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Preexisting adrenal masses in patients with adrenocortical carcinoma: clinical and radiological factors contributing to delayed diagnosis
Levent Ozsari1 . Merve Kutahyalioglu1,2 . Khaled M. Elsayes3 . Rafael Andres Vicens3 . Kanishka Sircar4 . Tarek Jazaerly4 . Steven G. Waguespack1 . Naifa L. Busaidy1 .
Maria E. Cabanillas1 . Ramona Dadu1 . Mimi I. Hu1 . Rena Vassilopoulou-Sellin1 . Camilo Jimenez1 . Jeffrey E. Lee5 . Mouhammed Amir Habra1
Received: 16 April 2015 / Accepted: 16 July 2015 @ Springer Science+Business Media New York 2015
Abstract Adrenocortical carcinoma (ACC) is a rare endocrine malignancy that is usually large (>5 cm) at time of diagnosis. Delayed diagnosis significantly worsens sur- vival. We describe adrenal gland morphology prior to ACC diagnosis and discern potential causes of delayed diagno- sis. ACC patients seen at The University of Texas MD Anderson Cancer Center between 1998 and 2014 who had cross-sectional body imaging ≥3 months prior to their diagnosis. We conducted a detailed review of clinical and radiological features in these patients prior to ACC diag- nosis. Of 439 patients with ACC, 25 had imaging preced- ing ACC diagnosis (5 with normal adrenal glands and 20 with preexisting masses). On the first available images, the median mass size was 2.8 cm (range 0-9) with median precontrast density of 36 Hounsfield units (range 17-43)
The data were presented as an oral abstract at Endocrine Society’s 96th Annual Meeting in June 2014 in Chicago, Illinois.
Levent Ozsari and Merve Kutahyalioglu have contributed equally to this paper.
☒ Mouhammed Amir Habra mahabra@mdanderson.org
1 Department of Endocrine Neoplasia and Hormonal Disorders, Unit 1461, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
2 Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
3 Department of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
4 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
5 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
and became 9 cm (range 1-18) at the time of ACC diag- nosis. The median interval between first available image and ACC diagnosis was 20 months (range 3-89). In the 5 patients whose initial images showed normal adrenal glands, the time between the last normal scan and ACC diagnosis ranged from 5 to 36 months. The most common reason for delayed ACC diagnosis was the presumed benign status of the preexisting mass (n = 13, 65 %). Radiologically suspicious adrenal masses can precede ACC diagnosis and have variable growth patterns. ACC can also develop de novo within a few months in a radiologically documented normal adrenal gland. The presumed benig- nancy of preexisting masses based on size is the main reason for delayed ACC diagnosis.
Keywords Adrenocortical carcinoma · Delayed diagnosis · Hounsfield units · Computed tomography
Introduction
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy that has a relatively stable annual incidence of 0.72-1.30 cases per million people in the United States and Europe [1, 2]. ACC is a highly aggressive tumor that requires early diagnosis and prompt treatment. Delays in ACC diagnosis are expected to decrease the life expectancy of these patients. Current clinical guidelines recommend resection of adrenal tumors with diameters more than 4-6 cm because malignant potential increases in adrenal masses >4 cm and especially in those with a diameters >6 cm. Also, it is recommended to remove radiologically suspicious adrenal incidentalomas even if small [3, 4]. Although surgical series tend to overestimate the true prevalence of ACC, ACCs are thought to represent 2 % of
adrenal incidentalomas that are <4 cm at the largest diameter and 25 % of adrenal incidentalomas with diam- eters >6 cm [5]. Furthermore, patients with stage I ACC (≤5 cm and confined to the adrenal gland) have a 5-year overall survival rate approaching 80 %; in contrast, patients with stage IV ACC have a 5-year overall survival rate of about 10-15 % [6]. Unfortunately, most ACC cases (52-59 %) are diagnosed at stage III/IV, with few patients (3.3-5.5 %) diagnosed at stage I [6, 7]. Therefore, although rare, ACCs need to be identified earlier to improve out- comes. Diagnosing ACC at stage I or II allows complete surgical resection with curative intent, but advanced ACC (stages III and IV) is often inoperable and is associated with poor outcomes [7-9].
The premise of this study is that the reliance on adrenal mass size alone reduces the ability to diagnose ACC at earlier stages (at sizes <4 cm). However, data on events leading to ACC development are limited. In particular, it is unclear whether ACC develops de novo or from a preex- isting adrenal mass. Based on clinical observations, we suspected that some ACC patients would have initial findings of adrenal incidentalomas that were presumed to be benign because they were <4 cm. Thus, radiological features other than size could predict the malignant potential of adrenal masses.
In this report, we assessed the adrenal gland morphology prior to ACC diagnosis and summarized potential causes of delayed ACC diagnosis.
Patients and methods
Under an Institutional Review Board approved protocol, we retrospectively reviewed the records of patients with ACC seen at The University of Texas MD Anderson Cancer Center between 1998 and 2014. We included only patients who underwent cross-sectional body imaging studies involving the adrenal glands at least 3 months before their ACC diagnosis. Essential demographic and clinical features such as age, sex, and potential reasons for delayed ACC diagnosis were collected from patients’ medical records. The available cross-sectional images were independently reviewed by two body imaging radiologists (K.M.E. and R.A.V.). Tumor sizes, growth rates, and important radio- logical characteristics (size, heterogeneity, calcifications, and precontrast density) were derived from the first available cross-sectional scans involving the adrenal glands and from subsequent scans until the ACC diagnosis. Unenhanced density was measured using a circular region of interest covering at least one-half of the adrenal mass while avoiding cystic, necrotic, or calcified regions [10].
If the adrenal mass had been biopsied or surgically resected before referral to MD Anderson, the pathological
diagnosis of ACC was confirmed at our institution as part of our standard practice during the patient’s first visit. From these data, we summarized key pathological features including Weiss score (ACC if Weiss score ≥3) and markers of cellular proliferation (Ki67 % or mitotic rate) when available [11-13]. Disease stage was determined at the time of ACC diagnosis according to the European Network for the Study of Adrenal Tumors staging system. Stage I ACC is defined as ACC confined to the adrenal gland and measuring ≤5 cm, stage II is defined as ACC confined to the adrenal gland but measuring >5 cm, stage III is defined by either having a primary tumor with extra adrenal invasion of surrounding tissues (T3) or surrounding organs/great vessels (T4) or the presence of regional lymph node metastasis (N1), and stage IV is defined by the presence of distant metastasis (M1) [6].
Descriptive statistical measures (medians, ranges, and frequencies) were calculated to define patients’ demo- graphic and clinical features. Stata 12 statistical software (College Station, TX) was used.
Results
Patient characteristics
Of 439 patients with ACC seen at MD Anderson between 1998 and 2014, 37 (8.4 %) had reported preexisting adrenal images before their ACC diagnosis. Twelve of 37 patients had adrenal masses on imaging documented only in the written medical records (without imaging available for review), and these patients were excluded from our anal- ysis. The other 25 patients who had available cross-sec- tional images involving the adrenal glands formed our study population (Fig. 1). In 23 of the 25 patients, the first images had been obtained outside our institution, and the
ACCs with imaging prior to diagnosis 439
Prior imaging documented in medical records only 12
Prior imaging studies available for review 25
Preexisting mass 20
Normal adrenal glands 5
patients were referred to us later, around the time of their ACC diagnosis.
Table 1 summarizes the essential features of these 25 patients (15 women and 10 men).
The median age at diagnosis was 53 years (range 22-82 years) and the majority were white (76 %).
Radiological features
Of the 25 patients with available cross-sectional adrenal images obtained prior to ACC diagnosis, 19 had computed tomography (CT) of the abdomen, three had CT of the chest, two had positron emission tomography/CT, and one had magnetic resonance imaging of the abdomen. The number of available studies per patient before ACC diag- nosis ranged from one to five (13 patients with one image, six with two images, three with four images, and three with five images). The indications that led to the first available studies are summarized in Table 1.
| Characteristic | Valueª |
|---|---|
| Median age at ACC diagnosis (range) | 53 (22-82 years) |
| Sex | |
| Female | 15 |
| Male | 10 |
| Race | |
| White | 19 |
| Hispanic | 4 |
| Black | 2 |
| Stage at ACC diagnosis | |
| Stage I | 3 |
| Stage II | 6 |
| Stage III | 7 |
| Stage IV | 9 |
| Type of first imaging | |
| CT of the abdomen | 19 |
| CT of the chest | 3 |
| Positron emission tomography/CT | 2 |
| Magnetic resonance imaging of the abdomen | 1 |
| Indication for first imaging study | |
| Incidentalomab | 14 |
| Cancer surveillance | 4 |
| Suspected hormonal overproduction | 4 |
| Hypertension work-up | 2 |
| Unknown | 1 |
a Frequencies are shown except where otherwise indicated
b Imaging was indicated for medical reasons other than a need to assess the adrenal glands
Of these 25 patients, five had normal adrenal glands on the first available imaging studies, whereas 20 patients had preexisting adrenal masses on the imaging studies pre- ceding ACC diagnosis. The median tumor diameter on the first available images was 2.8 cm (range 0-9 cm) and 9 cm (range 1-18) at the time of ACC diagnosis (Fig. 2). The size of the adrenal mass on the initial study was <4 cm in 14 of 20 patients (70 %), and 4-6 cm in three other patients (15 %).
The median interval between the first available study and ACC diagnosis was 20 months (range 3-89 months). On their first study, heterogeneous appearance of the adrenal mass was noted in 14 patients (70 %). The pre- contrast density of the mass was measurable in 15 of these 20 patients, with a median value of 36 Hounsfield units (HU) (range 17-43). Absolute percentage washout values were not available, as none of the initial scans were done with an adrenal protocol.
Calcification of the adrenal masses was detected on three CT studies. Growth patterns of preexisting masses from the first available scans through ACC diagnosis are shown in Fig. 3.
Clinical and pathological features
The indications that led to the first adrenal imaging studies in our patient population were variable. The most common indications were medical reasons other than a need to assess the adrenal glands (incidental findings), followed by cancer surveillance and suspected hormonal overproduction.
In 18 evaluable cases, Weiss scores ranged between 3 and 8. In six patients, Weiss score was not calculated because the ACC was diagnosed on clinical grounds sup- ported by fine-needle aspiration. In one female patient,
2
15
Size (cm)
10
:
5
0
First Available Image
At ACC diagnosis
(a) Patients with normal adrenal gland on initial scans (n=5)
18
17
16
14
Tumor Size (cm)
12
10
8
6
4
2
0
0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
90
Months from first image to initial diagnosis
(b) Patients with adrenal mass seen on prior scans (n=20)
18
17
16
☒
14
☒
Tumor Size (cm)
12
☒
10
8
6
☒
4
2
0
0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
90
Months from first image to initial diagnosis
☐ Stage 1
☐ Stage 2
Stage 3
☐ Stage 4
ACC was diagnosed clinically after the patient experienced severe virilization, with biochemical confirmation of increased adrenal androgen levels and imaging studies showing a large adrenal mass and metastases. Ki67 is often used as a marker of cell proliferation, and Ki67 data were
available in eight cases with a median of 35 % (range 12-70 %), indicating a high rate of proliferation. Mitotic rate is another marker of cellular proliferation. In the 16 cases with available mitotic rates, the median mitotic rate per 50 high-power fields was 29 (range 7-130), suggestive
of high rate of proliferation (Table 2). These patients who harbored adrenal masses on their initial adrenal imaging studies were not sent for surgical resection because of the presumed benign status of preexisting masses (n = 13; 65 %), missed follow-up or delayed surgery (n = 4; 20 %), missed masses on outside radiology report (n = 2; 10 %), and stability lasting more than 2 years of a mass that eventually grew larger (n = 1; 5 %). In the five patients with normal adrenal glands on imaging prior to ACC diagnosis, the time difference between the last normal scan and ACC diagnosis ranged from 5 to 36 months. At last follow-up (mean 16 months), 14/25 (56 %) patients were still alive (eight with disease and six with no evidence of disease), and 11/25 (44 %) had died.
Discussion
We found preexisting adrenal masses in 20 of 25 ACC patients who had previous adrenal imaging. These masses did not have the radiological appearance of benign, lipid- rich adenomas.
CT features of benign adrenal masses include homo- geneity, small size (usually <5 cm), smooth borders, pre- contrast density <10 HU, and an absolute washout of 60 % or higher [10, 14, 15]. In our study, the median precontrast density of 36 HU (range 17-43 HU) does not support the assumed benign status of the lesion in many cases and should have triggered more intensive surveillance or con- sideration for resection. Furthermore, six patients had heterogeneous adrenal masses on the first available images.
The leading reason that preexisting masses were not suspected as ACC was diameter <4 cm (range 0-9 cm). Despite the limitations of our review, we believe that an over-reliance on size alone to determine whether to resect adrenal incidentalomas could have contributed to the unwanted delays. The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons guidelines recommend using size with other radiological features in the decision-making process of adrenal incidentalomas. It remains unclear if these rec- ommendations are implemented by practicing physicians in daily clinical encounters [4]. Other factors identified leading to delayed diagnosis of these ACCs included missed follow-up appointments or lack of access to care, leading to delayed surgery in four cases, and missing a small adrenal mass on outside radiology review in two cases. One patient had stable imaging results of more than 2 years’ duration showing a small adrenal mass and was later diagnosed with stage IV ACC (an enlarging adrenal mass with biopsy-proven hepatic metastases).
Based on current clinical guidelines, patients with inci- dental adrenal masses will have a minimum of 3 cross-
sectional imaging studies (at baseline, at 3-6 months, and at 12-24 month intervals) [4]. As CT is the most com- monly used test to detect and monitor adrenal masses, these studies add to the radiation-associated increased risk of cancer. The single use of multi-phase CT of the abdomen exposes patients to a median of 23-31 mSV of ionizing radiation (equivalent to 442 chest radiography series) with a corresponding median adjusted lifetime attributable risk of cancer of 4 cancers per 1000 patients and a 1 in 430 to 1 in 2170 chance of causing a radiation-associated fatal malignancy [16, 17]. While magnetic resonance imaging (MRI) does not carry the risk of ionizing radiation expo- sure, the time needed to perform the study and the higher cost compared with CT imaging makes the routine use of MRI of less practical.
A fine balance must be achieved between the small risk of ACC in most patients with adrenal incidentalomas, the devastating consequences of delayed ACC diagnosis, and the burden of repeated cross-sectional body imaging (both cost-effectiveness and risk of radiation exposure). As all the preexisting adrenal masses in our study had precontrast density >10, we believe that patients with homogeneous adrenal adenomas and precontrast density <10 may not need prolonged or frequent radiological surveillance.
As many as 25-30 % of adrenal nodules cannot be well characterized by CT and MRI and are therefore labeled as indeterminate. For select individuals with radiologically indeterminate adrenal masses, PET/CT can be used to determine the malignant potential of the mass with high sensitivity (97 %) and specificity (91 %) [18].
The development of hormonal excess syndromes during follow-up will be an obvious reason to perform surgery in these patients. For those patients with normal hormonal profile, the hope is to identify reliable biomarkers (blood or urine) for early recognition of malignancy that will reduce the burden of repeated imaging studies.
Sixteen patients (64 %) in our study were diagnosed with stage III or IV ACC, of whom 14 had a preexisting adrenal mass. Hypothetically, had their adrenal masses been identified as ACC at the time of the first available imaging and removed at that time, the vast majority of the patients in our cohort would have been diagnosed with stage I or II disease. Our findings suggest that ACC can develop either de novo or may result from a malignant transformation of an existing adrenal mass. We docu- mented five cases of normal adrenal glands on first avail- able imaging followed by ACC development later, supporting de novo formation of ACC from a previously normal-appearing adrenal gland. The de novo development of ACC occurred in as soon as 5 months following imaging demonstrating normal adrenal glands (Fig. 4). We also found cases of preexisting adrenal incidentalomas that remained stable for many months before a sudden increase
(a)
(b)
(c)
(d)
(a)
(b)
(c)
(d)
Fig. 5 a-d The development of ACC from a preexisting adrenal mass seen on axial non- enhanced CT images. a Shows a well circumscribed oval nodule measuring 2.5 cm with attenuation value of 17 HU involving the right adrenal gland seen 72 months prior to ACC diagnosis (white arrow). In b and c this nodule remained stable at 48 and 24 months prior to ACC diagnosis (white arrows). d Shows an interval enlargement of the right adrenal mass (arrow) which measured 5.3 cm and attenuation value 30 HU at the time of ACC diagnosis
in size (Fig. 5), raising the possibility of ACC developing from a preexisting (possibly benign) mass that could have accumulated carcinogenic molecular alterations, similar to the pathogenesis of colorectal carcinomas from preexisting colonic polyps [19, 20].
It is also challenging to predict the acquisition of dele- terious mutations in atypical adrenal adenomas that can change the clinical behavior of adenomas towards rapid growth and metastatic potential after a prolonged period of clinical silence, as documented in Fig. 5.
| Patient number | Tumor on first study | Sex | Age at diagnosis (year) | Size on first study (cm) | Initial imaging modality | Precontrast density | Time till ACC diagnosis (month) | Size at time of ACC diagnosis (cm) | Stage | Weiss score | Ki67 % | Mitotic rate/50 HPF |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | No | F | 63 | 0 | CT abdomen | NA | 24 | 7.5 | 2 | 6 | NA | 30 |
| 2 | No | F | 46 | 0 | FDG PET/CT | NA | 51 | 1 | 1 | 4 | NA | 20 |
| 3 | No | F | 22 | 0 | CT abdomen | NA | 35 | 15.5 | 3 | 6 | 26 | 100 |
| 4 | No | M | 29 | 0 | CT abdomen | NA | 34 | 3.8 | 1 | 5 | 12 | 12 |
| 5 | No | F | 61 | 0 | CT chest | NA | 13 | 8 | 3 | 7 | 69 | 16 |
| 6 | Yes | M | 77 | 1.4 | CT chest | 22 | 26 | 2.9 | 4 | NA (FNA) | NA | NA |
| 7 | Yes | F | 53 | 1.8 | CT abdomen | 38 | 43 | 6.5 | 2 | 8 | NA | 30 |
| 8 | Yes | F | 60 | 2 | CT abdomen | NAb | 12 | 11.2 | 4 | NA(FNA) | NA | NA |
| 9 | Yes | F | 49 | 2.1 | CT abdomen | 20 | 27 | 9 | 4 | NA (FNA) | NA | NA |
| 10 | Yes | M | 51 | 2.3 | CT abdomen | 36 | 12 | 18 | 3 | 8 | 40 | 130 |
| 11 | Yes | F | 59 | 2.5 | CT abdomen | 17 | 76 | 5.3 | 4 | NA (FNA) | NA | NA |
| 12 | Yes | M | 64 | 2.6 | CT abdomen | 40 | 7 | 3.6 | 1 | 3 | NA | NA |
| 13 | Yes | M | 40 | 2.8 | CT abdomen | 37 | 8 | 8.2 | 3 | 3 | NA | 35 |
| 14 | Yes | F | 37 | 3 | CT abdomen | 39 | 89 | 14 | 4 | NAª | NA | NA |
| 15 | Yes | F | 63 | 3 | CT chest | 43 | 32 | 16 | 4 | 6 | NA | 65 |
| 16 | Yes | M | 82 | 3.7 | CT abdomen | 26 | 8 | 9 | 4 | 6 | 30 | 8 |
| 17 | Yes | M | 56 | 3.8 | CT abdomenb | NAb | 7 | 11.6 | 3 | 5 | 50 | 75 |
| 18 | Yes | M | 23 | 3.9 | CT abdomenb | NAb | 3 | 9.5 | 2 | 4 | NA | 27 |
| 19 | Yes | F | 34 | 3.9 | FDG PET/CT | 34 | 25 | 6.5 | 2 | 5 | NA | 7 |
| 20 | Yes | F | 53 | 4.3 | CT abdomen | NAb | 14 | 13.2 | 4 | NA (FNA) | NA | NA |
| 21 | Yes | F | 32 | 6 | CT abdomen | 30 | 22 | 11.5 | 4 | NA (FNA) | 70 | NA |
| 22 | Yes | M | 49 | 6 | CT abdomen | 35 | 9 | 6.8 | 2 | 5 | NA | NA |
| 23 | Yes | M | 74 | 7 | MRI | NA | 3 | 10.8 | 3 | 7 | NA | 25 |
| 24 | Yes | F | 56 | 8.2 | CT abdomen | 39 | 20 | 11 | 2 | 5 | 20 | 9 |
| 25 | Yes | F | 49 | 9 | CT abdomen | 40 | 3 | 17 | 3 | 6 | NA | 84 |
FDG PET/CT fluorodeoxyglucose positron emission tomography/computed tomography
a Clinically diagnosed stage IV ACC
b CT with contrast (no precontrast images)
Recently published data identified two molecularly dif- ferent groups of ACCs with different clinical outcomes [21]. Our findings could be in line with these findings as the rapidly evolving ACCs might have genetic make-up dif- ferent from ACCs developing from a preexisting adrenal mass that could have gained genetic aberrations leading to a malignant phenotype.
In five patients (21-25 in Table 2), surgery was delayed by 3-22 months despite the presence of tumors ≥6 cm on first available imaging. Patient #21 had a 6-cm adrenal mass that was presumed to be benign based on an earlier biopsy. This finding resulted in less frequent imaging, which delayed ACC diagnosis by 22 months. Similarly, patient #22 had an incidental finding of a 6-cm mass in the context of spontaneous splenic rupture, and ACC diagnosis was delayed by 9 months after a non-diagnostic biopsy led
to the assumption of hematoma as the diagnosis. Patient #23 had a 7-cm adrenal mass with 3-month interval between the first imaging study and diagnosis. This delayed treatment was secondary to delays in access to care and referral. Patient #24 had an 8.2-cm mass that was presumed to be a “benign adenoma and less likely malignant” per clinical documentation prior to referral. This assumption resulted in a lack of initial follow-up contrary to guidelines and delayed diagnosis by 20 months. Patient #25 had a 9-cm adrenal mass, and his treatment was delayed by 3 months because of poor performance status that con- traindicated surgical resection.
Despite these limitations, size remains suggestive but not diagnostic of malignancy. In one series of 117 patients with adrenal masses, 13.5 % of ACCs were <5 cm, while 26 % of benign adrenal tumors were >5 cm. This
significant size overlap between benign adrenal tumors and ACCs shows that size is suggestive but not diagnostic of malignancy [22]. Furthermore, the lack of tumor growth during short follow-up is reassuring but cannot predict malignant potential. A few cases are reported in the liter- ature illustrating missed opportunities to diagnose ACC at an earlier stage, and careful integration of clinical, radio- logical, and pathological data is needed to avoid missing ACC [23].
While anatomical (CT and MRI) and functional (FDG- PET) imaging studies could help in differentiating benign from malignant adrenal tumors, they remain unable to predict the underlying pathology in a significant number of cases. The presence of multiple other pathologies that can mimic ACC (adrenal metastases, pheochromocytomas, sarcomas, lymphomas, and fungal infections) adds to the complexity of early ACC diagnosis. The use of image- guided biopsy can help in select cases, but the routine use of biopsy to diagnose ACC is not recommended because the procedure is often unnecessary and may carry the risk of peritoneal seeding as well as the potential of delayed diagnosis, as we have seen in two cases included in our series [24].
As our study only included confirmed ACC cases, the prevalence of ACC among radiologically atypical adrenal incidentalomas remains unknown. However, we think that adrenal masses with atypical radiological features (pre- contrast density >10, necrosis, heterogonous, or calcifica- tions) should be viewed with suspicion compared with adrenal adenomas with benign radiological features (pre- contrast density <10, homogenous). However, the presence of heterogeneous density is not synonymous with malig- nancy, as 20 % of benign adrenal masses and 68 % of malignant masses were reported to harbor some degree of heterogeneous density on CT imaging [25].
Future studies of patients with incidentally identified adrenal tumors will be needed to address some of the uncertainties about ACC development and to explore the potential utility functional imaging or circulating tumor markers in patients with adrenal incidentalomas.
Some strengths of our study were the number of cases included, considering the rarity of ACC, and our radio- logical verification of key features in most cases, including tumor size and precontrast density. Nevertheless, our report has the inherent shortcomings of a retrospective study design, including the potential referral bias, as most patients underwent their earlier imaging outside our insti- tution and were referred to our institution later, around the time of the ACC diagnosis. There exists the potential bias due to the inclusion criterion of having verifiable imaging of the adrenal glands. Also, the protocols used for imaging did not allow the calculation of other important features such as washout details. Another expected limitation of our
work is the unavailability of data from hormonal evalua- tions done at the time of the first available imaging studies. Through detailed record review, 4 patients had clinical documentation that the first imaging study was done out of suspicion of hormonal imbalance. At the time of ACC diagnosis, 12 patients (48 %) had non-functioning ACC while hormonally active ACC was seen in the remaining 13 (52 %) (6 androgen, 4 cortisol, 2 aldosterone, and 1 mixed hormonal production).
In summary, most ACC patients who underwent earlier imaging that involved the adrenal glands harbored a mass with atypical radiological features. The measured precon- trast density on CT images of these masses was >10 HU, which is not compatible with benign lipid-rich adenoma. ACCs appeared de novo or from preexisting adrenal mas- ses. The main reason for delayed ACC diagnosis was presumed benign status based on images of a preexisting adrenal mass. We conclude that using radiological features such as precontrast density and heterogeneity should be used in addition to size to prevent delayed ACC diagnosis.
Acknowledgments We thank Bryan F. Tutt, scientific editor from the Department of Scientific Publications, for his editorial assistance.
Compliance with ethical standards
Conflict of interest The authors declare that there are no conflicts of interest.
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