Key words
adrenocortical cancer - FDG-PET - prognostic value - mitotane
ACC Adrenocortical carcinoma
PET Positron emission tomography
SUVmax Standardized uptake value
FDG Fluorodeoxyglucose
Introduction
Adrenocortical cancer (ACC) is a rare tumor entity with an overall poor prognosis
[1]. The heterogeneous course requires
personalized therapeutic approaches that include surgery of the primary tumor, local
ablation of single metastases, adrenolytic medical approaches and/or
systemic chemotherapies [2]. Both in adjuvant
setting and in advanced ACC, mitotane is treatment of first choice - alone or in
combination with cytotoxic drugs [3]
[4]. While some histological markers [5] and information from molecular profiling
[6]
[7] can provide prognostic information,
therapeutic decisions often rely on imaging at initial diagnosis or during
follow-up.
Positron emission tomography (PET) in combination with computed tomography (CT) is
gaining increasing attraction as imaging modalities for the clinical care of ACC
patients. As in other tumor entities, fluorine-18 fluorodeoxyglucose (F-18 FDG)
PET/(CT) is used for both primary diagnosis as well as for follow-up after
surgery or during systemic treatment [8]
[9]. By quantifying the metabolic activity,
PET/CT offers valuable advantages at diagnosis and for monitoring of therapy
compared to the sole assessment of tumor morphology by means of CT or MRI. For
differential diagnosis, the additional information of PET imaging can help to
distinguish between benign and malignant adrenal tumors [10]
[11]. In general, FDG uptake is regarded as
having some prognostic value as it reflects the proliferative properties of the
tumor tissue. For ACC, intensity of FDG uptake of the primary tumor appears to be
related to survival of affected patients [12]
[13]. In the context of systemic chemotherapy,
therapeutic responses might be determined earlier based on the metabolic activity of
the tumor in comparison to changes in size or morphology [8]
[9].
As ACC patients often receive FDG PET/CT as additional imaging tool in the
course of their initial diagnosis and during follow-up [2], FDG accumulation of the remaining adrenal
gland following unilateral adrenalectomy has been documented in earlier studies
[14]
[15] and might lead in less experienced
centers to the misdiagnosis of another adrenal malignancy. However, the relationship
of this observation to the clinical course of the individual patient has not been
studied in detail. In fact, there are several reasons that could potentially explain
this phenomenon: First, surgical resection of an endocrine active adrenal tumor will
initiate reactivation of the hypothalamus-pituitary-adrenal axis and growth of the
contralateral adrenal gland. While this compensatory adrenal growth has mainly been
studied in animal models [16]
[17]
[18], it is likely also to occur in humans.
Secondly, therapy with the adrenolytic substance mitotane is known to affect the
remaining adrenal gland to a similar extent as adrenocortical cancer cells [19] and results in adrenal insufficiency [20]. Thereby, mitotante induced cell death
followed by local inflammation could lead to local FDG accumulation. Thirdly, the
contra-lateral adrenal gland can be the target of hematological metastatic spread of
the initial tumor or the origin of a secondary tumor in cases of hereditary
syndromes [21]. In these cases, FDG uptake
would indicate the presence of malignant disease, which would likely be of clinical
relevance. Finally, also healthy organs enrich FDG to a variable extent. As for the
adrenal gland maximum Standard Uptake Values (SUVmax) vary considerably between 0.95
and 2.46 [22] and between 0.82 and 3.65,
respectively [23].
In the current study, we have made use of a cohort of ACC patients being followed
with FDG PET imaging in the course of their disease to correlate these data with
clinical courses, treatment modalities and outcome parameters.
Ethical Approval
All procedures performed in studies involving human participants were in accordance
with the ethical standards of the institutional and/or national research
committee and with the 1964 Helsinki declaration and its later amendments or
comparable ethical standards.
Patients and Methods
Patients
Patients were enrolled at the University Hospitals of Munich and Würzburg
(Germany) as part of the registry of the European Network for the Study of
Adrenal Tumors (ENSAT, www.ensat.org) following written informed consent. The
study protocol was approved by the ethics committees of the University of Munich
and of the University of Würzburg, respectively. For the retrospective
data analysis, inclusion criteria were histologically confirmed diagnosis of ACC
and the availability of at least one PET/CT following unilateral
adrenalectomy. The mitotane group consisted of patients who had received
mitotane therapy for a period of at least 3 months following surgery while
patients were included in the control group who had never received mitotane.
Basic clinical annotations including tumor recurrence and survival as well as
mitotane plasma levels (for the mitotane group) were documented and correlated
with the findings from PET/CTs before and within the first 18 months
after surgery and/or the start of mitotane treatment.
PET/CT protocols
At the Munich center, PET/CTs were carried out with a “General
Electric Discovery 690” PET/CT device (GE Healthcare, Pollards
Wood, United Kingdom) and were performed between 55 and 75 min after
administration of a body weight adapted activity of 18-FDG. In addition,
intravenous contrast agent, 20 mg furosemide and 20 mg
butylscopulamine were administered. The patients were fasting for at least
4 h at the time of the examination and had blood glucose levels between
4 and 7 mmol/l. Attenuation correction was performed using
diagnostic CT. Images were examined using the Hermes Hybrid Viewer (Hermes
Medical Solutions, Stockholm, Sweden).
At the Würzburg center, examinations were carried out with a Siemens
Biograph mCT 64 PET/CT device (Siemens Medical Solutions, Germany) and
performed 60 min after administration of 307 Mbq 18-FDG on average.
Blood glucose levels were <9 mmol/l at the time of
examination. The anatomical correlation and attenuation correction was performed
using a low-dose CT or a diagnostic full-dose CT with or without contrast agent.
The reconstruction and evaluation of the images was carried out with the help of
“Siemens E-soft” software.
FDG uptake was quantified using the Standard Uptake Value (SUV). In the remaining
adrenal gland, tracer uptake was determined using SUVmax. One or more spherical
volumes of interest (VOI) in variable sizes >1 cm were used as
measuring ranges. The size was based on the extent of a visible lesion or the
adrenal gland, respectively. In cases, where the adrenal gland could not be
distinguished from the background by PET imaging alone, the SUVmax was
determined in the area corresponding to the morphological position of the
adrenal gland. Special care was taken not to include any physiological
accumulations from adjacent organs, for example from the liver or kidney, into
the measuring area.
In accordance with EANM guidelines [24],
for each examination the SUVmean of the liver and the mediastinum were
determined to include physiological uptake. In the liver, a sphere with a
diameter of 3 cm was used as VOI to determine the SUVmean. The measuring
site was always the right lobe of the liver, in an area with as few vessels as
possible without metastases or other tumors. In the mediastinum, a sphere with a
diameter of 2 cm was used as VOI to quantize the SUVmean. The measuring
site was always the right atrium of the heart, in a central area without the
involvement of cardiac tissue. To allow for inter-individual comparability, from
the SUVmax of the adrenal gland and the SUVmean of the liver and the mediastinal
blood pool the respective ratios (SUVmax/SUVmean) were calculated.
Statistical evaluation
Descriptive data are provided using absolute and relative frequency, mean, median
and standard deviations, as appropriate. The chi-squared test was used to
compare distribution of nominal scaled data. The Mann–Whitney U-test was
used to compare non-parametric data between patients or patient groups, while
the Wilcoxon sign-rank test was utilized to compare non-parametric data in
connected samples. Survival curves were determined by Kaplan–Meier
analysis and compared by log-rank test. Cox regression analysis was used to
estimate the hazard ratios. Statistical significance was set as a p-value
<0.05 using the SPSS Software Version 24 (SPSS, Inc., Chicago, IL,
USA).
Results
Patient cohorts
From a total of 82 included patients, 66 were enrolled into the mitotane group
and 16 in the control group, respectively. Overall, patients were aged between
27 and 87 years. All tumor stages (ENSAT I-IV [25]) were present with stage I in 8 patients (9.8%), stage II
in 45 patients (54.9%), stage III in 15 patients (18.3%), and
stage IV in 11 patients (13.4%) while remaining three patients
(3.7%) had an unknown stage at diagnosis. A total of 291 PET/CT
data sets were examined with a median of 4 examinations per patients during the
observation period of a median of 10 months. In 14 patients (5 in the mitotane
group and 9 in the control group), only 1 PET/CT data set was available,
so that these were excluded from further analysis of uptake progressions. A
summary of patient characteristics is provided in [Table 1].
Table 1 Characteristics of patient cohorts.
|
Characteristics
|
Mitotane group
|
Control group
|
p-Value
|
|
Age (years)
|
|
|
|
|
Median (range)
|
56 (27–81)
|
53 (30–87)
|
0.847
|
|
Sex - no. (%)
|
|
|
|
|
male
|
28 (42.4)
|
8 (50)
|
|
|
female
|
38 (57.6)
|
8 (50)
|
0.584
|
|
Tumor stage - no. (%)
|
|
|
|
|
I
|
6 (9.1)
|
2 (12.5)
|
|
|
II
|
35 (53.0)
|
10 (62.5)
|
|
|
III
|
13 (19.7)
|
2 (12.5)
|
|
|
IV
|
10 (15.2)
|
1 (6.3)
|
|
|
uncategorized
|
2 (3)
|
1 (6.3)
|
0.763
|
|
Resection status (%)
|
|
|
|
|
R0
|
42 (63.6)
|
13 (81.3)
|
|
|
non-R0
|
24 (36.4)
|
3 (18.8)
|
0.179
|
|
Polychemotherapy - no. (%)
|
|
|
|
|
nono
|
31 (47.0)
|
15 (93.8)
|
|
|
yes
|
35 (53.0)
|
1 (6.2)
|
0.001
|
|
Blood mitotane level
|
|
|
|
|
No. of analyzed samples
|
208
|
0
|
|
|
Median (range) - mg/l
|
13.1 (0–42.2)
|
n.d.
|
|
|
No. of PET/CTs
|
|
|
|
|
Total
|
254
|
37
|
|
|
Median per patient (range)
|
4 (1–7)
|
1.5 (1–6)
|
|
|
Progression free survival non-R0
†
- d
|
|
|
|
|
Median (range)
|
188 (30–2 937)
|
−* (72–1 091)
|
|
|
Recurrence free survival R0
†
- d
|
|
|
|
|
Median (range)
|
396 (20–2 898)
|
−* (81–2 370)
|
|
|
Overall survival non-R0
†
- d
|
|
|
|
|
Median (range)
|
−* (238–3 529)
|
105 (102–1 091)
|
|
|
Overall survival R0
†
- d
|
|
|
|
|
Median (range)
|
2 378 (201–3 805)
|
−* (234–2 370)
|
|
*<50% events in observation period;
† n (R0 Patients >1 PET/CT):
mitotane group 42, control group 13; n (non-R0 patients >1
PET/CT): mitotane group 24, control group 3; n.d., not
determined.
Median duration of follow-up was 10.3 months, which was similar in the
mitotane-group (10.5 months) and in the control-group (9.2 months,
p=0.512). During this interval, 27 (48.2%) of 55 R0 resected
patients experienced disease recurrence with 23 (28.0%) in the
mitotane-group and 4 (30.8%) in the control-group (p=0.340).
Moreover, during this time, 8 (9.8%) of the overall cohort of 82
patients died with 6 (9.1%) in the mitotane-group and 2 (12.5%)
in the control group (p=0.247).
FDG uptake in the liver and mediastinum
Considering the uptake of the liver, there were significant differences in the
mean values between the two groups, which concerned the time points of 3 months
[mitotane group vs. control, 2.92 (2.18–3.88) vs. 2.17
(1.67–2.48), p<0.01], 6 months [2.97 (1.42–4.30) vs.
2.28 (1.71–2.90), p<0.001], and 9 months [3.17
(2.00–4.24) vs. 2.60 (2.01–3.06), p<0.01] ([Fig. 1a]) after surgery, respectively.
While it is plausible, that mitotane treatment might have contributed to the
observed increase in hepatic SUV, no correlation with mitotane plasma levels
were evident (3 months: r=0.281, p=0.148; 6 months:
r=0.071, p=0.661; 9 months r=−0.142,
p=0.409) (Supplemental Fig. 1S)
In contrast, for the mediastinum, no significant difference in SUV was
detectable between the two groups at 3 months [mitotane group vs. control, 1.86
(1.37–2.91), vs. 1.57 (1.02–1.93), p=0.105], 6 months
[1.72 (0.42–2.88) vs. 1.49 (1.23–2.11), p=0.244], and 9
months [1.82 (1.06–2.59) vs. 1.78 (1.43–2.39), p=0.744]
([Fig. 1b]), respectively. In
consideration of the less variable mediastinal FDG uptake, this value was
further utilized for normalization of the SUVmax of the adrenal gland by
calculation of the ratio SUV adrenal gland/SUV mediastinum.
Fig. 1 Time course of FDG uptake in the liver a,
mediastinum b, and normalized adrenal SUVmax (SUV adrenal
gland/SUV mediastinum) c in patients during mitotane treatment
and control patients.
Adrenal FDG uptake
In a subgroup of patients, FDG-PET was performed also prior surgery. In these
patients, uptake in the adrenal gland contralateral to the ACC before surgery
was not different between the two groups [mitotane group (n=9), 1.36
(0.56–1.68) vs. control group (n=2), 1.72 (1.02–2.42),
p=0.727]. During the course of their disease, overall 55/68 patients
(81%) displayed a temporary increase in adrenal FDG uptake, which was
defined as an increase of 0.5 above the lowest of all individual values. More
specifically, this observation tended to be more prevalent in the mitotane group
with 51/61 patients (84%) in comparison to the control group (4/7,
57%), although this difference was not found to be statistically
significant (p=0.288). In 58% of the patients, adrenal FDG
uptake returned to baseline values within 18 months after surgery, while in the
remaining patients, adrenal FDG uptake decreased without reaching baseline
values (24%) or did not decrease within the observation period of 18
months (18%).
As summarized in [Fig. 1c], the mean
values of adrenal uptake between the patients receiving mitotane were not
significant different from those of the control group at any time point. In most
instances [42/61 patients (69%)], the peak in adrenal uptakes
was found in the time interval between 3 and 6 months after the start of
mitotane therapy. In relation to surgery, this occurred in 28/47
patients (60%) of the mitotane group and 3/7 (43%)
patients of the control group (p=0.404). The highest maximum value
occurred in both groups 6 months after surgery.
Temporary increase and peak adrenal uptakes were determined in all patients who
had received more than one PET/CT (mitotane group 61/66
(92%); control group 7/16 (44%)). In the mitotane group,
29 of 57 patients (51%) had at least one higher value in the first 18
months of therapy than the highest measured value before surgery. In the control
group, this was true in 4 out of 16 patients (27%, p=0.094). In
the mitotane group, however, significantly higher values were observed 3 months
[2.14 (0.65–6.04), p=0.002] and 6 months [2.39
(1.02–7.23), p=0.018] after the start of mitotane treatment in
comparison to baseline [1.26 (0.56–1.68)]. These differences were not
significant in the control group {3 months [1.61 (1.24–2.01),
p=0.317] and 6 months [2.03 (1.40–3.21), p=n.d.] vs.
baseline [1.72 (1.02–2.42)]}. When comparing the mean values of mitotane
plasma levels and adrenal uptake, there was no indication of any dependence of
the increased uptake on the level of plasma mitotane levels
(r=−0.028, p=0.683).
None of the 291 PET/CTs examined provided indication of tumor development
in the remaining adrenal gland. Specifically, in no case suspicious increases in
adrenal FDG uptake were associated with morphological correlates in the CT scan
of the current or follow-up examinations.
Correlation of adrenal FDG uptake with survival in patients treated with
mitotane
To assess, whether adrenal FDG uptake in patients treated with mitotane might
have a prognostic impact, different measures were investigated: Peak as well as
mean values of normalized adrenal SUVmax were used to group patients in those
with high uptake (above the median uptake) and low uptake (below or equal the
median uptake). Similarly, the area under the curve of normalized adrenal SUVmax
was calculated and patients were grouped in those with high and low uptake. For
those analyses, patients were further grouped in those following R0 and non-R0
resection.
Overall, in comparison patients with R0 vs. non-R0 resection status, there were
no differences in postoperative FDG uptake at any time point. Based on peak
normalized adrenal SUVmax values, patients following R0 resection (n=37)
tended to have longer recurrence free survival (HR 1.41; CI 0.42–4.75;
p=0.059) when FDG uptake was above the median, while overall survival
was not different (HR 1.62; CI 0.15–17.15; p=0.770). Non-R0
resected patients (n=23) had similar progression free (HR 2.27; CI
0.26–19.67; p=0.232) and overall survival (HR 0.00; CI
0.00–3.698E+149; p=0.124) independent of adrenal FDG
uptake ([Fig. 2]). Similar tendencies
were found for overall survival, where higher adrenal FDG uptake tended to be
associated with better outcome (data not shown). In all cases, however, no
significant differences were evident.
Fig. 2 Survival of mitotane treated patients in relation to peak
normalized adrenal SUVmax related survival. Recurrence free survival of
R0 resected patients (HR 1.41; CI 0.42–4.75; p=0.059.
a Progression free survival of non-R0 resected patients (HR
2.27; CI 0.26–19.67; p=0.097. b Overall survival
in R0 resected patients (HR 1.62; CI 0.15–17.15;
p=0.770. c Overall survival of non R0 resected patients
(HR 0.00; CI 0.00–3.698E+149; p=0.124. d
Continuous line, high uptake >median uptake vs. dotted line, low
uptake ≤median uptake.
Discussion
FDG-PET imaging has become a corner stone in the follow-up of ACC patients and often
provides the basis of treatment decisions. Herein, we provide a comprehensive
description of FDG uptake in ACC patients following initial surgery in relation to
mitotane therapy and clinical outcome. The current investigation provides more
detailed results on the FDG uptake of the remaining adrenal in ACC patients than any
previous studies. However, the detection of FDG uptake in the remaining adrenal
gland in a patient following adrenal surgery seems to be a common finding that
should not alarm affected patients and their physicians and seem not to require
changes in the follow-up algorithm.
According to our current findings, increased uptake values of the adrenal are neither
an obligatory finding following surgery nor during mitotane therapy. However, a
large proportion of patients are characterized by a temporarily increase in adrenal
uptake. Patients from both the mitotane and control group were affected to varying
degrees by this phenomenon. A common factor for both groups that could impact
adrenal FDG uptake is unilateral adrenalectomy. Reactive changes in contralateral
adrenal gland were previously described in animal models and concerned only the
morphology, but not the signaling behavior in PET [17]. Compensatory adrenal growth response following unilateral
adrenalectomy is tightly controlled by both humoral and neuronal factors that are
dependent upon a neural reflex arc with afferent nerve connections from one adrenal
gland to the hypothalamus and an efferent limb back to the other adrenal [26]. In addition, there is indication in the
literature that post-secretory cleavage of the N-terminus of POMC is also required
for the proper initiation of compensatory growth [18]. Autonomous secretion of glucocorticoids by an adrenal tumor results
in suppression of the HPA axis and atrophy of the contralateral adrenal cortex.
Following resection of this tumor, ACTH secretion resumes inducing a growth signal
on the remaining adrenal gland. However, depending on the duration and extent of
glucocorticoid excess, normalization of secondary/tertiary adrenal
insufficiency can vary widely [27]. It is
therefore possible, that those variables have precluded to find a consistent pattern
in FDG uptake in our control group and it might be worthwhile to implement a larger
number of patients that would allow to investigate sub-groups with early and late
normalization of adrenal insufficiency.
Within the current dataset, we fail to demonstrate significant differences regarding
the clinical outcome based on the FDG uptake in the remaining adrenal gland in
patients during mitotane therapy. However, it is interesting to note, that by trend
the patient group with the higher median uptake has a better recurrence free and
overall survival. As maximum FDG uptake in comparison to baseline was more prominent
in the mitotane treated group of patients, the adrenal destructing properties of
mitotane are likely to contribute to this phenomenon. Our initial hypothesis, that
the remaining adrenal could be used as a “sentinel” tissue to
quantify mitotane-induced action on adrenocortical cancer cells cannot clearly be
supported on the basis of the current data set. Reasons for this outcome –
in addition to a false hypothesis – can be a patient group that is too small
or too diverse to allow for the detection of significant differences. A further
weakness of the current dataset concerns the retrospective study design and
inclusion of patients from two different study sites.
Our study further suggests that the FDG uptake of the liver in the case of mitotane
therapy is higher than in patients without mitotane therapy. It could be speculated,
that this difference reflects hepatic metabolic processes induced by mitotane.
Indeed, increase in cholestasis parameters is commonly observed in patients treated
by mitotane. We could not ascertain a significant correlation between mitotane
plasma levels and the extent of FDG uptake in the liver. However, considering the
long half-live and complex pharmacodynamics properties of mitotane, effects on the
hepatocytes that could affect FDG uptake might not be reflected by plasma levels at
the same time point. Independent of its cause, the liver SUVmean does not appear as
the most suitable parameter for calculating an adrenal uptake ratio. The extent of
this influence on the interpretation of SUV values cannot be determined from this
study. However, since a certain effect seems to exist, it should be considered in
the interpretation of adrenal uptake in patients under mitotane therapy.
In summary, FDG uptake in the contralateral adrenal gland in patients who had
undergone surgery for ACC is a common finding that is more distinct in the context
of mitotane treatment. While there is only a tendency to an association with better
clinical outcome, this phenomenon is unlikely to reflect the presence of malignant
disease.
