Key words: adrenal cancer, adrenal incidentaloma, adrenal magnetic resonance imaging, adrenal malignancy, fine-needle aspira- tion cytology, norcholesterol scintigraphy.
Introduction
The incidental discovering of adrenal masses (inci- dentalomas) has become a common finding during ab- dominal computed tomography (CT) scanning or mag- netic resonance imaging (MRI) performed for unrelated reasons1. Adrenal imaging studies, which actually may reveal adrenal masses greater than 5 mm in diameter, have resulted in the detection of unsuspected adrenal in- cidentalomas in 1-5% of studies2. Once an adrenal hy- perfunction has been excluded, reliable criteria to ex- clude or confirm malignancy should be established for each patient. Unfortunately, serum tumor marker mea- surements and endocrinologic tests are not useful in dif- ferentiating between benign and malignant adrenal masses, and management strategies based exclusively on size criteria are neither sensitive nor specific3.
The purpose of this preliminary prospective study was to compare the sensitivity, specificity and accuracy
of CT scan, MRI, norcholesterol adrenal scintigraphy (NCS), and image-guided fine-needle aspiration cytol- ogy (FNAC) in the management of noncancer patients with nonfunctioning adrenal incidentalomas, with the aim of excluding or confirming malignancy before surgery.
Patients and methods
Study population
Patients without signs or symptoms suggesting adren- al diseases, observed between January 2001 and De- cember 2003, were candidates for inclusion in this prospective trial if they had undergone abdominal CT scan showing a unilateral adrenal incidentaloma of 3 cm or more in the greatest diameter. Those with a histo- ry of malignancy had previously been excluded. There were 18 (42.9%) men and 24 (57.1%) women, with a
Acknowledgments: This work was presented in part at the 57th Annual Cancer Symposium of the Society of Surgical Oncology, New York, NY (USA), March 18-21, 2004.
Correspondence to: Prof Franco Lumachi, Endocrine Surgery Unit, Dipartimento di Scienze Chirurgiche e Gastreoenterologiche, University of Padua, School of Medicine, Via Giustiniani 2, 35128 Padua, Italy. Tel +39-049-8211812, fax +39-049-8211378, e-mail flumachi@unipd.it
Received November 6, 2006; accepted February 2, 2007.
median age of 54 years (range, 25-75 years). The base- line hormonal assessment included: 1) 24-h urinary epi- nephrine and norepinephrine, 2) upright plasma aldos- terone and plasma renin activity, and 3) plasma cortisol (8:00 am) measurements. Patients with abnormal base- line plasma cortisol (n = 3) underwent a 1 mg overnight dexamethasone suppression test. In hypertensive pa- tients (n = 12) and in those normotensive with nonho- mogeneous CT appearance of the mass (n = 6), repeated (at least two) measurements of 24-h urinary metanephrines and normetanephrines were also ob- tained. Once the patients had given their informed con- sent, they underwent image-guided FNAC. Moreover, abdominal MRI was performed in 33 (78.6%) patients, and 26 (61.9%) underwent NCS before FNAC.
Computerized tomography scanning
Helical CT examination was carried out with a single detector scanner (Siemens Somatom Emotion). Stan- dard parameters used for adrenal glands study were 130 kV and 150 mAs. The volume was acquired with 3 mm collimation, 1.5 pitch, 1.5 mm reconstruction thickness, and gantry rotation time of 0.8 sec. Images were ob- tained before and 70 sec after intravenous injection of a non-ionic iodinated contrast agent (100-120 ml, at a flow rate of 3 ml/sec). An attenuation value lower than 10 Hounsfield units (HU) was considered a sign of be- nignancy, whereas higher values of attenuation expres- sion suggested a malignant lesion. The density of adren- al glands was also measured after contrast administra- tion. Signs of malignancy were the presence of a non- homogeneous pattern suggesting tissue necrosis, infil- tration of the surrounding structures, and lymph nodes enlargement.
Magnetic resonance imaging
Non-enhanced MR images were acquired on a 1 Tesla scanner (Siemens Harmony 1T) equipped with a gradi- ent system of 20 mT/m, slew rate 25 mT/m/ms. The ex- amination included axial T1 weighted (TE 13, TR 384 ms) and T2 weighted (TE 108, TR 4000 ms) turbo spin echo sequences with 4 to 6-mm-thick slices and a gap of 0.4-0.6 mm. A phase array body coiling was used to im- prove the signal-to-noise ratio. The chemical shift char- acteristics were evaluated with in phase and out of phase sequences. After gadolinium-DTPA intravenous injec- tion (0.1 mmol/kg at a flow rate of 2.5 ml/sec), T1 weighted images with fat saturation showed the vascular pattern of the adrenal glands. Isointensity of the adrenal mass to the surrounding tissues at nonenhanced images and a homogeneous pattern after contrast were consid- ered signs of a benign lesion. T2 hyperintensity, no sig- nal reduction in the out of phase, and a nonhomoge- neous vascularization pattern suggested a malignancy.
Norcholesterol scintigraphy
NCS was performed using a radiolabeled cholesterol analogue (131I-6-ß-iodomethyl-norcholesterol). Medica-
tions that could interfere with uptake of the radiopharma- ceutical were suspended for the appropriate time. More- over, to prevent thyroid uptake of unbound iodine, pa- tients received Lugol’s solution two days before radiola- beled cholesterol administration. Three, 5 and 7 days af- ter intravenous injection (20 to 40 MBq) of the radio- pharmaceutical, posterior and occasionally lateral images containing between 200 and 400 k-counts per image were acquired. Images of kidney using 99mTc-DTPA were usually obtained for a better localization of the mass. A single-headed large field-of-view gamma camera (Sopha Medical DSX) equipped with a high-energy parallel-hole collimator was used. The intensity of adrenal uptake was evaluated with regard to background activity, especially hepatic and bowel activity. Weak or absent uptake on the side of the adrenal mass and regular uptake in the con- tralateral side represented signs of malignancy.
Image-guided FNA cytology
Ultrasound-guided (n = 31) or CT-guided (n = 11) FNAC using a spinal-type narrow-gauge (0.8 mm, 23 G) needle was performed in all patients. The technique has been previously described4. Local anesthesia was administered before ultrasound- and CT-guided FNAC. The smears of the FNA samples were spread on stan- dard glass slides, air dried and stained with May-Grün- wald-Giemsa stain, and the material was prepared by the cytopathologist who was present during the entire procedure4.5. No patient required hospitalization. Signs of malignancy were hyperchromasia due to coarsely granular chromatin, necrotic background, cellular pleo- morphism, increased nucleus-to-cytoplasm ratio, and the presence of prominent and large nucleoli6,7. All specimens were read by the same cytopathologist (SB). Nondiagnostic smears (n = 2) were immediately re- peated.
Surgery and pathology
All patients underwent laparoscopic (n = 26) or open (n = 16) unilateral adrenalectomy from two to three days after FNAC and were followed for at least 12 months after the operation. Reasons for surgery were one or more of the following: 1) greatest diameter of the mass 4 cm or more (n = 36), 2) suspicious appearance on CT scan (n = 15), MRI (n = 14) or both, 3) no uptake (n = 10) or increased uptake (n = 3) on NCS, 4) smears reading malignancy (n = 14), and 5) increase in size of the mass during the follow-up (n = 1). Open adrenalec- tomy was performed in patients with FNAC suggesting malignancy and in those with adrenal masses of 10 cm or more at CT scan. The patients were followed for at least 2 years. Weiss criteria were used to distinguish ma- lignant from benign tumors on final pathology8.
Statistical analysis
The reported data are expressed as mean ± standard deviation (SD), and comparisons between different groups were performed using the two-tailed Student’s t
test or the x2 test, as appropriate. Pearson’s correlation coefficient (R) calculation was used to evaluate the lin- ear relationship between pairs of variables. A value of P <0.05 was considered to be statistically significant. Sen- sitivity was defined as true-positive (TP)/TP + false- negative (FN), specificity as true-negative (TN)/TN + false-positive (FP), positive predictive values as TP/(TP + FP), negative predictive values as TN/(TN + FN), and accuracy as (TN + TP)/overall patients. Benign or prob- ably benign findings were considered as negative (TN or FN), whereas malignant or probably malignant find- ings were interpreted as positive (TP or FP)4.
Results
One-mg dexamethasone administration suppressed plasma cortisol to less than 3 g/dl in patients who un- derwent an overnight test, and repeated 24-h urinary metanephrine and normetanephrine measurements were within the normal range in all patients. The baseline hormonal assessment of the other patients was normal. The mass was right sided in 21 and left sided in 21 pa- tients. Table 1 reports the results of baseline endocrino-
| Parameter | Results | Normal range |
|---|---|---|
| Men : women | 18:24 | - |
| 24-h urinary epinephrine | 63.0 ± 20.6 | 5-110 nmol/d |
| 24-h urinary norepinephrine | 305.4 ± 124.7 | 40-600 nmol/d |
| Upright plasma aldosterone | 0.50 ± 0.4 | 0.14 -. 80 pmol/L |
| Upright plasma renin activity | 2.8 ±1.2 | 1.3-5.2 ng/L/s |
| Plasma cortisol (8 am) | 444.9 ± 155.5 | 198-695 nmol/L |
| Size at CT scan | 6.6±4.5 | - |
| Size at MRI | 7.0±5.3 | - |
| Size at final pathology | 6.9±5.1 | - |
| No. of patients | 42 | - |
logic screening and the size of the mass (mean ± SD) at CT scan and MRI. There was no relationship (R = 0.13, P = NS) between age of the patients and size of the mass.
The revised final pathology showed 30 (71.4%) be- nign adrenal incidentalomas (26 adrenocortical adeno- mas, of which 3 were atypical, 2 were ganglioneuro- mas, and 2 were nonfunctioning benign pheochromocy- tomas) and 12 (28.6%, 95% CI = 15-42) adrenal malig- nancies (8 adrenocortical carcinomas and 4 unsuspected adrenal metastases). Table 2 reports the histological fea- tures in patients with adrenocortical carcinomas accord- ing to the Weiss criteria. In all patients, the definitive diagnosis of adrenocortical carcinoma was obtained on the basis of local invasion at surgery or metastases.
The mass that increased in size during the follow-up was an adrenocortical adenoma. Patients with malignant adrenal incidentalomas were older than those with be- nign lesions (61 ± 12 vs 49 ± 14 years; P = 0.007). Baseline biochemical parameters did not differ signifi- cantly (P = NS) between groups. Seven of 30 benign tu- mors were 6 cm or more in diameter, and 5 of 12 malig- nant adrenal masses were 4 cm or less in diameter. Overall, no significant difference (P = NS) in size at CT scan, MRI, or final pathology was found between the two groups of patients, although benign adrenal inci- dentalomas were smaller than malignant masses. Thus, the size criteria was not useful to predict malignancy in our series. The size of the adrenal masses on removal was slightly underestimated by CT scan, but the differ- ence was not significant (P = 0.78). The results of adrenal imaging and image-guided FNAC are reported in Table 3. No relationship was found between histolog- ic features and adrenal imaging, whereas the mass of the patient with a false-negative FNAC was relatively small (3.5 cm).
| Patient no. | Nuclear grade (1) | Mitotic rate per 50 hpf | Atypical mitoses (2) | Cytoplasm (% clear) | Architecture of tumor (3) | Necrosis (3) | Invasion of venous structures (3) | Invasion of sinusoid (3) | Invasion of tumor capsule (3) |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 8 | 5 | 6 | 12% | 1 | 1 | 1 | 1 | 1 |
| 2 | 6 | 8 | 5 | 20% | 1 | 1 | 1 | 1 | 1 |
| 3 | 4 | 3 | 4 | 11% | 0 | 1 | 1 | 1 | 1 |
| 4 | 8 | 6 | 5 | 35% | 1 | 1 | 1 | 1 | 1 |
| 5 | 6 | 5 | 4 | 20% | 0 | 1 | 1 | 1 | 1 |
| 6 | 4 | 3 | 4 | 10% | 1 | 1 | 1 | 0 | 1 |
| 7 | 4 | 6 | 3 | 20% | 1 | 1 | 1 | 0 | 1 |
| 8 | 8 | 3 | 3 | 20% | 1 | 1 | 1 | 1 | 1 |
(1) Grade I = 0, Grade II = 4, Grade III = 6, Grade IV = 8; (2) number of atypical mitoses; (3) absent = 0, present = 1.
| TP | FP | TN | FN | Total | Sensitivity | Specificity | PPV | NPV | Accuracy | |
|---|---|---|---|---|---|---|---|---|---|---|
| CT | 9 | 4 | 26 | 3 | 42 | 75% | 66.7% | 69.2% | 89.6% | 83.3% |
| MRI | 11 | 1 | 20 | 1 | 33 | 91.7% | 95.2% | 91.7% | 95.2% | 93.9% |
| NCS | 8 | 1 | 16 | 1 | 26 | 88.9% | 94.1% | 88.9% | 94.1% | 92.3% |
| FNA | 11 | 0 | 30 | 1 | 42 | 91.7% | 100% | 100% | 96.8% | 97.6% |
TP, true-positive; FP, false-positive; TN, true-negative; FN, false-negative; PPV, positive predictive value; NPV, negative predictive value; CT, CT-scan; MRI, magnetic resonance imaging; NCS, norcholesterol scintigraphy; FNA, image-guided fine-needle aspiration cytology.
Immediate periprocedural complications occurred in 2 (4.7%, 95% CI, 2-11) patients. These included self- limited pneumothorax (n = 1) and severe pain (n = 1) requiring analgesic therapy. No postprocedural or late complications were observed. Figure 1 reports photomi- crographs of FNAC specimens from a patient with an adrenocortical adenoma and an adrenocortical carcino- ma, respectively.
CT scan had the lowest sensitivity and positive pre- dictive value, but the results of adrenal imaging and FNAC did not differ significantly (P = NS, x2 test). The patient with a FN smear had both MRI and NCS sug- gestive of malignancy. The sensitivity, negative predic- tive value and accuracy of FNAC + MRI together were 100%.
Discussion
Improvements in the resolution of imaging tech- niques have increased the number of asymptomatic adrenal incidentalomas, especially in patients with a history of malignancy9. The estimated prevalence of adrenal incidentalomas is about 2% in autopsy series, 0.1% among general health population screened by ul- trasonography, and 0.4% among patients evaluated for nonendocrinologic symptoms10. Approximately 80% of patients with adrenal incidentalomas have nonfunction- ing tumors, and less than 10% have subclinical hyper- cortisolism11. Few studies have reported a higher rate of subclinical Cushing’s syndrome (19%) or preclinical mild hormonal alterations (64%) among patients with adrenal incidentaloma, with an estimated cumulative risk of mass enlargement of 14% and 29% at 2 and 5 years, respectively11. In more than 50% of patients with a history of extra-adrenal malignancy, the adrenal mass may be a metastasis12. In contrast, in non-oncologic pa- tients the likelihood of malignancy of an adrenal inci- dentaloma is usually considered low, even though from 5% to 25% of masses show an enlargement in size dur- ing the follow-up9,13.
However, a high rate of malignant tumors (16%) and unsuspected pheochromocytomas (11%) was found in a group of 88 patients with adrenal incidentalomas select- ed for surgery by Luton et al.14 Moreover, in another group of 85 patients with adrenal incidentalomas treated by surgery, 17 adrenocortical carcinomas and 12 unsus- pected adrenal metastases were found, with an overall rate of adrenal malignancy of 34%15. The probability of malignancy is clearly related to tumor size, and there is a tendency of an association between age, male sex and risk of malignancy16,17.
The 2002 NIH Consensus Conference suggested that adrenalectomy should be considered both in patients with clinically inapparent functional adrenal tumors and in those with nonfunctioning adrenal incidentalomas ≥6 cm in diamemter18. Thus, in patients with adrenal inci- dentalomas between 4 and 6 cm in diameter, criteria other than size should be considered, with the aim of suggesting monitoring or surgery.
Both CT scan and MRI contribute significantly to the study of patients with adrenal masses, and CT is usually used as the primary method for the characterization of adrenal incidentalomas17,19. An inverse correlation be- tween adrenal lipid content (expressed as percentage of lipid-rich cortical cells) and both low attenuation at CT- scan and a signal intensity decrease at chemical shift MRI has been shown20. Similarly, Bae et al.21 found an inverse correlation between the mean attenuation of both unenhanced and contrast-enhanced adrenal adeno- mas and the percentage of pixels with less than 0 HU (negative pixel) in histogram analysis of CT images. This method was more sensitive than the 10-HU thresh- old method for diagnosis of adrenal malignancy. Re- cently, a 100% specificity using a noncontrast CT atten- uation value of 10 HU as a cutoff in characterizing whether an adrenal mass is adenoma or nonadenoma was reported19.
However, MRI was reported in several studies to be more effective than CT scan to distinguish between be- nign and malignant adrenal lesions, and the reported
specificity ranged between 90% and 95%22. Unfortu- nately, masses less than 1.5 to 2 cm in diameter were not correctly detected by NCS. However, in patients with adrenal incidentalomas of 3 cm or more in diame- ter, the sensitivity and accuracy of NCS in identifying adrenal adenomas reached 100% and 95%, respective- ly23,24. Dwamena et al.23 calculated that at a baseline ma- lignancy rate of 0.25, the diagnostic utility of CT scan and NCS could be 0.31 and 0.96, respectively. In our series, NCS and MRI had similar specificity (94% vs 95%) and accuracy (92% vs 94%), whereas CT scan was less sensitive than both NCS and MRI.
The usefulness of FNAC in the diagnosis of primary and metastatic adrenal lesions has long been reported25. Percutaneous image-guided adrenal biopsy is useful to confirm the presence and nature of suspected adrenal metastases, especially in patients with equivocal imag- ing characteristics. FNAC may reveal unsuspected adrenal malignancies, and the long-term follow-up sug- gests that negative biopsy truly excludes malignancy, with a negative predictive value of 100%26,27. In a multi- centric study, Saeger et al.28 reported that the sensitivity and specificity of adrenal biopsy were 94.6%, and 95.3%, respectively. Twenty-two adrenal carcinomas and 15 unsuspected adrenal metastases were found,
with an overall malignancy rate of 17%. Recently, Jhala et al.29 reported that endoscopic ultrasound-guided FNA may offer a novel opportunity to evaluate and obtain cytology samples from adrenal masses. In this study, 7 of 24 (29%) samples showed a adrenal malignancy.
At present, image-guided FNAC should be consid- ered a morbidity-free technique, since in the last 20 years few complications have been reported in the Eng- lish literature, ranging from 5% to 8%9,29,30.
In conclusion, several studies have shown a high rate of malignant masses among patients with adrenal inci- dentalomas, ranging from 16% to 34%6,14,15. A recent re- view of 50 biopsies performed in patients with adrenal masses revealed that only 6 (12%) were adenomas or be- nign masses, whereas 39 (78%) were an adrenal malig- nancy18,26. Unfortunately, the correct diagnostic approach to a patient with adrenal incidentalomas has not yet been established, and several preoperative imaging studies and algorithms of determining the optimal management of these lesions have been proposed3. In our preliminary study, the combination of image-guided FNAC and MRI reached 100% accuracy. We therefore suggest that it could be considered the strategy of choice in patents with nonfunctioning adrenal incidentalomas measuring 3 cm or more, with the aim of selecting patients for surgery.
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