Key words
adrenal mass - adrenal adenoma - incidentaloma - adrenal tumor
Introduction
Incidentalomas are adrenal tumors that are discovered during diagnostic evaluation
for other conditions [1]. Their prevalence has
been reported to be 1–6% in adults [1]
[2] and to increase with the
growing use of technological advances in imaging and with the ageing of the
population [1]. Most of these tumors are
nonfunctional and benign [3]: if they have an
attenuation of 10 Hounsfield units or less in non-enhanced computed tomography (CT)
and they are smaller than 4 cm in greatest diameter, they generally do not
warrant intervention or long-term follow-up [1]. In a meta-analysis involving 4121 patients with such nonfunctioning
adrenal lesions, adrenocortical carcinoma did not develop in any of the patients
[4]. Subsequently, the risk is estimated
to be<2% in these patients. In the presence of a history of or known
current primary cancer, however, the risk of malignancy has been described to be up
to 21% [5]. Although adrenal surgery
meanwhile is mostly minimally invasive and associated with low morbidity and almost
no mortality, compromise of adrenal function is a serious possible consequence and
indication should be posed judiciously. Therefore, the management of adrenal masses
should be individualized and involve a multidisciplinary judgement.
In the last decades, most academic medical centers and some community hospitals have
established multidisciplinary organ specific tumor boards in order to improve
patients’ care [6]. Multidisciplinary
team care has been shown to be associated with improved survival, timeliness of
treatment, and adherence to guidelines [7]
[8]
[9]
[10]
[11]
[12]
[13].
Besides providing best management through diagnostic and treatment recommendations
generated according to a consensus-based method and supported by guidelines, tumor
boards enable appropriate and timely patients’ referral, identification of
available clinical trials and educate clinicians by sharing expertise from each
discipline in an open environment [13].
Endocrine tumor boards (ETBs), in contrast to classic oncologic boards include
patients with both benign, beside malignant disease. The consensus opinions for
diagnostic issues ranges from not pursuing any further testing to performing
invasive procedures for more precise tumor characterization, including when to
operate and how extensive a surgery should be performed [14]. A recent analysis showed that the
suggested treatment was changed in 15% of presentations, with additional
imaging being the most frequent reason (43%) [15]. Twenty-four percent of attendees reported
intending to use a more evidence/guideline-based approach after attending
[15].
At the University Clinic of Cologne, Germany an ETB has been established in 2014.
The
number of cases discussed by the board has increased from 120 in 2014 to 743 in
2020, including thyroid, parathyroid, adrenal pathologies, and neuroendocrine
tumors. In the present study, we evaluated the indications and outcome of adrenal
surgery recommended by the ETB, with focus on adherence to the guidelines for the
management of adrenal incidentalomas published in 2016 by the European Society of
Endocrinology in collaboration with the European Network for the Study of Adrenal
Tumors [5].
Patients and Methods
Patients
The last consecutive 100 adrenalectomies taking place in our Department for
Endocrine Surgery at the University Hospital of Cologne, Germany were included.
The first surgery included was performed on 24.02.2016, the last one on
21.10.2021 (5 years and 8 months). Surgical procedures performed for extra
adrenal pathologies with adrenal involvement (e. g., multivisceral
resections of sarcomas) were excluded.
The endocrine tumor board (ETB)
As mentioned above, at the University Clinic of Cologne, Germany an ETB has been
established in 2014 and it is certified by the German Cancer Society (Deutsche
Krebsgesellschaft, DKG). It takes place every Thursday from 1 PM to 2 PM. One
nuclear medicine specialist (M.S.), one endocrinologist (M. F.), and one surgeon
(C.C.) are in charge of the board. The presence of all three members or at least
one deputy from every of their disciplines is required by the DKG. An
experienced pathologist (A.M.S.) is also regularly present. Radiation therapy is
only present when required, as well as ENT and radiology. Radiological material
is generally presented by nuclear medicine specialists. Adherence to ETB
recommendations and outcomes are checked on yearly basis. Once every three
months a morbidity and mortality conference is performed.
Standard diagnostic workup of adrenal masses
All endocrine masses included in this study received radiologic workup (using
either enhanced or non-enhanced CT, MRI, or PET CT), at least minimal
endocrinologic diagnostic including aldosterone/renin ratio, serum
metanephrine and normetanephrine levels and a dexamethasone suppression test. In
case of positive aldosterone/renin ratio, suggestive of Conn Adenoma,
the next step consists of saline load test and selective adrenal vein sampling
for patients>35 years at our institution. Malignancy was suspected in
tumors>6 cm in diameter, with increasing size {“if
the lesion enlarges by more than 20% (in addition to at least a
5 mm increase in maximum diameter) during 6–12
months” [5]} or in the
presence of elevated Hounsfield unit attenuation in non-contrast CT scan.
Unclear tumors were followed up in 6–12 months with another radiologic
modality including MRT and PET scan beside non-contrast CT scan. Our internal
algorithm is based on the guidelines for the management of adrenal
incidentalomas of the European Society of Endocrinology in collaboration with
the European Network for the Study of Adrenal Tumors [5].
Retrospective validation of the malignancy risk
For all included patients, radiological image data available in the
institution’s Picture and Archiving System (PACS) were identified and
retrospectively reevaluated in a blinded fashion by an experienced radiologist
(D.P.d.S.), who had not been involved in tumor board discussions. External
examinations are regularly imported into the PACS preoperatively to be available
in all operation rooms. However, they are removed after 6 months, in some cases,
depending on the uploading procedure used, in which case they were not included
in this study (n=19).
Surgery
Surgery was performed either as laparoscopic or retroperitoneoscopic
adrenalectomy, according to the technique introduced 1995 in Germany by
Professor Martin K. Walz [16]. Only in
eleven cases (11%), open adrenalectomy was performed for adrenal cell
carcinoma and huge bilateral metastases with possible extracapsular
infiltration. Laparoscopic access is chosen at our institution for masses
suspicious of malignancy but without signs of extra-adrenal invasion, due to the
lower risk of capsular disruption given by the larger space in transperitoneal
access [17]. Retroperitoneoscopic access
is preferred for functional benign tumors and in patients with previous
abdominal surgery, where adhesions are expected. All patients were seen
regularly one week postoperatively for wound control in the surgical department
and in the endocrinological department for further follow up, especially in case
of corticosteroid substitution.
Histology
All histologic specimens were examined in the Department of Pathology of the
University Hospital of Cologne and included Hematoxylin and Eosin (H &
E) and respective IHC-staining depending on the case.
Data Collection and Analysis
Electronic and paper data of the University Hospital of Cologne were
retrospectively collected and analyzed. The study was performed according to the
rules for retrospective analysis of the ethical committee of the University
Hospital Cologne. Data were analyzed using IBM SPSS Statistics for Windows,
Version 25.0. Armonk, NY, USA. Variables were expressed as median with range. If
the data was normally distributed, groups were compared using the T-test. The
Chi-square test of independence was used for testing hypotheses when the
variables were nominal. A p-value<0.05 was considered significant.
Results
Patients
One hundred consecutive patients undergoing adrenalectomy at our institution were
included in this study. They consisted of 55 (55%) men and 45
(45%) women. Their median age was 54.8 years (range 21–87). Men
were significantly older than women (57.5, range 21–87 vs. 51.4, range
22–73; p=0.01).
Indications for surgery included 22 (22%) cases of primary
hyperaldosteronism (PHA), 20 (20%) pheochromocytomas, 13 (13%)
adrenal Cushing adenomas, 5 (5%) myelolipomas (>5 cm)
and 40 (40%) tumors, which were deemed suspicious of malignancy,
including 3 (7.5%) cases with additional functional activity.
Cushing adenomas were diagnosed significantly more frequent in female patients
(92.3 vs. 7.7%), whereas myelolipomas (80 vs. 20%) and
suspicious tumors (70.7 vs. 29.3%) were seen more frequently in male
patients (p=0.001, [Table
1]).
Table 1 Indications for surgery in 100 consecutive
adrenalectomies.
|
Male n=55
|
Female n=45
|
Σ=100
|
|
PHA
|
11 (50%)
|
11 (50%)
|
22
|
|
Pheochromocytoma
|
10 (50%)
|
10 (50%)
|
20
|
|
Cushing
|
1 (7.7%)
|
12 (92.3%)
|
13
|
|
Myelolipoma
|
4 (80%)
|
1 (20%)
|
5
|
|
Suspicious of malignancy
|
29 (72.5%)
|
11 (27.5%)
|
40
|
There was a significant gender specific difference with Cushing being
diagnosed more frequently in females, myelolipomas and suspicious tumors
being diagnosed more frequently in men (p=0.01).
Median age of patients was 45 (range 21–62) for primary
hyperaldosteronism, 54 (range 41–72) years for Cushing, 58.5
(22–73) years for pheochromocytoma and 61 (range 25–87) years
for malignant histology.
Imaging studies
In 81 cases, imaging studies were available at the University’s PACS and
could be retrospectively evaluated. Imaging modalities included native CT,
contrast enhanced CT, MRI, contrast enhanced sonography and/or PET CT.
Twenty-two (26.8%) of patients received only one imaging study, 26
(31.7%) two, and the rest 33 (40.7%) received≥3.
Median tumor size before surgery was 20 mm (range 10–53) for PHA,
23 mm (range 10–126) for metastases, 37.5 mm (range
16–66) for Cushing and 41 mm (range 16–62) for
pheochromocytomas. Median non-enhanced CT attenuation before surgery was 9.5
(–4 to –30) in PHA, 10 (–14 to –33) in Cushing,
33.5 (14 to –53) in pheochromocytomas and 32.5 (20 to –41) in
metastases. The three adrenal cell carcinomas included in this study measured
61, 116, and 160 mm before surgery and displayed non-enhanced CT
attenuation values>30 HU.
A significant increase (>20%) in tumor size 6–12 months
after primary radiologic study was diagnosed in 24 (29.2%) adrenal
masses, including one hemangioma, one hematoma and two PHA adenomas in addition
to 20 malignant tumors.
Blinded validation of the malignancy risk
The blinded retrospective assessment of the malignancy risk by an independent
experienced radiology consultant diagnosed a suspicion of malignancy in 48
(59.2%) of 81 cases. However, final histology confirmed malignancy in
only 31 (64.5%) of these cases and classified as non-malignant 17
(35.5%) cases ([Table 2]).
Table 2 Results of the independent blinded radiologic
reevaluation.
|
Histologic malignant
|
Histologic benign
|
Σ
|
|
Radiologic suspicion
|
31
|
17
|
48
|
|
No radiologic suspicion
|
2
|
31
|
33
|
|
Σ
|
33
|
48
|
81
|
Sensitivity of the radiologic reassessment for malignancy was
96.9% (95% CI 83.8–99.9%), specificity
65.3% (95% CI 50.4–78.33%). The positive
predictive value 64.6% (95% CI
55.3–72.9%); the negative predictive value 97%
(95% CI 82.1–99.6%).
These 17 cases wrongly assessed as suspicious based on sole radiologic criteria
included 3 (30%) of 10 Cushing adenomas, 1 (20%) of 5
myelolipoma, 1 hemangioma, one 6 cm large benign adenoma with androgene
and cortisol secretion, and one adenoma in a patient with a neuroendocrine tumor
(patient 7, [Table 3]), beside 10
(83.3%) of the 12 pheochromocytomas.
Table 3 Nonfunctional adenomas removed by
surgery.
|
Patient
|
Gender
|
Age
|
Side
|
Size
|
Native HU density
|
Signal dropout on opposed-phase images (MR)
|
PET
|
History of cancer
|
Histology
|
|
Pt1
|
f
|
59
|
left
|
2 cm↑
|
contrast CT
|
|
|
G2 NSCLC pT2 (3.1 cm) pN0 (0/35) L0 V0 pn0
R0, FD 1 year before
|
adenoma
|
|
Pt2
|
f
|
35
|
right
|
2.5 cm
|
26
|
|
|
B-symptomatic, unclear diarrhea
|
adenoma
|
|
Pt3
|
m
|
57
|
right
|
3.6 cm ↑
|
20
|
–
|
|
Renal cell carcinoma of the right kidney, FD 1 year
before
|
adenoma
|
|
Pt4
|
f
|
56
|
right
|
3.5 cm↑
|
contrast CT
|
+
|
|
Appendix mucinous adenocarcinoma pT3, pN0 (0/16), L0,
V0, R0 ; FD 3 years before
|
hematoma
|
|
Pt5
|
m
|
62
|
left
|
1.5 cm↑
|
contrast CT
|
–
|
|
Poorly differentiated adenocarcinoma of the stomach ypT3,
ypN0 (0/42), L1, V0, Pn1, R0 ; FD 3 years before
|
hemangioma
|
|
Pt6
|
f
|
52
|
left
|
2.5 cm
|
26
|
|
+
|
Hodgkin lymphoma in complete remission after chemotherapy, FD
same year
|
adenoma
|
|
Pt7
|
m
|
54
|
left
|
4.8 cm
|
28
|
|
|
Ileum G1 NET pT3, pN1 (4/29 ece+), L0, V0,
Pn1, R0, FD same year
|
adenoma
|
In these patients, malignancy risk was “wrongly”
assessed. [Table 3] contains the
last information available to the ETB for recommending surgery. The
arrow represents a tumor increase>20% (in addition to at
least a 5 mm increase in maximum diameter) during 6–12
months, as recommended by the ENSAT; NSCLC: Non-small cell lung cancer;
RCC: Renal cell carcinoma; NET: Neuroendocrine tumor; FD: Time of first
diagnosis.
Only 1 (4.3%) melanoma metastasis was wrongly classified as
non-suspicious in blinded radiologic reassessment based on a non-enhanced
attenuation of 0. 1 (4.1%) NCC metastasis was classified as unclear
(non-enhanced CT was not available).
Sensitivity of the radiologic reassessment for malignancy was 96.9%
(95% CI 83.8–99.9%), specificity 65.3%
(95% CI 50.4–78.33%). The positive predictive value
64.6% (95% CI 55.3–72.9%); the negative
predictive value 97% (95% CI 82.1–99.6%).
Surgery
Most surgeries (89%) were performed in minimally invasive technique. 43
(43%) were performed transperitoneally as laparoscopic and 46
(46%) extraperitoneally as retroperitoneoscopic adrenalectomy. Eleven
(11%) of surgical procedures were performed as open adrenalectomy for
strong suspicion of malignancy and possible infiltration of nearby organs. There
was no mortality. Morbidity included two self-limiting pancreatic fistulas in
pheochromocytomas of the left adrenal gland after laparoscopic resection of two
pheochromocytomas. One of them was hemorrhagic.
Final histopathologic assessment of tumors removed for malignancy
risk
Among the 40 tumors deemed suspicious of malignancy by the ETB, final
histopathologic assessment diagnosed metastases in 30 (75%) and adrenal
cell carcinomas in 3 (7.3%) cases. Metastases included 9 melanomas, 4
Non-Small Cell Lung Cancer (NSCLC), 8 upper GI tumors, 3 renal cell carcinomas,
2 lymphomas, 2 hepatocellular carcinomas, one lung carcinoid, and one thyroid
carcinoma.
Seven (17%) tumors were non-functional and were surgically removed
exclusively due to a wrongly assumed suspicion of malignancy based on guideline
recommendations (non-enhanced attenuation>20 HU, increasing size,
history of extra-adrenal cancer): the final histopathology diagnosed adrenal
adenomas. [Table 1] depicts the
characteristics of these tumors.
In 6 (85.7%) of 7 cases patients had a history of extra adrenal
neoplastic disease. In only 4 (57.2%) cases non-enhanced CT was
available and attenuation was>20 IU ([Fig. 1]). In 3 cases (42.8%) an increase of tumor
size>20% in 6–12 months had been observed. Two cases had
been deleted in the radiologic archive of the university and original radiologic
material was not available, only the initial radiology report. In 3
(60%) of 5 cases with complete radiologic material, malignancy was also
wrongly assumed in blinded reassessment, based on the current guideline
recommendations.
Fig. 1 Large tumor of 2.5 cm at the left adrenal gland in
a 52-year-old patient with history of lymphoma. Beside a non-enhanced
attenuation>20 HU, this tumor was PET positive. It turned out to
be a benign adenoma in final histopathologic assessment.
Discussion
In the present study, we examined the quality of the indications for adrenal surgery
recommended by the ETB at our institution. Demographics, clinic-pathologic
characteristics, treatment and outcome of 100 consecutive adrenalectomies performed
at our institution according to a recommendation of the endocrine tumor board, based
guidelines for the management of adrenal incidentalomas of the European Society of
Endocrinology in collaboration with the European Network for the Study of Adrenal
Tumors [5] were analyzed.
First finding was a gender specific difference: male patients were older and had more
frequently myelolipomas and suspicious masses, whereas female patients were younger
and had more often cortisol secreting tumors, confirming the previous observations
of Alesina et al. [18]. Secondly endocrine
activity was present in 55% of tumors, again in accordance with other
surgical and non-surgical series [3]
[19].
In 40% of cases, the indication for surgery consisted in a suspicion of
malignancy, confirmed in 33 (82.5%) patients in final histopathology. A
33% malignancy rate is higher than that recently reported for the Eurocrine
data [19]. At the same time, our 7%
rate of nonfunctional benign tumors wrongly deemed suspicious and thus removed
appears lower than in the Eurocrine data, considering that their reported rate of
endocrine activity is 55% and that of malignancy 15%. One possible
reason for that is that the Eurocrine data include cases from 21 different hospitals
in Germany, Austria, and Switzerland with different volumes (658 surgeries,
performed in 21 hospitals over 5 years) [19]:
it is possible, that not all centers included have multidisciplinary preoperative
boards. Because of this 7% rate of “unnecessary” adrenal
surgery despite complete adherence to the international Guidelines [5]
[20],
we decided to focus on these cases.
The current Guidelines report a risk of 25% malignancy for
tumors>6 cm and recommend surgery [5]. For tumors<6 cm the risk of malignancy is recommended
to be assessed in non-enhanced CT [5].
Wash-out CT with the established thresholds for absolute and relative percentage
wash-out (APW/RPW) has been shown to be insufficient to reliably diagnose
adrenal masses [21]. MRI is recommended in
case non-enhanced CT is inconclusive [5]. In
non-enhanced CT benign adenomas can be reliably diagnosed for masses with Hounsfield
density of<10 units. However, increasing the unenhanced CT tumor attenuation
threshold to 20 HU increased specificity for ACC, while maintaining sensitivity in
the EURINE-ACT study [22]. The first
consideration is that most patients present with contrast enhanced CT scan in
day-to-day clinical routine. Although non-enhanced CT is the adequate imaging
modality for assessing malignancy, there is a comprehensible reluctance in requiring
additional non-enhanced CT in younger patients, especially if radiology report
already suggests a risk of malignancy and the patient is worried. The fact that for
most patients (72.8%) in the present study≥2 radiologic studies, and
MRI in 48 (59.2%) cases were available, is explained by a certain selection
due to the fact that patients were treated in a university oncologic center. In case
the radiologic report of enhanced CT scan cannot clearly rule out malignancy, most
patients are reluctant to undergo active surveillance, and follow up in 6–12
months.
Based on sole radiologic criteria, our independent retrospective blinded evaluation
delivered a sensitivity of 96.9% (95%CI 83.8–99.9%)
and a specificity of 65.3% (95% CI 50.4–78.33%),
with 83.3% of pheochromocytomas being classified as malignant. The mean
unenhanced CT attenuation of pheochromocytoma was 35±9 HU in a Mayo Clinic
cohort and 35.6 HU in 1217 tumors extrapolated from 23 studies [23]. This explains why pheochromocytoma can
easily be wrongly classified as possibly malignant in the lack of information on
their biochemical activity ([Fig. 2]). It is
unclear, why at least four benign adrenal adenomas had non-enhanced
attenuation>20 HU. One of them was even positive in PET scan.
Fig. 2 Large pheochromocytoma of 4.5 cm of the left adrenal
gland in a 46-year-old patient. This tumor was seen as possibly malignant in
blinded radiologic assessment, due to its non-enhanced
attenuation>20 HU and its size.
Finally, this study confirms a high adherence to the current guidelines for the
treatment of adrenal masses. A rate of 33% for malignancy is high but due to
the patients’ selection seen in a university center. The 7% rate of
adrenal surgeries performed for non-functional benign tumors should be seen in the
light of the medical history of the patients’ undergoing adrenalectomy, who
had had extra adrenal neoplastic pathologies in 6 (85.7%) cases and criteria
warranting surgery according to the guidelines in all cases. The ENSAT Guidelines
suggest for patients with previous cancer history following steps: pheochromocytoma
should be ruled out; no further specific adrenal imaging follow up, if the lesions
can be characterized as benign by non-contrast CT; repeated imaging including PET
scan, biopsy or surgery, if the lesions cannot clearly be characterized as benign
by
non-contrast CT. In day-to-day clinical routine, patients with a history of cancer
are also willing to have tumors removed, even if malignancy is unlikely and rarely
accept surveillance. A retrospective study reported even a 80% rate of
patients choosing surgery instead of surveillance due to anxiety related to
potential malignant change [24]. Two thirds of
them even hat tumors<4 cm [24]. Nonetheless, at least in some of them CT guided biopsy might have
possibly obviated adrenal surgery and should be probably considered as option in ETB
discussion, once ACC and pheochromocytoma have been ruled out.
Conclusions
In summary, with a high adherence to the current European guidelines, non-functional
adrenal adenomas were resected in only 7% of adrenal surgeries in the
present study. A history of malignancy supported the indication to surgery in most
cases and criteria warranting surgery according to the guidelines. Adrenal biopsy,
however, might be an option for obviating surgery in these patients, once
pheochromocytoma and ACC have been ruled out.
