Positive Correlation Between 18F-FDG Uptake and Tumor-Proliferating Antigen Ki-67 Expression in Adrenocortical Carcinomas
Rossella Libé, MD,* Aurore Pais, MD,* Florian Violon, MD, ¿¿ Laurence Guignat, MD,*
Fideline Bonnet, MD,¿§|| Olivier Huillard, PhD, MD, / Guillaume Assié, PhD, MD, ** || Martin Gaillard, MD, *** Bertrand Dousset, PhD, MD, *** Sébastien Gaujoux, PhD, MD,#1; Maxime Barat, PhD, MD,¿||## Anthony Dohan, PhD, MD,#||## Mathilde Sibony, PhD, MD,1}
Jérôme Bertherat, PhD, MD,*#|| Anne Segolene Cottereau, PhD, MD,§§ Florence Tenenbaum, MD,§§ Joël Coste, PhD, MD,#|||| and Lionel Groussin, PhD, MD ** //
Purpose of the Report: Adrenocortical carcinoma (ACC) is an extremely rare endocrine malignancy, which cannot always be diagnosed during conven- tional radiology and hormonal investigations. 18F-FDG PET could help pre- dict malignancy, but more data are necessary to support future guidelines.
Methods: A cohort of 63 patients with histologically proven ACC (n = 55) or metastatic ACC with steroid oversecretion (n = 8) was assembled. All pa- tients underwent an 18F-FDG PET, and the SUV max and the adrenal-to-liver SUVmax ratio were calculated. The 18F-FDG PET parameters were com- pared with clinical, pathological, and outcome data.
Results: Fifty-six of 63 patients (89%) had an ACC with an adrenal-to-liver SUVmax ratio >1.45, which was a previously defined cutoff value to predict malignancy with 100% sensitivity. Seven ACCs (11%) had a lower uptake (adrenal-to-liver SUVmax <1.45), most of them with a proliferation marker Ki-67 expression level <10%. A positive correlation between 18F-FDG PET parameters (SUVmax and adrenal-to-liver SUVmax ratio) and tumor size, ENSAT (European Network for the Study of Adrenal Tumors) staging, total Weiss score, and the Ki-67 was found. The strong correlation between SUVmax and Ki-67 (r= 0.47, P = 0.0009) suggests a relationship between 18F-FDG uptake levels and tumor proliferation. No statistically significant
Received for publication October 17, 2022; revision accepted December 21, 2022. From the *Service Endocrinologie, French National Network for Adrenal Can- cers ENDOCAN-COMETE, and ¡Service d’Anatomo-Pathologie, AP-HP, Hôpital Cochin; ¿ Université Paris Cité; §Service d’Hormonologie, AP-HP, Hôpital Cochin; |Institut Cochin, INSERM Unité 1016, CNRS UMR
8104; ¡ Service d’Oncologie Médicale and ** Service de Chirurgie Digestive, Hépatobiliaire et Endocrinienne, AP-HP, Hôpital Cochin; ¡¡ Service de Chirurgie Viscérale et Endocrine, AP-HP, Pitié Salpetriere; and Service de Radiologie, §§Service de Médecine Nucléaire, and ||Service de Biostatistique, AP-HP, Hôpital Cochin, Paris, France.
Conflicts of interest and sources of funding: none declared.
R.L. and A.P. contributed equally to this work.
Author Contributions: All authors contributed to the study conception and design. The preparation of material and data collection was carried out by R.L., A.P., F.V., L. Guignat, F.B., O.H., G.A., M.G., B.D., S.G., M.B., A.D., M.S., J.B., A.S.C., F.T., and L. Groussin. Statistical analysis was done by J.C. The first draft of the manuscript was written by R.L., A.P., and L. Groussin, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committees and with the 1964 Helsinki Declaration and its latest amendments or comparable ethics standards. All patients who participated in the study provided their informed consent, and the study received the approval from the local ethics committee for Cochin Hospital publications (no. AAA-2020-08049).
Correspondence to: Lionel Groussin, PhD, MD, Hôpital Cochin, Service d’endocrinologie et des maladies métaboliques, 27 rue du Faubourg Saint- Jacques, 75014 Paris, France. E-mail: lionel.groussin@aphp.fr.
Copyright @ 2023 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0363-9762/23/4805-0381
DOI: 10.1097/RLU.0000000000004593
associations between outcome parameters (progression-free or overall sur- vival) and 18F-FDG PET parameters were found.
Conclusions: This large cohort study shows that most cases of ACC dem- onstrate high 18F-FDG uptake. However, the positive correlation observed between SUV max and Ki-67 expression levels seems to explain the possibil- ity of identifying some ACC with a low or inexistent 18F-FDG uptake. These findings have practical implications for the management of patients with an adrenal mass.
Key Words: 18F-FDG PET, adrenocortical carcinoma, Ki-67 (Clin Nucl Med 2023;48: 381-386)
A drenocortical carcinoma (ACC) is a rare endocrine malignancy with an annual incidence rate of 0.5 to 2 cases per million peo- ple, with an overall poor prognosis.1,2 Adrenocortical carcinoma cannot always be diagnosed by the combination of radiological fea- tures on CT and an abnormal steroid excretion profile.3 With the widespread use of imaging, the recognition of ACC among adrenal incidentalomas represents a common challenge in clinical practice. When an adrenal tumor does not meet the typical radiological criteria of benignity, other diagnostic tools are necessary. As stated in the European Society of Endocrinology guidelines4 and in rec- ommendations from oncologists,5 18F-FDG PET may help in the as- sessment of indeterminate adrenal masses. However, the evidence is considered insufficient to make a strong recommendation.º Despite this limitation, studies suggested that the adrenal-to-liver SUV, ratio is a good parameter to differentiate ACCs from benign adrenal lesions.7-10 The present study reports on the up-to-date largest co- hort of ACC explored with 18F-FDG PET, and we investigate the re- lationship between 18F-FDG uptake and clinical-pathological and outcome data. The tumor proliferation index marker Ki-67 was spe- cifically analyzed because of its major prognostic value in localized and metastatic ACC.11,12
PATIENTS AND METHODS
Patients
We retrieved clinical, hormonal, radiological, and histopatho- logical data from a cohort of 63 consecutive patients diagnosed with ACC between 2007 and 2018 in a single tertiary reference center. The patients were managed using French13 and European guide- lines.4 Fifty-five patients had histologically proven ACC, and 8 had metastatic secreting ACC corresponding to stage 4 of the ENSAT (European Network for the Study of Adrenal Tumors) clas- sification. Figure 1 shows the study design.
63 adrenocortical carcinomas with initial 18F-FDG PET parameters:
- adrenalSUVmax
- adrenal/liver SUVmax ratio
| Histology proven | Steroids excess and metastatic |
|---|---|
| n= 55 | n=8 |
Correlation with:
Clinical criteria
· Tumor size
· ENSAT stage
· Progression Free Survival (PFS)
· Overall Survival (OS)
Histological criteria
· Weiss score (total and each 9 items)
· Ki67 %
· Number of mitoses
· Immunostaining
· p53 IHC
· Beta-catenin
· CyclinE
FIGURE 1. Patients population and analysis description. Flowchart of the study design. All the 63 ACC patients included in the study underwent an 18F-FDG PET. Fifty-five patients had a histologically proven ACC, and 8 had steroid oversecretion with metastatic ACC corresponding to stage 4 of the ENSAT classification. Correlations between adrenal SUVmax and adrenal-to-liver SUVmax ratios and clinical/ histological criteria were explored.
18F-FDG PET/CT
18F-FDG PET/CT was performed preoperatively or during the initial evaluation for patients not operated on, on a Gemini TF 16 (Philips Medical System) that combined a helical dual-slice CT and a PET machine. 18F-FDG (5 MBq/kg) was administrated in- travenously, after at least 6 hours of fasting and if blood glucose level was less than 150 mg/dL. Imaging was performed 60 minutes later. An experienced nuclear medicine physician (F.T.) reviewed all the PET images, blinded to patient data, and measured the SUVmax of the adrenal lesion and the liver SUVmax used as a background. The liver SUV max was calculated using a 3-cm-diameter spherical volume of interest placed on the right side of the liver. Then, the adrenal-to-liver SUV max ratio was calculated. For metastatic ACC, SUVmax and the adrenal-to-liver SUVmax ratio were determined on primary lesion. For the 10 ACC patients with liver metastases, background liver SUV max analysis could be performed in a region with normal tissue. All the 18F-FDG PET/CT scans were performed using the standard procedure described in the European Association of Nuclear Medicine guidelines.14
Pathological Parameters
For operated-on ACC cases, the following histopathological characteristics were obtained: tumor size, Weiss score with the de- tail of the 9 items, immunohistochemistry (IHC) results for the pro- liferation marker Ki-67, p53, B-catenin, and cyclin E. Ki-67 index was assessed by IHC with MIB1 monoclonal antibody. Areas with the highest mitotic count (hotspots) in each slide were selected. The Ki-67 expression level was calculated from scanned images using automatic counting software (Immuno Ratio Freeware) or manual counting software (Fiji application) on at least 500 cells.
| No. Patients (%) | |
|---|---|
| Sex | |
| Female | 38 (60) |
| Male | 25 (40) |
| Clinical presentation | |
| Incidentaloma | 20 (31.7) |
| Adrenal steroid hypersecretion | 27 (42.8) |
| Palpable abdominal mass | 16 (25.5) |
| ENSAT stage | |
| 1 | 6 (9.5) |
| 2 | 34 (54) |
| 3 | 6 (9.5) |
| 4 | 17 (27) |
| Operated patients (n = 55) | |
| Laparoscopy | 14 (25) |
| Open surgery | 41 (75) |
| Resection status (n = 55)* | |
| R0 | 48 (87.3) |
| R1 | 4 (7.2) |
| R2 | 1 (1.8) |
| RX | 2 (3.7) |
| Tumor size, mean ± SD | 10±5 |
| (range), cm | (2.3-22) |
| Weiss score (n = 55)} | |
| 3 | 6 (11) |
| 4 | 5 (9.1) |
| 5 | 4 (7.3) |
| 6 | 10 (18.2) |
| 7 | 11 (20) |
| 8 | 10 (18.2) |
| 9 | 9 (16.3) |
| Ki-67% (n = 46) | |
| ≤10 | 18 (39) |
| 10-19 | 9 (19.5) |
| ≥20 | 19 (41.5) |
| No. mitoses (n = 55)} | |
| ≤5 | 12 (22) |
| >5 | 43 (78) |
*R0: complete resection; R1: microscopic residual tumor; R2: macroscopic resid- ual tumor; RX: resection cannot be assessed.
+Weiss score is the most widely system used to distinguish between benign adre- nal tumors and ACC, based on a combination of 9 histological criteria. A score of ≥3 (on a total of 9 criteria) indicates ACC.15
¿Mitotic count is part of Weiss score and is positive in presence of more than 5 mi- toses per 50 high-power field.
14
0 Ki67 ≤ 10%
Ki67 >10%
Adrenal/liver SUVmax ratio
· Ki67 unknown
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Statistical Analysis
Major characteristics of the study cohort are given as means ± SD or frequencies. Univariate analyses were carried out using nonparametric tests (x2, Wilcoxon test). Spearman rank order correlation test (and partial Spearman rank order correlation) was used to investigate the correlation between 18F-FDG PET parame- ters and other outcome predictors.
Overall survival (OS) is defined as the time between the ACC diagnosis and death. Progression-free survival (PFS) is defined as the time from primary tumor resection to the first radiological evi- dence of progression for stages 1, 2, and 3 ACCs and the time be- tween stage 4 diagnosis and progression. Overall survival and PFS curves were estimated by using the Kaplan-Meier method and were compared with the use of the Cox proportional hazards model (proportional hazards assumptions were checked with the use of Schoenfeld residuals and graphic methods).
RESULTS
Patients
The main characteristics of the patients are summarized in Table 1. Adrenal steroid hypersecretion (42.8%) was the most com- mon type of clinical presentation. More than half of the patients
(54%) had a localized tumor larger than 5 cm (ENSAT stage 2). Among the 55 patients operated on, 41 (75%) underwent an open sur- gery. Forty-eight (87.3%) patients operated on had a complete resection (R0). The Ki-67 labeling index was available for 46 of the 55 pa- tients who had undergone surgery. High expression of Ki-67 (>10%), which is the cutoff value for considering adjuvant therapy, and an excessive number of mitosis (>5), both criteria associated with poorer survival, were present, respectively, in 61% and 78% of the pa- tients. The median follow-up period was 3.3 years (range, 8-11.7 years) from the diagnosis of ACC. Mean SUVmax and mean adrenal-to-liver SUVmax ratios ± SD were 12.6 ±6.9 and 5.2±3.2, respectively.
Adrenal-to-Liver SUVmax Ratios and Weiss Scores
As the adrenal-to-liver SUVmax ratio is considered as being the best way to distinguish between benign and malignant adrenal tumors, this parameter is shown in Figure 2 in relation to Weiss scores obtained for the 55 cases of ACC that were operated on. The indicated threshold value of 1.45 represents the lowest pub- lished cutoff ratio to diagnose ACC with a sensitivity of 100%.7 In accordance, the ratio was ≥1.45 for most of the patients operated on (48/55 [87%]) and for the 8 cases of metastatic ACC not oper- ated on. Conversely, 7 patients (representing 13% of the cases of ACC operated on and 11% of all cases of ACC) had an adrenal- to-liver SUV max ratio <1.45, between 0.7 and 1.36, 4 of them with
| Clinical/Histological Parameters | Adrenal SUV max | Adrenal/Liver SUV, max | ||
|---|---|---|---|---|
| r | P+ | r | Pt | |
| Tumor size | 0.38 | 0.0018 | 0.43 | 0.0004 |
| ENSAT stage | 0.30 | 0.017 | 0.35 | 0.005 |
| Weiss score | 0.28 | 0.03 | 0.27 | 0.04 |
| Ki-67% | 0.47 | 0.0009 | 0.45 | 0.0015 |
| Cyclin E IHC | 0.46 | 0.004 | 0.31 | 0.05 |
| Capsular invasion | 0.26 | 0.05 | 0.24 | 0.07 |
*The correlation analysis between 18F-FDG PET parameters and tumor size, ENSAT stage, total Weiss score, cyclin E IHC, and capsular invasion was performed with 55 ACCs. The correlation analysis between 18F-FDG PET parameters and Ki-67 expression was performed with 46 ACCs, according to availability. +Statistically significant P value.
18
Spearman r=0.45 p=0.0015
☒ Dead
☒ Alive with disease
16
☐ Alive without disease
14
Adrenal/liver SUVmax
12
10
8
☐
☐
6
☐
4
2
1,45
0
0
10
20
30
40
50
60
70
80
Ki67 (%)
a ratio less than 1. Among these 7 patients, the Ki-67 was available for 6. Five of these 6 patients (83%) had a Ki-67 ≤10%, whereas only 13 (32.5%) of 39 patients with an adrenal-to-liver SUV max ≥1.45 had a Ki-67 ≤10%. The difference was statistically significant (P<0.03). Despite a low adrenal-to-liver SUV max ratio, 2 patients died of their metastatic ACC after 4 months and 3 years, respectively.
Correlation of 18F-FDG PET Parameters With Clinical and Histological Criteria
Next, we assessed whether the metabolic cancer activity that derived from 18F-FDG uptake correlated with disease histology
and/or clinical outcomes. Among the analyzed criteria (Fig. 1), a statistically significant positive correlation was found between tu- mor SUV max or adrenal-to-liver SUV max ratio and 5 clinical or his- tological parameters (Table 2). Considering individually the 9 items of the Weiss score, a positive correlation was found only be- tween tumor SUVmax and capsular invasion (P = 0.05). The strongest correlation was observed between the proliferation marker Ki-67 and the tumor SUV max (Spearman r = 0.47, Pofre- jection of correlation = 0.0009) or between Ki-67 and the adrenal-to-liver SUV max ratio (Spearman r = 0.45, P of rejection of correlation = 0.0015).
ACC 1
ACC 2
ACC3
| Adrenal SUVmax | 2.5 | 4.9 | 16.8 |
| Adrenal/liver SUVmax ratio | 0.83 | 1.3 | 12.9 |
| Weiss score | 3 | 4 | 9 |
| Ki67 | 2 % | 10 % | 30 % |
FIGURE 4. Relationship between 18F-FDG uptake and Ki-67 in 3 patients with ACC. CT scans showing 3 cases of ACC measuring respectively 4.5, 7, and 17 cm. The second patient had a 2-component mass. 18F-FDG uptake was localized to the anterior component corresponding to the malignant adrenocortical neoplasm. Histological appearance with nuclear Ki-67 immunostaining.
The significant correlation between adrenal-to-liver SUV max ratio and Ki-67 is shown in Figure 3. The Ki-67 threshold value at 10% represents the known cutoff value predicting ACC with a worse prognosis. Indeed, only 2 (11%) of 18 patients with Ki- 67 <10% died of their metastatic ACC compared with 15 (53.5%) of 28 patients with Ki-67 >10% (P<0.004).
To illustrate the relationship between 18F-FDG PET and the Ki-67, we chose images from patients with 3 different uptake inten- sities correlating with an increased proliferating marker (Fig. 4).
Tumor SUV max and adrenal-to-liver SUV max ratio were associ- ated with reduced OS, albeit not achieving significance (hazard ratio [HR] for death, 1.04; 95% confidence interval [CI], 0.99-1.10; P= 0.16; and HR, 1.10; 95% CI, 0.98-1.23, P= 0.11, respectively). No statistically significant association between tumor SUVmax or adrenal-to-liver SUVmax ratio and PFS was observed (HR, 1.03; 95% CI, 0.96-1.20; P = 0.42; and HR, 1.05; 95% CI, 0.90-1.24; P = 0.38, respectively).
DISCUSSION
18F-FDG PET is mainly used in patients with adrenal masses and a history of extra-adrenal malignancy because of its high sen- sitivity (97%) and specificity (91%) in the diagnosis of adrenal me- tastases. The diagnostic capacity of F-FDG PET in adrenal incidentalomas to predict malignancy beyond the context of cancer has been studied less, explaining why current guidelines on adrenal tumors management cannot be evidence-based.1,2,4 The 2 largest series studying this question included 35 and 37 cases of ACC, respec- tively.10,17 Despite these limitations, current data suggest that 18F-FDG PET is a relatively reliable tool for recognizing ACC with few false-negative results.7,17 In 18F-FDG PET analysis, the adrenal-to-liver SUV max ratio was found to have a lower false-positive rate than adrenal SUV max to differentiate between adrenocortical adenoma and ACC.7,16 Thus, the adrenal-to-liver SUVmax ratio is considered as being the diagnostic criteria to use, even if there is variability in the reported ratios between 1.29 and 2.5.7-10,17-20
The present article, concerning a cohort of 63 proven cases of ACC, demonstrates for the first time a positive correlation between clinical-pathological parameters, in particular Ki-67 expression, and 18F-FDG uptake. In accordance with a previous study, we did not observe a correlation between steroid oversecretion and 18F-FDG uptake.21 Instead, and contrary to a previous study with 37 ACCs,22 significant correlations between adrenal-to-liver SUVmax ratios and tumor sizes or ENSAT stages were observed. Considering the path- ological parameters, a significant correlation was found between adrenal-to-liver SUV max ratio and total Weiss score, as previously reported.8 Capsular invasion was positively correlated with SUVmax, whereas no correlation was observed with the other Weiss items, con- firming the data by Tessonnier et al.22 The positive correlations con- cerning size, ENSAT stage, Weiss score, and Ki-67 corroborate the idea of a relationship between 18F-FDG uptake and tumor prolifer- ation.23 This correlation between Ki-67 expression and 18F-FDG uptake has also been described in different types of malignancy, such as ovarian, non-small cell lung, head and neck carcinomas, and malignant lymphomas.24-28 Considering the outcome data, no statistically significant associations with the PFS or OS were found in our cohort, in accordance with recent works including ENSAT stages 1, 2, 3, and 4 ACCs.22,29
The strong positive correlation between Ki-67 expression and F-FDG uptake seems to have implications for F-FDG PET use in clinical practice. Indeed, we observed 7 cases of ACC (11%) with an adrenal-to-liver SUVmax ratio lower than 1.45, the lowest previously defined ratio used to identify ACC with 100% sensitivity.7 These low ratios did not correlate with lower Weiss scores or lower ENSAT stages, but a Ki-67 ≤10% was present in
most of these cases of ACC. Even considering the lowest published ratio at 1.29,10 4 cases of ACC from the present series would have still been false-negative 18F-FDG PET imaging. Some other malig- nancies, including low-grade lung adenocarcinomas, renal cell can- cers, and mucinous neoplasms, have demonstrated low or absent 18F-FDG uptake, possibly due to low glucose metabolism or low cellularity.30 Prospective studies, including a large number of benign and malignant adrenocortical tumors, are expected to refine the threshold ratio to distinguish these 2 types of tumors. Correlation be- tween FDG uptake and other clinical parameters, such as Ki-67, is an interesting aspect of this research. Indeed, integrating clinicopatho- logical parameters and imaging-derived measurements opens up new possibilities for combined biomarkers that increase the prognos- tic value compared with each of them used independently.31
In conclusion, this large cohort of ACCs shows that most ACCs demonstrate high 18F-FDG uptake. However, we observe in our retrospective study that 11% of ACC cases may have low or absent FDG uptake. The positive correlation observed between SUVmax and the proliferation marker Ki-67 seems to be one possi- ble explanation. These findings have clinical implications for the management of patients with radiological indeterminate adre- nal masses. A study correlating other FDG parameters with radio- logical, molecular, and outcome data will be of interest to reinforce these data.
ACKNOWLEDGMENTS
The authors thank the doctors and nurses who cared for and man- aged patients included in this study.
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