18F-FDG Uptake at Initial Staging of the Adrenocortical Cancers: A Diagnostic Tool but Not of Prognostic Value
L. Tessonnier . C. Ansquer . C. Bournaud . F. Sebag .
E. Mirallie . J. C. Lifante . F. F. Palazzo . I. Morange .
D. Drui . C. de la Foucardère . J. Mancini . D. Taïeb
Published online: 22 September 2012 @ Société Internationale de Chirurgie 2012
Abstract
Background Adrenocortical carcinoma (ACC) is a rare cancer for which little level evidence exists to guide management. 18F-FDG PET (18F-fluorodeoxyglucose pos- itron emission tomography) is an increasingly used diag- nostic tool in patients with suspicious or indeterminate adrenal tumors. In some other solid tumors, 18F-FDG PET may offer prognostic information that can guide optimal patient treatment. The aim of the present study was to evaluate whether preoperative 8F-FDG PET based on SUVs assessments has a prognostic value in ACC patients.
Methods A retrospective analysis was performed in patients who underwent 18F-FDG PET/CT for the evalua- tion of ACC. Inclusion criteria were an unequivocal diag- nosis of ACC; all data from primary diagnosis available; 18F-FDG PET/CT performed prior to surgery or other treatment of the primary tumor; a minimum of 6-months follow-up for surviving patients. All 18F-FDG PET/CT procedures were reinterpreted in a blind fashion.
Results Thirty-seven patients (23 without metastasis [M0], 14 with metastasis [M1]) fulfilled the study criteria. Median uptake values were tumor standardized uptake values (SUV)max = 11 (range: 3-56) and a tumor/liver
L. Tessonnier . D. Taïeb ☒
Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University,
264 rue Saint-Pierre, 13385 Marseille Cedex 5, France
e-mail: david.taieb@ap-hm.fr
C. Ansquer
Department of Nuclear Medicine, University Hospital, Nantes, France
C. Bournaud
Department of Nuclear Medicine, Civil Hospices of Lyon, Lyon, France
F. Sebag · F. F. Palazzo
Department of Endocrine Surgery, La Timone University Hospital, Aix-Marseille University, 13385 Marseille, France
E. Mirallié
Department of Endocrine Surgery, University Hospital, Nantes, France
J. C. Lifante
Department of Endocrine Surgery, Civil Hospices of Lyon, Lyon, France
I. Morange Department of Endocrinology, La Timone University Hospital, Aix-Marseille University, 13385 Marseille, France
D. Drui Department of Endocrinology, University Hospital, Nantes, France
C. de la Foucardère
Department of Oncology, Leon Berard Cancer Centre, Lyon, France
J. Mancini Laboratory for Education and Research in Medical Information Processing (LERTIM, EA3283), Aix-Marseille University, 13385 Marseille, France
J. Mancini
Department of Public Health (SSPIM), La Timone University Hospital, Aix-Marseille University, 13385 Marseille, France
SUVmax ratio = 4.2 (range: 1.3-15). Median follow-up was 20 months. Although classic risk factors (tumoral stage, Weiss score) were associated with poor outcome, there was no correlation between primary tumor FDG uptake with overall survival (OS) and disease free survival (DFS) in MO patients and with overall survival in M1 patients. 18F-FDG uptake correlated inconsistently with sinister histological features, such as atypical mitoses or necrosis.
Conclusions At initial staging, primary tumor FDG uptake in ACC patients does not correlate with OS and DFS at 2 years. Patient prognosis and treatment strategy should not be based on uptake values.
Introduction
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an estimated worldwide incidence of 0.5-2 per million/year. It is characterized by a high risk of recur- rence and poor overall survival rates [1]. Retrospective studies have identified two major prognostic factors in ACC: the completeness of the primary resection and the stage of disease. Overall 5-year survival for tumors resected with curative intent is approximately 40 %. Unresectable or widely disseminated tumors have a very poor outcome indeed. Treatment in such cases is limited where appropriate to palliative debulking surgery, adjuvant mitotane treatment, systemic chemotherapy, and/or radiotherapy.
However, individual patient survival can be difficult to predict and appears to differ widely for any given tumor stage, reflecting the heterogeneity of the disease. The molecular mechanisms underlying this clinical phenotypic heterogeneity remain largely unknown. Identification of powerful predictors of prognosis and response to treatment could substantially improve the choice of treatment and the associated clinical outcome. 18F-FDG PET/CT has become a widely used imaging modality, principally for the diag- nosis, staging, and follow-up of ACC [2-10]. It has been controversially suggested that 18F-FDG PET/CT offers prognostic information in patients with metastatic lesions and late presentation [11]. The prognostic value of 18F-FDG PET/CT is established in some malignancies where it appears that the prognostic value of a high 18F- FDG uptake may act independently of tumor stage and therefore guide treatment. Indeed, it has even been sug- gested that glucose transporter GLUT1 expression, an important determinant of 8F-FDG uptake, has stage- independent prognostic value in ACC [12].
The aim of the present study was to evaluate whether high tumor standardized uptake values (SUV) and tumor/ liver SUV ratio values at initial presentation in ACC are correlated with poorer clinical outcome.
Materials and methods
Patients
Suitable patients were identified from the records of three tertiary French centers (Marseille, Nantes, Lyon) for the 6-year period from 2004 to 2010. Patient recruitment cri- teria included:
· An unequivocal diagnosis of ACC confirmed by histology and/or a Weiss score ≥3.
· All relevant data available at the initial diagnosis, including hormonal secretion status, surgical protocol, tumor stage (MacFarlane classification).
· 18F-FDG PET performed prior to surgery of the primary tumor or any other treatment.
· 6 months follow-up data for living patients. Evalua- tions were performed at three-month intervals during the first two years.
[18F]-FDG PET/CT
A standardized 18F-FDG PET protocol was adopted and the images were double reported blindly by two experienced nuclear physicians. A final consensus reading was performed in the case of discrepancies. The protocol consisted in a minimal 4-h fast, and an injection of 4-5 MBq/kg of FDG. The imaging was performed at 70 min (mean ± 15 min) post-injection. Attenuation correction was obtained by transmission imaging with computed tomography (CT). The images were reconstructed with an ordered subset expecta- tion maximization (OSEM) algorithm and reviewed in multiple planes. A region of interest (ROI) was drawn on the primary tumor. A large ROI was also drawn on a large homogeneous liver region (segment VIII). Activity counts in the ROIs were normalized to injected doses per kilogram of patient body weight (maximum standardized uptake value; SUV max). The SUV max in the ROI on PET images was then measured. A ratio of SUVmax tumor on SUVmax liver was calculated (SUV ratio).
Statistical analysis
The Kaplan-Meier method was applied to estimate overall survival (OS) and disease-free survival (DFS) rates. A log rank test was applied to assess the correlation of these end points with the tested binary risk factors (metastatic stage, primary tumor SUV > 10, ratio SUV > 4, tumor size > 100 mm, Weiss score > 6). Cox proportional haz- ards survival regression analysis was also used for continu- ous variables, including primary tumor characteristics. The Mann-Whitney test was used to compare primary tumor SUV depending on each Weiss score item. Given the number
of patients in the analysis, no multivariate analysis was performed. p values less than 0.05 were taken to be statisti- cally significant. Eleven statistical analyses were performed with SPSS 17.0 software; the 95 % confidence intervals for the survival rates were calculated using R 2.13.2.
Results
Patients
Patients and tumor characterisitcs are shown in Table 1. Thirty-seven patients (16 men, 21 women; 52 ± 15 years of age; range: 20-88 years) were included in the study. Median tumor size was 80 mm (range: 10-200 mm). One third of the patients had nonsecreting ACC, one half had hypercortisol- ism, and the remaining had hyperandrogenism or hyperal- dosteronism only. Tumor stage was reported according to the European Network for the Study of Adrenal Tumors (EN- SAT) classification staging system [13]. Twenty-three patients (62 %) were free from metastases (M0), and the remaining 14 patients had distant metastases (M1). Meta- static status was established from imaging diagnostic tools (at least diagnostic enhanced CT and 18F-FDG PET/CT) and surgical findings. Thirty-one patients underwent surgical resection of the primary tumor (all M0 patients and 8 M1 patients), at one of the primary centers. There was no evi- dence of residual disease at the first postoperative evaluation, except in four patients. All but two M1 patients received various chemotherapeutic agents. Median tumor size was 80 mm (range: 10-200 mm). The median interval between 18F-FDG PET and surgery was 33 days (range: 1-59 days). The Weiss score (a 9-point histopathological scoring system) was 3, 4, 5, 6, 7, 8, or 9 in 2, 3, 5, 5, 9, 4, and 3 patients, respectively (median value, 7). ENSAT stage (a 4-stage system) was 1, 2, 3, or 4 in 7, 3, 11, and 16 cases, respectively. The median follow-up was 20 months (from 4 days related to an early postoperative death to 79 months). Median uptake values were as follows: tumor SUV max = 11 (range: 3-56) and tumor SUV max/liver SUV max ratio = 4.2 (range: 1.3-15).
Disease outcome according to clinical, pathological, and imaging factors
At the last follow-up, 25 patients were alive and 12 patients had died (3 M0 including one early postoperative death, not excluded from analysis, and 9 M1 at diagnosis). Mean overall survivals were 49 months ± 6 for the entire popu- lation, 66 months ± 6 for M0 patients, and 16 months ± 2 for M1 patients.
Of the 23 M0 patients, 9 relapsed (with 2 subsequent deaths), whereas the remaining 14 patients were free from
| Patients | N = 37 |
| Age (mean ± DS) | 52 (±15; range: 20-88) |
| Male/female | 16/21 |
| Size tumor | 80 mm (median) ± 42; range: 10-200 mm |
| Stage | Death | Relapse | |
|---|---|---|---|
| M0 | 23 | 3 | 9 |
| M1 | 14 | 9 | NA |
| ENSAT stage | |||
| I | 7 | 0 | 1 |
| II | 3 | 0 | 0 |
| III | 12 | 3 | 6 |
| IV | 15 | 9 | 2 |
| Weiss score | |||
| 3 | 2 | 0 | 0 |
| 4 | 3 | 0 | 0 |
| 5 | 5 | 0 | 2 |
| 6 | 5 | 1 | 1 |
| 7 | 9 | 4 | 2 |
| 8 | 4 | 2 | 3 |
| 9 | 3 | 1 | 1 |
ENSAT European network for the study of adrenal tumors
disease. Mean DFS for M0 patients was 40 months (±.5). In patients with tumor reccurrence, mean time between surgery and relapse was 17 months (±17). In patients with M0 stage, tumor relapse occurred after open surgery in 8 (/18) cases and after laparoscopic surgery in 1 case (/5).
As expected, classic risk factors of aggressiveness (tumor stage, Weiss score) were found to be associated with poor outcome (Table 2). Neither dichotomized tumor SUVmax (threshold: SUVmax = 10) and ratio (threshold: ratio = 4) nor SUVmax and tumor/liver SUV max ratio were significantly predictive of OS in M1 and M0 patients (Table 2, Fig. 1). Indeed, the 21 SUVmax > 10 patients presented a 2-year survival of 75 %, compared to 59.1 % for the 16 SUV max < 10 patients. Concerning patients with SUV max > 10, 15 were alive and 6 had died by the end of the follow-up. No relationship was found between uptake values and DFS in M0 patients (Fig. 1).
Atypical mitosis was the only histological parameter significantly associated with higher values of SUVmax (p = 0.009) and ratio (p = 0.026). Necrosis was signifi- cantly correlated with the SUV ratio alone (p = 0.035).
Discussion
18F-FDG PET/CT has become a widely used supplementary imaging tool in the investigation of adrenal tumors, as well
| 1-year OS rate | 2-year OS rate | Log rank test p value | Cox proportional hazards analysis | |||||
|---|---|---|---|---|---|---|---|---|
| (%) | 95 % CI | (%) | 95 % CI | HR | CI | p Value | ||
| All patients | 85.1 | 73.9-98.1 | 68.1 | 52.4-82.6 | ||||
| Metastatic stage | ||||||||
| M0 | 95.7 | 87.7-100 | 88.3 | 73.8-100 | ||||
| M1 | 61.9 | 38.1-100 | 24.8 | 7.6-80.4 | <0.001 | |||
| ENSAT stage (as continuous value) | 5.2 | 1.6-17 | 0.005 | |||||
| Weiss score (as continuous value) | 1.7 | 1.1-2.8 | 0.03 | |||||
| 3-6 | 100 | 100-100 | 100 | 100-100 | ||||
| 7-9 | 87.1 | 71.8-100 | 56.5 | 32.9-97.0 | 0.009 | |||
| Tumor size (per 10 mm increase) | 1.2 | 1-1.3 | 0.02 | |||||
| <100 mm | 90.9 | 79.7-100 | 84.8 | 70.2-100 | ||||
| >100 mm | 75.0 | 53.5-100 | 32.1 | 10.9-94.6 | 0.014 | |||
| SUV max(as continuous value) | 0.98 | 0.88-1.08 | 0.7 | |||||
| <10 | 87.1 | 71.8-100 | 59.1 | 35.9-97.2 | ||||
| >10 | 83.3 | 67.7-100 | 75.0 | 55.9-100 | 0.6 | |||
| SUV ratio (as continuous value) | 0.87 | 0.67-1.14 | 0.3 | |||||
| <4 | 81.9 | 65.3-100 | 72.8 | 52.7-100 | ||||
| >4 ☒ | 87.5 | 72.7-100 | 64.2 | 43.0-95.7 | 0.7 | |||
as in the staging and follow-up of ACC patients [2-10, 14]. The prognostic value of 18F-FDG PET/CT has been shown in other malignancies. A high 18F-FDG uptake appears to represent an additional stage-independent prognostic factor. The prognostic utility of 18F-FDG PET has been found in lymphoma [15, 16], lung cancer [17], head and neck squa- mous cancer [18], cervical cancer [19], and esophageal cancer [20]. Tumor glycolytic activity as determined by 18F- FDG uptake is an important marker of tumor biology and provides critical information about the behavior of most malignancies at different stages of the disease. The link between cancer and altered metabolism is not new, but interest has been renewed in recent years, as it has become clear that many of the signaling pathways that are affected by oncogenetic mutations have a profound effect on core metabolism [21].
To our knowledge, just one single-center study suggests that this also applies to ACC in a population with meta- static disease [11]. The objective of the present series was to establish in a large series of its type whether this applies to patients with primary ACC at initial staging. In the present study, we found that high primary tumor FDG uptake, as measured by SUV max and tumor/liver SUV max ratio, was not significantly associated with poorer outcome as indicated by a shortened OS and DFS. High FDG uptake at initial staging does not portend a poor prognosis and should therefore not be used at this time to direct therapy or to exclude patients from potentially curative surgery. Uptake values did, however, correlate with atypical mitosis
and the presence of necrosis as listed in the Weiss score criteria. As expected, tumor stage and Weiss score were the key correlates with patient survival. Twenty-five patients received variable, non-continuous, inhomogeneous sys- temic therapies after surgery, including mitotane therapy and/or chemotherapy. We acknowledge that the sample size was probably too small to detect subtle differences between patients, and that no statistical adjustment could be made for potential confounding factors. However, with an incidence of 1-2 per million per annum our three-center study remains a large series to date and indeed was suffi- cient to confirm that the classic risk factors were, as expected, significantly associated with poor outcomes while no tendency was observed for FDG uptake values. Negative studies are notoriously difficult to interpret because the risk of a sample size error is always a concern. To detect a statistically proven difference with a statistical power of 80 % using bilateral log rank testing with a 5% type 1 error, it would be necessary to perform FDG-PET on 254 patients with proven ACC. This is unlikely to occur outside a pan-European study. Our limited sample size did not allow accurate correlations between SUVs and other parameters (i.e., tumor grade, microvascular invasion, lymphatic invasion, subgroup after excluding R1 patients, stage-to-stage comparisons).
In a study published by Leboulleux and colleagues, PET/CT was performed a median of 3 years after surgery of the primary tumor on a very disparate patient group of 28 mainly metastatic patients that included 19 patients with
A
B
1.0
SUVmax
≤ 10
1.0
> 10
$ 10-censored
++ > 10-censored
Overall Survival Probability
0.8
MO+M1
Overall Survival Probability
0.8
M1
0.6
0.6
0.4
0.4
0.2
0.2
0.0
0.0
12
24
36
48
60
72
12
24
36
48
60
72
C
Follow-up (months)
D
Follow-up (months)
1.0
1.0
Overall Survival Probability
Disease Free Survival Probability
MO
MO
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0.0
0.0
12
24
36
48
60
72
12
24
36
48
60
72
Follow-up (months)
Follow-up (months)
known residual metastatic disease [12]. The previous treatment modalities in these patients also varied greatly and including reoperative surgery, systemic chemotherapy, liver chemoembolization, and external beam radiation. At analysis, 22 patients had evidence of disease, with FDG uptake in 21 cases (one false negative liver metastasis). The univariate analysis showing that the SUVmax (>10) and the FDG uptake tumor volume (>150 mL) were sig- nificantly associated with decreased overall survival (with a short median follow-up period of 8 months) needs to be interpreted in this context. Curiously, the number of affected organs (>2) did not determine the prognosis.
Our differing findings may be considered more reliable given the larger number and greater homogeneity of our patient group, as well as the reliable timing of the PET scan at the time of initial diagnosis. This is of relevance because tumor de-differentiation with time may change the bio- logical behavior of the malignant tissue. Such changes may be associated with the molecular changes that culminate in the metabolic reprogramming of tumor cells that in turn cause an increased expression of glucose transporters and glycolytic enzymes, and therefore FDG-PET positivity.
The high expression of factors involved in glucose metabolism and/or hypoxic pathways have been previously shown to be associated with shortened survival in some tumor entities, but not specifically in ACC. Fenske and colleagues, from the German ACC Registry Group, eval- uated the expression of four markers of glucose metabo- lism in adrenal tissue [12]. Immunohistochemical studies were performed on tissue microarrays that contain more than 150 ACC specimens (mainly primary tumors). They demonstrated that the vast majority of ACC do not exhibit membranous expression of GLUT1 (66.5 %) or GLUT3 (86.3 %). Expression was detected in the remaining cases with high expression patterns in only 10.5 % for GLUT1 and 3.9 % for GLUT3. These results support our findings that ACC exhibit a moderate FDG uptake per ml of tumor tissue, as well as the view that ACC are less dependent on glucose metabolism as their main source of energy than other tumor types. Because ACC are usually large, the partial volume effect in PET that affects the quantification is reduced. Nevertheless, ACC usually show moderate to intense FDG uptake values. Combining our findings with those of Leboulleux and colleagues [12], it can be
hypothesised that the high-GLUT1/high-SUV phenotype may be present at diagnosis but is expressed more with time as dedifferentiation occurs with the acquisition of additional mutations and/or the adaptive response to hypoxia. This theory, however, remains to be further evaluated, and our longer term follow-up of survivors may clarify this.
Conclusions
Notwithstanding the need for longer-term follow-up and the limitations of performing studies on small numbers of patients with an uncommon tumor such as ACC, it is fair to suggest that in primary tumor FDG uptake in ACC is likely not correlated with OS and DFS at 2 years and at this time should not be used to guide treatment plans and adjuvant therapies.
Conflict of interest The authors declare that they have no conflict of interest.
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