Prevalence of Adrenal Carcinoma Among Incidentally Discovered Adrenal Masses
A Retrospective Study From 1989 to 1994
Massimo Terzolo, MD; Anna Alì, MD; Giangiacomo Osella, MD; Enrico Mazza, MD; for the Gruppo Piemontese Incidentalomi Surrenalici
Background: The incidental discovery of an adrenal mass poses the problem of distinguishing between the frequent benign masses and the infrequent malignant ones that require surgery. Univocal guidelines to approach this problem are unavailable.
Objective: To perform a survey of the clinical manage- ment of incidentally discovered adrenal masses (ie, ad- renal incidentalomas).
Design: A multicentric retrospective analysis of hospi- tal medical records of adrenal incidentalomas diag- nosed during a 5-year period; the medical records were scrutinized for demographic data and clinical details by means of a specifically tailored questionnaire.
Setting: The major surgical and medical centers of Pied- mont, a northern Italian region with approximately 4 mil- lion inhabitants. The recruitment pattern of these cen- ters was unselected.
Patients: The definition of adrenal incidentaloma was limited to patients with a physical examination and a clini- cal history unindicative of adrenal disease. Exclusion cri-
teria also included hypertension of suspected endocrine origin and a history of neoplasms known to metastasize frequently in the adrenal glands. Two hundred twenty- four medical records were collected, and 210 were ana- lyzed (14 excluded a posteriori).
Results: Most patients were in their 50s and 60s, and women were predominantly affected. The frequency of adrenocortical cancer was 13% among patients oper- ated on. The tumor diameter was highly correlated with the risk of cancer; a cutoff at 5 cm had a sensitivity of 93% with a specificity of 64% in discriminating between benign and malignant cortical lesions.
Conclusions: The occurrence of adrenocortical carci- noma among adrenal incidentalomas is not rare. The evaluation of the mass size is a simple and effective method for selecting patients at risk for cancer. The indication for surgery of masses larger than 5 cm, or of masses of any diameter that have suspicious imaging characteristics, limits unnecessary operations and costs.
Arch Surg. 1997;132:914-919
From the Clinica Medica Generale, Dipartimento di Scienze Cliniche e Biologiche (Drs Terzolo, Ali, and Osella) and Endocrinologia, Dipartimento di Fisiopatologia Clinica (Dr Mazza), Università di Torino, Turin, Italy. A complete list of the members of the Gruppo Piemontese Incidentalomi Surrenalici appears in the box on page 915.
A DRENAL incidentaloma re- fers to any adrenal mass discovered serendipi- tously during an abdomi- nal imaging evaluation per- formed for extra-adrenal complaints. Adrenal incidentaloma is accepted as a separate nosographic entity.1 This com- prehensive definition applies to many pathological entities, benign or malig- nant, adrenal or even para-adrenal, shar- ing the same modality of discovery.
After the detection of an inciden- taloma some diagnostic concerns arise. The first and most important one is to distin- guish between the frequent benign masses and the infrequent malignant ones, pri- mary or secondary. Radiological studies may help in identifying malignant masses through different imaging techniques, such as computed tomography (CT), adrenal scintigraphy, and magnetic resonance im- aging, sometimes used in combination.1-3
The second concern is to recognize hor- monal hypersecretion, usually by a corti- cal adenoma, because slight cortisol ex- cess may worsen associated diseases such as hypertension or diabetes. Incidentally discovered cortical adenomas could dis- play different alterations in the cortico- steroid secretory pattern that are recog- nized by an extensive endocrine wrkup. 4-6
Radiological series indicate a remark- able prevalence of adrenal inciden- taloma, present in approximately 3% of ab- dominal CT scans.7 The importance of this finding, and the consequent effect on health care costs, seems clear consider- ing that the use of CT will be ever grow- ing in the future. Univocal guidelines to
This article is also available on our Web site: www.ama-assn.org/surgery.
SUBJECTS AND METHODS
This is a retrospective study of patients with inciden- tally discovered adrenal masses in Piedmont. Twenty- six endocrinologic, surgical, or urologic centers of this region participated in the study. They were asked to search for all hospital medical records of patients bear- ing adrenal incidentalomas observed between 1989 and 1994. The recruitment pattern of these centers was un- selected, including either patients referred by general practitioners, radiologists, and other surgical or medi- cal specialists or patients in whom the diagnosis was first made in the center. A total of 224 cases have been identified from hospital medical records; these cases were scrutinized for demographic data and clinical details by means of a specifically tailored questionnaire. Requested information was about complaints leading to an abdomi- nal imaging study, imaging characteristics of the inci- dentally discovered adrenal mass, outcome of surgery, when performed, and survival of patients with adrenal cancer (Table 1). Imaging data were obtained by re- viewing radiologists’ reports. The definition of an in- cidentally discovered adrenal mass was limited a priori to cases with a physical examination and a clinical his- tory unindicative of adrenal disease. Exclusion crite- ria included the presence of paroxysmal or severe hy- pertension, ie, hypertension resistant to therapy or as- sociated with hypokalemia and a history of neoplasms known to metastasize with high frequency in the ad- renal glands (ie, lung, kidney, or breast cancer and mela- noma). The participating centers were also requested to search for all hospital medical records of patients with clinically overt adrenal cancer (ie, symptomatic for cor- tisol or sex hormone hypersecretion or both, mass ef- fect, or metastases) observed during the same period (1989-1994). Requested information was about demo- graphic data, disease extent, hormone secretion, and survival. Even if a central independent review of his- tological diagnoses was not set up, all specimens were evaluated by expert pathologists. Common criteria were followed for diagnosing primary adrenal carcinoma. In cases without metastatic involvement, the diagnosis was based mainly on regressive changes (ie, necrosis, hem- orrhage, fibrosis, or calcification); invasion of the ad- renal capsule, blood vessel wall, or both; and atypical mitotic figures.
All questionnaires were collected, reviewed, and analyzed in one center. Data were entered and analyzed with a software program (Statistics, Microsoft Corp, Tulsa, Okla) run on a personal computer (M386/25, Olivetti, Ivrea, Italy). Because criteria of normal distri- bution were not satisfied with the Wilk-Shapiro test, statistical analysis was performed using nonparamet- ric methods. A Mann-Whitney U test, a Kolgomorov- Smirnov test, and a Kruskal-Wallis 1-way analysis of variance were used for numerical variables, as appro- priate. The Fisher exact test or a x2 test for 2 by 2 tables was used for categorical variables. The relationship of the occurrence of adrenal carcinoma as a function of age, sex, and size of the mass was evaluated by multiple logistic regression analysis. Correlation analysis was per- formed using the Spearman rank correlation method. Levels of statistical significance were set at P <. 05. Data are expressed as the median and range.
Gruppo Piemontese Incidentalomi Surrenalici
Clinical Centers and Principal Investigators
A. O. Molinette, Torino: Sergio Abeatici, MD; Franco Camanni, MD; Marcello Dei Poli, MD; Ettore Masenti, MD; Carlo Maria Fronticelli, MD; Gian Michele Molinatti, MD; Paolo Limone, MD; Francesco Morino, MD; Antonio Mussa, MD; Anto- nio Robecchi, MD; Salvatore Rocca Rossetti, MD; Carlo Ter- rone, MD. Ospedale Sant’Andrea, Vercelli: Fernando Acan- fora, MD. A. O. San Luigi, Orbassano: Alberto Angeli, MD; Dario Fontana, MD; Maurizio Bellina, MD. Ospedale Civ- ile, Castellamonte: Arturo Baldi, MD. Ospedale Civile, Chi- vasso: Fiorenzo Ballario, MD. Ospedale Civile, Alessandria: Carmelo Boccafoschi, MD; Giuseppe Spinoglio, MD. Os- pedale Civile, Giaveno: Antonello La Brocca, MD.A. O. Santa Croce e Carle, Cuneo: Giorgio Borretta, MD; Gian Paolo Magro, MD; Luigi Quaranta, MD. Ospedale Mauriziano, Torino: Luigi Capussotti, MD; Pier Giorgio Nasi, MD; Do- menico Fonzo, MD. Ospedale Maggiore, Novara: Marcello Garavoglia, MD. Ospedale Valdese, Torino: Luigi Locatelli, MD. Ospedale Valdese, Pomaretto: Flavio Maina, MD. Os- pedale di Borgomanero, Borgomanero: Mariano Martinoli, MD. Ospedale Maria Vittoria, Torino: Michele Messina, MD.
Table 1. Information Requested by Questionnaire
General data: name initials, sex, age at the time of diagnosis, and date of diagnosis
Diagnosis modality: imaging procedure leading to the diagnosis and reason for the imaging procedure Associated diseases: hypertension, diabetes mellitus, endocrine diseases, and neoplasms Physical examination results
Radiological evaluation: side of incidentaloma, radiological characteristics of the mass at ultrasonography and computed tomography (ie, size, density, shape, and margins), and results of iodine 131-60-iodomethylnorcholesterol and 1311 metaiodobenzylguanidine adrenal scintigraphy
Pathological diagnosis: date of surgery or fine needle aspiration biopsy and histological (or cytologic) diagnosis Hormonal evaluation: type of endocrine workup (ie, basal or dynamic testing) and outcome Survival of patients with adrenal cancer
approach the incidentally discovered adrenal masses are lacking. To create cost-effective protocols, a better knowl- edge of the epidemiological features of adrenal inciden- taloma is warranted, and this objective can be reached only by evaluating large series.
We performed a retrospective analysis of adrenal in- cidentaloma diagnosed during a 5-year span in 26 cen- ters of Piedmont, a northern Italian region with approxi- mately 4 million inhabitants.
RESULTS
Twenty-six centers, 8 medical and 18 surgical, partici- pated in the study. Two hundred ten of 224 collected cases were included, whereas 14 were excluded a posteriori be- cause they did not fulfill the inclusion criteria. The re- cruited cases were evenly obtained during the observa- tion period. Medical and surgical series consisted of 118 (56%) and 92 (44%) of the patients, respectively. Eighty- five patients were men and 125 were women (40% vs 60%,
70
60
50
No. of Patients
40
30
20
10
0
10
20
30
40
50
60
70
80
90
Age, y
160
120
No. of Patients
80
40
0
5
10
15
20
25
30
Diameter Found by CT, cm
| Patient No./ Age, y/Sex | Reason for Radiological Study | Computed Tomographic Characteristics* | Survival, mo | |||
|---|---|---|---|---|---|---|
| Diameter, cm | Density | Shape | Margins | |||
| 1/45/F | Renal colic | 15.0 | Inhomogeneous | 14 | ||
| 2/43/M | Fever | 6.0 | Inhomogeneous | Irregular | Irregular | +12 |
| 3/58/F | Abdominal pain | 8.0 | Irregular | |||
| 4/20/F | Abdominal pain | 13.0 | Inhomogeneous | Round | Irregular | 12 |
| 5/70/F | Weight loss | 9.5 | Hypodense | Oval | ||
| 6/38/M | Check up | 3.7 | Inhomogeneous | Irregular | Irregular | +12 |
| 7/58/F | Abdominal pain | 7.5 | Inhomogeneous | Round | +48 | |
| 8/56/M | Asthenia | 25.0 | Inhomogeneous | Irregular | +12 | |
| 9/31/F | Abdominal pain | 6.0 | Inhomogeneous | Oval | Regular | 1 |
| 10/42/M | Dyspepsia | 10.5 | Inhomogeneous | Irregular | +48 | |
| 11/31/M | Abdominal pain | 6.5 | Irregular | 1 | ||
| 12/49/M | Abdominal pain | 13.0 | Inhomogeneous | Irregular | Irregular | +36 |
| 13/67/M | Renal colic | 5.0 | Inhomogeneous | |||
| 14/55/F | Abdominal pain | 5.6 | Inhomogeneous | Irregular | Irregular | 6 |
| 15/43/M | Abdominal pain | 6.0 | Inhomogeneous | Irregular | Irregular | 24 |
*Ellipses indicate data not available.
P <. 001); the patients were aged 18 to 83 years (mean±[SD], 55.3±13.7 years; median, 57.0 years). Fifty-six percent of the patients were in their 50s and 60s (Figure 1). The main complaints leading to an abdominal imaging procedure were abdominal pain (30%), medical checkup (20%), postsur- gery follow-up (12%), and renal colic (7%). In 25% of the cases, an abdominal evaluation was done for other rea- sons, including abdominal trauma or acute abdomen (miss- ing data, 6%). The adrenal mass was discovered by ultra- sonographic (US) scan in 150 cases (71%) and by CT in 55 cases (26%). All US diagnoses were confirmed by CT. Magnetic resonance imaging was also performed in 15 cases. Four cases were discovered during surgery, and one (a cal- cified lesion) was discovered by plain x-ray film. Masses were more frequent on the right compared with the left side (119 cases [57%] vs 74 cases [35%], P <. 001), while bilat- eral lesions accounted for 6% (missing data, 2%). When considering separately the cases diagnosed by CT, the side difference was no longer apparent (right side, 21 cases [40%]; left side, 29 cases [55%]; and bilateral lesions, 3 [5%]). The diameter of the masses ranged from 0.5 to 25.0 cm (median, 3.1 cm) and was significantly larger in sur- gical than medical series (median, 4.0 vs 2.9 cm; range, 1.5- 25.0 vs 1.0-15.0 cm; P <. 001). No significant difference in
diameter by side was observed (right vs left side median, 3.2 vs 3.4 cm; range, 1.0-25.0 vs 0.5-14.0 cm; P =. 80). The median size of nonoperated on masses was 2.5 cm (range, 0.5-8.0 cm). Most masses (74%) had a diameter that was smaller than 5 cm (Figure 2). It was possible to compare the mass size measured by US scanning with CT scanning in 148 patients. The 2 imaging procedures were superim- posable for size measurement (r=0.93, P <. 001).
One hundred seventy-eight patients (85%) underwent an endocrine work-up, even incomplete, and 115 (54%) un- derwent adrenalectomy with removal of 59 cortical adeno- mas (51%), 15 carcinomas (13%), 14 lipomas-myelolipomas (12%), 10 pheochromocytomas (9%), 8 tumors of neuro- nal lineage (7%), 7 cysts (6%), 1 metastasis from an undif- ferentiated adenocarcinoma (1%), and 1 calcified reliquate of a tubercular lesion (1%). Individual data for patients with incidental adrenal cancers are given in Table 2. Data from the 12-month clinical and radiological follow-up were avail- able for 41 of the 95 patients who were not operated on. Overt signs of hormone hypersecretion did not develop in any of the patients, and the mass size was found to be notably in- creased in only 1 patient. This patient was operated on, and the histological diagnosis was cortical adenoma. Two patients, who had masses with diameters of 8.0 and 7.5 cm, under-
28
24
Diameter Found by CT, cm
20
16
12
.
8
.
.
.
.
-
.
4
.
L
1
1
0
Carcinoma
Myelolipoma
Neural Lineage
Other
Adenoma
Cyst
Metastasis
Pheochromocytoma
went a fine needle aspiration biopsy, which led to diagno- sis of adrenal carcinoma in both cases; both patients refused surgery. A fine needle aspiration biopsy was also performed on a patient in whom a lung mass was found after the dis- covery of the adrenal incidentaloma; in this patient, the di- agnosis was metastasis from small-cell lung cancer.
No significant age difference was found between pa- tients with adrenocortical carcinoma or adenoma (50 years [range, 20-70 years] vs 56 years [range, 20-83 years], P =. 06). Overall, adenomas were smaller than carcinomas (3.1 cm [range, 2-15 cm] vs 8.0 cm [range, 3.7-25.0 cm], P <. 001; mean[±SD], 3.9±2.0 vs 9.4±5.6 cm) (Figure 3). For the multivariate analysis, diameter was the only variable sig- nificantly correlated with cancer (P <. 001). To evaluate the diagnostic value of different diameter cutoffs for identify- ing adrenal cancer, the standard methods for calculating sensitivity, specificity, and predictive value were used: sensitivity=true positive/(true positive+false negative); specificity=true negative/(true negative+false positive); positive predictive value=true positive/(true positive + false positive); and negative predictive value=true negative/ (true negative + false negative). The cutoff at 5 cm proved to be the best discriminant (Table 3). The CT picture of adrenal adenomas was a round-oval hypodense mass with regular margins in most cases. Conversely, adrenal carci- nomas were mostly hyperdense or inhomogeneous masses with an irregular shape and irregular margins (Figure 4).
During the same 5-year period, 16 clinically overt ad- renal cancers were observed and operated on. Cushing syn- drome was apparent in 11 patients, and metastases were present at diagnosis in 4 patients. The comparison of sex distribution, age, and tumor diameter of overt compared with incidental adrenal cancers did not yield significant differences (M/F, 6 of 10 vs 6 of 9, P =. 76; 42 years [range, 17-63 years] vs 50 years [range, 20-70 years], P =. 51; 10.0 cm [range, 6.0-15.0 cm] vs 8.0 cm [range, 3.7-25.0 cm], P =. 81). Follow-up data for patients with adrenal cancer were available for 12 incidental and 14 clinically known cancers with a median follow-up of 20 months (range, 1-56 months). Overall, 61% of the patients died of disease pro- gression during this period (6 of them had incidental can- cers and 10 had overt cancers).
| Cutoff, cm | Sensitivity, % | Specificity, % | Positive Predictive Value, %* | Negative Predictive Value, %* |
|---|---|---|---|---|
| 3.0 | 100 | 18 | 15 | 100 |
| 4.0 | 93 | 43 | 19 | 98 |
| 5.0 | 93 | 64 | 28 | 98 |
| 6.0 | 78 | 75 | 31 | 96 |
* The positive predictive value equals TP/(TP+FP), where TP indicates a true positive (ie, adrenocortical cancer with a diameter larger than the examined cutoff) and FP indicates a false positive (ie, a benign mass with a diameter larger than the examined cutoff). The negative predictive value equals TN/ (TN+FN), where TN indicates a true negative (ie, a benign mass with a diam- eter smaller than the examined cutoff) and FN indicates a false negative (ie, adrenocortical cancer with a diameter smaller than the examined cutoff).
R
L
Pheochromocytomas, as a group, had a larger di- ameter than cortical adenomas (5.0 cm [range, 3.0-9.5 cm] vs 3.1 cm [range, 2.0-15.0 cm], P <. 01; mean[±SD], 5.8±2.0 vs 3.9±2.0 cm) (Figure 3). The age of patients with pheochromocytoma was superimposable with that of patients with cortical adenoma (56.5 years [range, 32-76 years] vs 56 years [range, 20-83 years], P =. 92).
COMMENT
The prevalence of serendipitous adrenal lesions in pa- tients who underwent CT scanning for reasons other than suspected adrenal disease is between 0.4% and 4.3%.8-13 The prevalence is expected to increase in the future due to in- creasing use of high-resolution imaging procedures. In large autopsy series, the prevalence of adrenal masses found in patients who died without any premortem suspicion of ad- renal disease ranged from 1.4% to 8.7%.10,14-18 Incidentally discovered adrenal masses pose the problem of distinguish- ing the rare malignant lesions from the vast majority of be- nign ones, avoiding unnecessary surgery.
In the past few years, several studies4,10.19,20 have ex- amined endocrine or radiological features of inciden- talomas in an attempt to define management strategies. Nevertheless, univocal guidelines arising from epide-
miological studies are still lacking. Therefore, this study gathered demographic, clinical, and radiological data on patients with adrenal incidentaloma who sought medi- cal or surgical advice in Piedmont from 1989 to 1994.
This study confirms that, even with a wide age distri- bution, most patients with adrenal incidentaloma are in their 50s and 60s.13 The higher prevalence in women could be partly due to a referral bias (ie, more imaging studies are recommended for women) even if this sex difference was also observed for adrenal masses found at autopsy.16,18 The predominance of US diagnoses reflects the frequent use of this technique in the diagnostic work-up of various medi- cal problems. This series is representative of the modality of discovery of incidental adrenal masses in Italy, but the practice in other countries could well be different. The most frequent occurrence of an incidentaloma on the right side is likely due to the better US visualization of an adrenal mass on that side, as US scanning was the diagnostic examina- tion in most cases. In fact, the side predominance disappeared considering separately the cases diagnosed by CT. Mass size measured by US and CT scans was superimposable; this find- ing may be in favor of US scans for the follow-up of such patients to reduce radiation exposure and expense.
Because of the multicentric nature of the study, in- dications for surgery were not identical everywhere, but they were mainly based on the size of the mass, as inci- dentalomas of patients enrolled by surgical centers were larger than those of patients enrolled by medical cen- ters. Patients who did not undergo surgery usually had small lesions or large masses with clear CT features of myelolipoma. However, many patients underwent adre- nalectomy, which was possibly an overtreatment in some cases. A critical appraisal of this experience should lead to more stringent indications for surgery. The fol- low-up data of patients who were not operated on show that in most of them, at least in the short-term, overt signs of hormone hypersecretion do not develop and that their adrenal masses do not increase in size. These findings should be confirmed in a large prospective study; they suggest a more conservative therapeutic approach.
The occurrence of adrenocortical carcinoma was not rare, accounting for 13% of operated on lesions. In the over- all series, 15 histologically proven adrenal cancers were found in 210 cases. Two other patients in whom cortical carcino- ma was diagnosed by a fine needle aspiration biopsy refused surgery. Due to the inherent difficulties in the histological distinction between well-differentiated adrenal cancer and adrenal adenoma, 19 some adjunctive cases could have been lost. The lack of a central histological review is a limit of this study. However, common histological criteria for ad- renal cancer were employed, and the survival rate of the pa- tients with cancer was consistent with the diagnosis.
During the same 5-year period, 16 clinically symp- tomatic adrenocortical carcinomas were diagnosed in the same centers. These data fit well with the notion that hy- persecretory carcinomas account for approximately half of all diagnosed primary adrenal cancers.20 No notable difference was found between overt and incidental can- cers for sex distribution, age at diagnosis, and tumor size. Metastases at diagnosis were apparent only in the group of patients with overt cancers; they were found in 25% of the cases. In most series of hypersecretory cancers
women outnumber men, while the opposite is found for nonfunctioning cancers.21 Elderly patients are reported to have a higher incidence of silent carcinomas.22 This study confirms these assumptions only partially.
Data from Italian Cancer Registries report an inci- dence of adrenocortical cancer of approximately 0.2 to 0.3 per million persons per year.23 The frequency observed in this study distinctly exceeds that estimate and indicates that the annual incidence could be at least in the range of 1.0 to 2.0 per million persons, as reported in the United States and Finland.24-26 Specific epidemiological observatories are needed to ascertain precisely the frequency of this particu- lar cancer.
In subjects without any known primary extra-adrenal tumor the overall hazard of discovering a primary malig- nant lesion of the adrenal glands is low. In a recent meta- analysis, 26 cortical carcinomas were reported for 630 in- cidentalomas (4%; range, 0%-25%); series with a higher prevalence were probably biased by the small sample size.20 Attempts to separate benign from malignant lesions have been based on imaging characteristics, scintigraphic pat- terns, and biochemical screening, sometimes in combina- tion. Categorization from imaging studies was especially focused on size. The probability of cancer increases as a func- tion of mass size,27 but there is no consensus on the thresh- old below which a lesion may be safely considered benign. The tumor size requiring surgical removal has been vari- ously set at 2.5, 3.0, 3.5, 4.0, 5.0, and 6.0 cm,8,10,11,13,22,28-31 but the rate of benign lesions exceeds that of malignant ones at any of these cut points. 13,32.33 Copeland22 estimated that at a threshold diameter of 6 cm, more than 60 adrenalec- tomies would be needed to remove 1 adrenal carcinoma. The detractors of size criteria underline that, at an early stage, adrenal cancers are small and at this point surgical inter- vention may be more beneficial.20 In addition, adrenal tu- mors smaller than 2.5 cm have occasionally been reported. 34
This study adds new data in favor of the size crite- rion, as the tumor diameter was highly correlated with the risk of cancer. Moreover, the size comparison between cor- tical carcinomas and adenomas, the most frequent cause of incidental masses, yielded a statistically significant dif- ference even with a partial overlap. The higher diagnostic value was found with a cutoff at 5.0 cm, which would have missed one carcinoma (at 3.7 cm), resulting in a sensitiv- ity of 93% in discriminating between benign and malig- nant lesions, with a specificity of 64%. The positive pre- dictive value was 28%, and the negative predictive value was 98%. It was previously calculated that the negative pre- dictive value for an adrenal carcinoma with a diameter smaller than 6.0 cm was close to 100%.29
Some anatomical features on high-resolution CT are useful to characterize incidentally discovered adrenal masses. Adrenal adenomas appear as smoothly margin- ated, homogeneous masses with a relatively low CT den- sity, whereas adrenal carcinomas often exhibit irregular margins and inhomogeneous density.35,36 Myelolipomas and simple cysts have recognizable characteristics on CT; nevertheless, many masses exhibit nonspecific fea- tures.35.36 The results of this study confirm that CT may be of value in the differential diagnosis of adrenal carci- nomas even if the lack of a central radiological review lim- its the interpretation of CT characteristics. The only car-
cinoma smaller than 5 cm exhibited irregular margins and appeared inhomogeneous on a CT scan.
Biochemical screening for hormone hypersecretion could allow the detection of subtle cortisol excess that, in the absence of any physical stigmas, is typical of adreno- cortical adenomas.45 Conversely, an increase in andro- gens, in particular dehydro-3-epiandrosterone sulfate, may be taken as a marker of adrenocortical carcinomas.4 How- ever, biochemical markers are not sufficiently sensitive.5 In this series, an adequate endocrine evaluation was per- formed only in relatively few patients, thus rendering a sta- tistical evaluation unsuitable. In the past, an extensive bio- chemical screening was not recommended, as a purely statistical approach gave an estimated chance of 58 carci- nomas per 100 000 patients bearing an adrenal mass.28,37 From the analysis of recent literature and from this study, it seems that such an estimate underscores the problem.
Adrenal metastases in this series were found in only one patient who underwent surgery and in another patient who underwent a fine needle aspiration biopsy. An expla- nation is offered by strict inclusion criteria. In the setting of known extra-adrenal primary malignant lesions, the fre- quency of adrenal metastases has ranged from 32% to 73%.20
Clinically silent pheochromocytomas were well rep- resented among incidentalomas (9% of the patients who un- derwent surgery). This finding is not surprising, as many pheochromocytomas remain undiagnosed and may be dis- covered postmortem.38,39 It is well known that many patients with pheochromocytoma may have mild signs and symp- toms.+ In this series, only 6 of 10 patients with pheochro- mocytoma were defined as hypertensive. Pheochromocy- tomas were larger than adrenocortical adenomas, with a di- ameter larger than 5 cm in all but one. However, any incidental pheochromocytoma requires extirpation because it could cause potentially lethal hypertensive crises.40 A high mortality has been reported in patients with unsuspected pheochromocytoma who underwent surgery or were anes- thetized.38,39 Clearly, a biochemical screening aimed to ex- clude this possibility is strongly advocated (it was done in only 7 of 10 patients in this series).
This study suggests that the pathological diagnosis of adrenal incidentaloma may be primary adrenal carcinoma or pheochromocytoma in many cases. The evaluation of the tumor size by CT is a simple and cost-effective discriminat- ing criterion, and imaging characteristics are also helpful. A cutoff at 5 cm has a good sensitivity for defining patients at high risk of cancer or pheochromocytoma who are, there- fore, candidates for surgery. On the other hand, the indi- cation for surgery of masses larger than 5 cm, or of masses with any diameter that have suspicious imaging character- istics, limits unnecessary operations and costs.
Reprints: Massimo Terzolo, MD, Clinica Medica Generale, Azienda Ospedaliera San Luigi, Regione Gonzole 10, 10043 Orbassano (TO), Italy.
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