ENDOCRINE SOCIETY
OXFORD
Case Report
Oncocytic Adrenocortical Carcinoma With Low 18F-FDG Uptake and the Absence of Glucose Transporter 1 Expression
Naru Babaya,1 Shinsuke Noso,1 Yoshihisa Hiromine,1 Yasunori Taketomo,1 Fumimaru Niwano,1 Keisuke Monobe,1 Shuzo Imamura,1 Kazuki Ueda,2 Yuto Yamazaki,3 Hironobu Sasano,3 and Hiroshi Ikegami1
1Department of Endocrinology, Metabolism and Diabetes, Kindai University Faculty of Medicine, Osaka-sayama, Osaka 589-8511, Japan; 2Department of Surgery, Kindai University Faculty of Medicine, Osaka-sayama, Osaka 589-8511, Japan; and 3Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
ORCID numbers: 0000-0003-2466-1228 (N. Babaya); 0000-0002-0943-8450 (S. Noso); 0000-0002-7317-236X (Y. Hiromine); 0000-0003-1366-2049 (Y. Taketomo); 0000-0003-4673-9401 (F. Niwano); 0000-0001-7139-4404 (K. Ueda); 0000-0002-6600-8641 (H. Sasano); 0000-0001-8808-4605 (H. Ikegami).
Abbreviations: ACC, adrenocortical carcinoma; ACTH, adrenocorticotropic hormone; CT, computed tomography; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; ENSAT, European Network for the Study of Adrenal Tumors; FDG, 18F-fluorodeoxyglucose; GLUT1, glucose transporter 1; HDL, high-density lipoprotein; HU, Hounsfield unit; LDL, low-density lipoprotein; MRI, magnetic resonance imaging; PET, positron emission tomography; SUV, standardized uptake value.
Received: 18 July 2021; Editorial Decision: 19 August 2021; First Published Online: 23 August 2021; Corrected and Typeset: 7 September 2021.
Abstract
Adrenocortical carcinoma (ACC) is a rare tumor, and some histological variants (oncocytic, myxoid, and sarcomatoid ACCs) have been reported in addition to the con- ventional ACC. Among these subtypes, oncocytic ACC is histologically characterized by the presence of abundant eosinophilic granular cytoplasm in the carcinoma cells owing to the accumulation of mitochondria, which generally yields high 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET). Herein, we report the case of a 21-year-old woman with oncocytic ACC with low FDG uptake on PET scan. Her circu- lating levels of androgens were high, and androgen-synthesis enzymes were detected in carcinoma cells. The patient also had hypocholesterolemia. However, glucose trans- porter 1 (GLUT1) was not detected in the tumor, which was considered to account for the low FDG uptake by the tumor. To the best of our knowledge, this is the first case of low FDG uptake by oncocytic ACC without GLUT1 expression. Additionally, since hypocholesterolemia was reported in 3 previous reports of androgen-producing tumors, a possible correlation between androgenicity in adrenal tumors and the development of hypocholesterolemia could be postulated; however, further investigations are needed for
@ The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.
clarification. This case highlights important information regarding the diversity of ACC and its impact on hypocholesterolemia.
Keywords: adrenal incidentaloma, androgen, cholesterol, DHEA-S, ENSAT, SUVmax
Adrenocortical carcinoma (ACC) is a rare malignancy with an annual worldwide incidence of 0.5-2 cases per million population [1]. Apart from the conventional ACC, some histological variants (oncocytic, myxoid, and sarcomatoid ACCs) have been characterized in the latest World Health Organization classification [1, 2]. Oncocytic ACC is histologically characterized by tumor cells with abundant eosinophilic granular cytoplasm, reflecting the accumula- tion of mitochondria [1-3].
Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) has been used to clin- ically detect various malignant lesions. ACC has been reported to harbor markedly increased FDG uptake, sur- passing the liver background [4]. Even in the case of be- nign adrenocortical tumors, adrenocortical oncocytoma has been reported to be associated with increased FDG up- take owing to the presence of numerous intracellular mito- chondria [5] and increased glucose transporter 1 (GLUT1) expression [6]. Herein, we report a rare case of oncocytic ACC with low FDG uptake. To the best of our knowledge, no similar case has been reported previously. GLUT1 ex- pression was very low in the tumor, which could account for the decreased FDG uptake. Additionally, marked hypocholesterolemia was observed in the patient. Only 3 cases of hypocholesterolemia associated with adrenal tu- mors have been reported in the English literature [7-9], and these concomitant cases will be discussed.
Case Presentation
A 21-year-old Japanese woman was referred to our hos- pital for the characterization of a left adrenal tumor, which was incidentally detected on abdominal computed tomography (CT) after a traffic accident. The oval-shaped tumor measured 7.7 x 4.5 cm2 and had a homogeneous density of 40 Hounsfield units (HU) on a plain CT scan (Fig. 1A).
The patient underwent a detailed endocrine examin- ation. She was aware of secondary amenorrhea since the age of 20 years; however, she had not paid any particular attention to it. She had no symptoms associated with excess hormone levels in the adrenal cortex or medulla, including hirsutism, and no medical history. Physical examination re- vealed no significant findings. Clinical parameters were as follows: body height, 162 cm; body weight, 54.0 kg; blood pressure, 110/58 mmHg; and heart rate, 71 beats/minute.
Laboratory data at the time of admission are summar- ized in Table 1. The complete blood count and blood bio- chemistry tests were within the normal range, except for extremely low serum total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol levels. As for the endocrine findings, blood and 24-hour urine cat- echolamine levels were within the normal range. Plasma aldosterone concentration was high (438 pg/mL); however, plasma renin activity of 2.2 ng/mL/h and aldosterone/renin ratio of 199 were within the normal range; these values may reflect a reduction in salt intake after hospitalization rela- tive to before. Cortisol and adrenocorticotropic hormone (ACTH) levels early in the morning were 10.4 ug/dL and 73.0 pg/mL, respectively. Serum dehydroepiandrosterone (DHEA)-sulfate (DHEA-S), testosterone, and urine 17-ketosteroid levels, especially at the DHEA level, were extremely high, which indicated an excess of adrenal an- drogens. Because a large adrenal mass was found, the patient underwent an overnight 1 mg dexamethasone sup- pression test. The cortisol level was 1.7 ug/dL, which ruled out the autonomous secretion of cortisol.
Magnetic resonance imaging (MRI) revealed a left mass measuring 7.2 × 4.6 cm2 (Fig. 1B-1E). The tumor showed a clear margin and isointense signal on T1-weighted images and iso- to hyperintense on T2-weighted images (Fig. 1B and 1C). On chemical shift MRI of the adrenal glands, the loss of signal intensity was not detected in out-of-phase im- aging when compared with that of the spleen (Fig. 1D and 1E). On FDG-PET (Fig. 1F), the maximum standardized uptake value (SUVmax) of the left adrenal tumor was 2.8, and the adrenal to liver SUVmax was 0.98. There were no signals detected anywhere that would make us suspect a malignant tumor.
The patient underwent laparoscopic left adrenalectomy. The resected left adrenal gland weighed 130 g, and the tumor measured 82 mm × 50 mm × 50 mm. Representative histological findings are presented in Fig. 2. The tumor cells contained abundant eosinophilic cytoplasm (Fig. 2A). Capsular and sinusoidal invasions were not identified, and the normal adrenal cortex was detected in a compressed fashion near the capsule. Nuclear atypia (Fig. 2B) and a high mitotic index were detected with a diffuse growth pattern (Fig. 2C). The patient’s Weiss score was 4, and the tumor met a major criterion for the Lin-Weiss-Bisceglia system. The Ki-67 labeling index was 6% at hot spots (Fig. 2D). Tumor cells were immunopositive for steroidogenic
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factor 1 (Fig. 2E), indicating a tumor of the adrenal cortex. Tumor cells were diffusely and intensively immunopositive for mitochondria (Fig. 2F), indicating an oncocytic tumor. To evaluate steroid synthesizability in the resected tumor, we immunohistochemically evaluated the expres- sion of steroidogenic enzymes (Fig. 3). The tumor cells were immunohistochemically positive for steroidogenic acute regulatory proteins (StAR), 21-hydroxylase, 11ß- hydroxylase (CYP11ß1), 17a-hydroxylase, DHEA- sulfotransferase, and 17ß-hydroxysteroid dehydrogenase 5. The tumor was negative for 3ß-hydroxysteroid dehydro- genase and 18-hydroxylase (CYP11ß2). These results dem- onstrated that tumor cells produced DHEA and DHEA-S, but not cortisol and aldosterone. The final diagnosis was oncocytic ACC with an androgen-producing ability.
These results led to a new question: why was this tumor negative on FDG-PET? We hypothesized that glucose up- take in this tumor could be suppressed, and immunostaining for GLUT1, which is usually highly expressed in oncocytic ACC, revealed no immunoreactivity in the tumors (Fig. 4).
The postoperative course of the patient was unre- markable. Amenorrhea, which was the only symptom of
androgen excess, improved after surgery. Postoperative steroid treatment was not required. Mitotane was not ad- ministered because of the low-grade nature of the ACC. Postoperative blood cortisol and ACTH levels early in the morning were 6.7 ug/dL and 27.7 pg/mL, respectively. Plasma aldosterone concentration of 73.6 pg/mL, plasma renin activity of 0.8 ng/mL/h, and aldosterone/renin ratio of 92 were within the normal ranges. Serum DHEA-S level regressed to 293 µg/dL and testosterone level to 0.35 ng/ mL. Serum total cholesterol, triglyceride, HDL-cholesterol, and LDL-cholesterol levels were 142 mg/dL, 44 mg/dL, 51 mg/dL, and 82 mg/dL, respectively, which were within the normal ranges. At 1 year postoperatively, there were no signs of ACC recurrence.
Discussion
A large left adrenal tumor measuring >7 cm was inciden- tally detected in our patient. The tumor showed a density of approximately 40 HU on a CT scan. Our case was of a functional tumor, but even if it was a nonfunctional tumor, consideration of surgery would have been appropriate. In
| Peripheral blood | Endocrinological data (plasma or serum) | ||||
|---|---|---|---|---|---|
| WBC | 5370/mm3 | (3300-8600) | Epinephrine | 43 pg/mL | (0-100) |
| RBC | 486 × 104/mm3 | (386-492) | Norepinephrine | 159 pg/mL | (100-450) |
| Hemoglobin | 14.7 g/dL | (11.6-14.8) | Dopamine | 6 pg/mL | (0-20) |
| Hematocrit | 41.7% | (35.1-44.4) | Renin activity | 2.2 ng/mL/h | (0.3-5.4) |
| Platelets | 22.4 × 104/mm3 | (15.8-34.8) | Aldosterone | 438 pg/mL | (29.9-159) |
| ARR | 199 | (<200) | |||
| Biochemical data | ACTH | 73.0 pg/mL | (7.2-63.3) | ||
| Total protein | 6.5 g/dL | (6.6-8.1) | Cortisol | 10.4 µg/dL | (6.2-19.4) |
| Albumin | 4.2 g/dL | (4.1-5.1) | DHEA-S | 4060 µg/dL | (18-391) |
| Total bilirubin | 1.1 mg/dL | (0.4-1.5) | Testosterone | 3.51 ng/ml | (0.11-0.47) |
| AST | 13 U/L | (13-30) | |||
| ALT | 9 U/L | (7-23) | Endocrinological data (urine) | ||
| LDH | 168 U/L | (124-222) | Epinephrine | 4.0 µg/day | (3.4-26.9) |
| ALP | 189 U/L | (106-322) | Norepinephrine | 45.1 µg/day | (48.6-168.4) |
| rGTP | 7 U/L | (9-32) | Metanephrine | 0.09 mg/day | (0.04-0.19) |
| BUN | 10 mg/dL | (8-20) | Normetanephrine | 0.09 mg/day | (0.09-0.33) |
| Creatinine | 0.72 mg/dL | (0.46-0.79) | (17-ketosteroid fraction) | ||
| Natrium | 142 mEq/L | (138-145) | Androsterone | 22.44 mg/day | (0.4-3.0) |
| Potassium | 4.1 mEq/L | (3.6-4.8) | Etiocholanolone | 23.42 mg/day | (0.3-2.5) |
| Chlorine | 105 mEq/L | (101-108) | Dehydroepiandrosterone | 493.86 mg/day | (0.04-2.6) |
| Glucose | 78 mg/dL | (73-109) | 11-ketoandrosterone | 0.70 mg/day | (0.0-0.07) |
| T.chol | 47 mg/dL | (142-220) | 11-ketoetiocholanolone | 1.32 mg/day | (0.03-0.5) |
| Triglyceride | 32 mg/dL | (30-150) | 11-OH androsterone | 8.42 mg/day | (0.22-1.6) |
| HDL-c | 32 mg/dL | (40-103) | 11-OH etiocholanolone | 0.53 mg/day | (0.02-0.65) |
| LDL-c | 9 mg/dL | (65-140) | |||
| sIL-2R | 243 U/mL | (121-613) | |||
Reference ranges are in parentheses.
Abbreviations: ACTH, adrenocorticotropic hormone; ALP, alkaline phosphatase; ALT, alanine transferase; ARR, aldosterone/renin ratio; AST, aspartate transam- inase; BUN, blood urea nitrogen; DHEA-S, dehydroepiandrosterone sulfate; HDL-c, high-density lipoprotein-cholesterol; LDH, lactate dehydrogenase; LDL-c, low-density lipoprotein-cholesterol; RBC, red blood cells; rGTP, y-glutamyl transferase; sIL-2R, soluble interleukin-2 receptor; T.chol, total cholesterol; WBC, white blood cells.
some papers, tumors measureing >4 cm [11, 12] should be considered for surgery; in others, tumors measureing >4.6 cm or with an attenuation of >20 HU on CT scan [13], should be considered for surgery, because of the possi- bility of malignancy. On chemical shift MRI of the adrenal glands, the loss of signal intensity was not detected on out- of-phase imaging when compared with that of the spleen, suggesting the possibility of malignancy rather than ad- enoma [14]. The FDG-PET scan was negative in our case; however, adrenalectomy was performed because the tumor was functional, and imaging findings other than the FDG- PET scan were suspicious for carcinoma.
The pathological diagnosis after surgery was oncocytic ACC. Weiss’s criteria are considered the gold standard cri- teria for diagnosing ACC, with a combined score of ≥3 con- sidered as malignancy [1, 2]. In our patient, the following 4 criteria were met: high nuclear grade, <25% of clear cells, diffuse architecture, and high mitotic index. Because the first 3 of Weiss’s criteria are characteristic of oncocytic neoplasms, Weiss’s criteria could result in the overdiagnosis
during the pathological diagnosis of oncocytic ACC; hence, it may be better to use the Lin-Weiss-Bisceglia system [1, 2, 15]. In our patient, 1 major Lin-Weiss-Bisceglia criterion, a high mitotic index, was met, indicating malignancy. However, the differentiation between benign and malig- nant adrenal oncocytic tumors in pathological diagnosis remains controversial.
FDG-PET is useful for the differential diagnosis of benign and malignant lesions. Several studies on adrenocortical neoplasms demonstrated that the cutoff values of SUVmax for adrenal lesions ranged from 2.5 to 5.2, and the cutoff value of adrenal to liver SUVmax ratio ranged from 1.53 to 1.8 [16-19]. However, it is also true that the patients included in those studies were diagnosed with metastatic adrenal carcinoma. Owing to the rarity of ACC, little evi- dence exists for the cutoff values. Groussin et al reported that in a study of 22 ACC cases and 43 adrenocortical ad- enoma cases, using a cutoff value of >1.45 for the adrenal to liver SUVmax ratio could differentiate between ACC and adrenocortical adenoma [4]. In the same study, an SUVmax
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cutoff value of >3.4 for adrenal lesions was also proposed [4]. Tessonnier et al reported that 37 patients with ACC ☒ harbored median uptake values of SUVmax = 11 (range, 3-56) on FDG-PET scans [20]. In our patient, the SUVmax for the left adrenal tumor was 2.8, and the adrenal to liver SUVmax was 0.98. Therefore, this tumor was considered benign on FDG-PET scans, contrary to the malignant find- ings in the pathological diagnosis.
One major question in our case was the extremely low FDG uptake despite the presence of oncocytic ACC. Most aggressive malignant tumors, such as ACC, are known to utilize aerobic glycolysis to derive a substantial amount of energy [21]. Therefore, a large amount of glucose is usu- ally taken up by malignant cells. Labeled deoxy-glucose, which is a glucose analog used in FDG-PET, enters the cell through specific transmembrane carrier proteins, es- pecially GLUT1 [22]. Even in the case of benign tumors, oncocytic tumors such as those of the parotid gland, renal cells, adrenocortical cells, and thyroid Hurthle cells have been reported to be associated with increased FDG uptake
[6, 21, 23, 24] owing to the presence of numerous intra- cellular mitochondria [5] and increased GLUT1 expres- sion [6]. FDG uptake was expected to be high in our case considering the oncocytic nature of the lesion. Therefore, to further explore the pathogenesis of low FDG uptake in this oncocytic tumor, we hypothesized that tumoral glucose uptake could be suppressed, and proceeded to investigate GLUT1 expression. No immunoreactivity of GLUT1 was detected, which was one of the reasons for FDG-PET nega- tivity. The reason for the decreased expression of GLUT1 in this tumor is unknown; however, it has been reported that GLUT1 expression is not always observed in conventional ACCs that are not oncocytic [25, 26]. Since no similar cases have been reported in the literature, additional reports of oncocytic ACC cases are needed to clarify this phenomenon.
Oncocytic ACC produced androgens in our patient. Because of the rarity of oncocytic ACC, there have been only a few reports; however, approximately one-third of oncocytic ACCs have been reported to produce andro- gens [27, 28]. To the best of our knowledge, ours is the
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first report of a detailed analysis of the expression of steroidogenic enzymes in functional oncocytic ACC. The results revealed that the status of the enzymes in the
tumor tissue and corresponding circulating hormone levels were consistent, which also confirmed the usefulness of immunohistochemical evaluation of steroidogenic enzymes
| Author, year (ref) | Age (year) | Gender | Symptom | Excess hormone | T.chol (pre-operation) | T.chol (post-operation) | Diagnosis, affected side, tumor size |
|---|---|---|---|---|---|---|---|
| Leichter & Daughada, 1974 [8] | 48 | Female | Hirsutism, amenorrhea | Androgen | 95 mg/dL | 185 mg/dL | Benign adenoma, right, 20 cm |
| Nakagawa et al., 1995 [9] | 16 | Female | Hirsutism, amenorrhea | Androgen, cortisol | 23 mg/dL* | > 115mg/dL* | Benign adenoma, right, 10 cm |
| Benvenga, 1995 [7] | 20 | Female | Hirsutism, oligomenorrhea | Androgen, cortisol | 30 mg/dL* | 127 mg/dL* | Nonmalignant adrenal tumor, right, 15 cm |
| Present case | 21 | Female | Amenorrhea | Androgen | 47 mg/dL | 142 mg/dL | Oncocytic ACC, left, 8.2 cm |
Abbreviations: ACC, Adrenocortical carcinoma; T.chol, total cholesterol; ref, reference. *Values that had been reported in millimole per liter were converted to milligram per deciliter by dividing by 0.0259.
in exploring the features of neoplastic steroidogenesis in functioning adrenocortical tumors. Additionally, serum an- drogen levels decreased after surgery, and amenorrhea clin- ically improved. Recently, Harada et al reported a similar case of oncocytic ACC; however, it was nonfunctional [29], and neither PET results nor GLUT1 immunostaining were reported.
ACC is a rare tumor; thus, treatment decisions are dif- ficult. However, the European Network for the Study of Adrenal Tumors (ENSAT) and the European Society of Endocrinology have published guidelines on the manage- ment of adrenocortical carcinoma in adults [30]. Before surgery, our case was evaluated as ACC amenable to com- plete resection (stage II according to the ENSAT staging system). Complete resection was performed, and the Ki-67 labeling index was <10%; therefore, the risk of recur- rence was determined to be low/moderate. The guidelines above, however, did not necessarily mention that adju- vant mitotane therapy was always necessary but empha- sized that the requirement of adjuvant mitotane therapy should be discussed on an individual basis. Our patient was not administered mitotane postoperatively because of the oncocytic nature of ACC, which was reported to have a better clinical outcome than conventional ACC [27, 28, 31]. Additionally, our case was GLUT1 negative. The higher expression of GLUT1 was associated with a worse prognosis in ACC; particularly, high GLUT1 expression in ACC indicated increased glucose uptake, which correlates with aggressive behavior [25, 26]. As expected, no recur- rence was detected in our patient at this juncture, 1 year after the surgery. Long-term imaging and biochemical (eg, blood DHEA-S level) follow-up are warranted since the outcome and clinical behavior of GLUT1-negative oncocytic ACC remain uncertain.
In our patient, marked hypocholesterolemia was ob- served. To date, 3 similar cases have been reported in the English literature [7-9]. The clinical features and diagnoses of the 4 patients, including ours, are summarized in Table
2. In all these reports, the cases involved women, and serum androgen levels were high, similar to our study. However, the tumors were reported as benign adenomas, which is different from our case of the malignant tumor. The patho- genesis of hypocholesterolemia in patients with adrenal tu- mors has been reported to be subsequent to increased LDL receptor activity and unrestricted uptake of LDL by the ad- renal tumor [9], but not the effect of increased serum levels of androgens on LDL receptors [9]. Because all 4 cases, including our case, showed high androgen levels, and be- cause there have been no reports of hypocholesterolemia in patients with adrenal tumors other than androgen- producing tumors, we assume that androgen-producing tumors themselves could play a role in the development of hypocholesterolemia; however, further investigation is re- quired for clarification.
In conclusion, we report the case of a patient with an oncocytic ACC with low 18F-FDG uptake. Particularly, the ACC masquerades as a benign lesion on PET/CT scans, and immunohistochemical analysis indicated low GLUT1 expression in the tumor. Since there are no similar cases reported in the literature, additional case reports are needed to prove this phenomenon. Moreover, the pres- ence of hypocholesterolemia with adrenal masses has been reported in 4 cases, including ours, all of which involved androgen-producing tumors. Therefore, a possible correl- ation between androgenicity in adrenal tumors and the development of hypocholesterolemia could be proposed; however, further investigation is warranted.
Additional Information
Correspondence: Hiroshi Ikegami, MD, PhD, Department of Endocrinology, Metabolism and Diabetes, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan. Email: ikegami@med.kindai.ac.jp
Disclosures: The authors have no conflicts of interest to report. The authors declare that they have no competing interests.
Data Availability: Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study.
Consent for Publication: Written informed consent was obtained from the patient for publication of this case report and any accom- panying images.
References
1. Torti JF, Correa R. Adrenal Cancer. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31536189. Accessed July 17, 2021.
2. Lam AK. Update on Adrenal Tumours in 2017 World Health Organization (WHO) of Endocrine Tumours. Endocr Pathol. 2017;28(3):213-227.
3. Botsios D, Blouhos K, Vasiliadis K, Asimaki A, Tsalis K, Betsis D. Adrenocortical oncocytoma - a rare tumor of undefined malig- nant potential: report of a case. Surg Today. 2007;37(7):612-617.
4. Groussin L, Bonardel G, Silvera S, et al. 18F-Fluorodeoxyglucose positron emission tomography for the diagnosis of adrenocortical tumors: a prospective study in 77 operated pa- tients. J Clin Endocrinol Metab. 2009;94(5):1713-1722.
5. Kim DJ, Chung JJ, Ryu YH, Hong SW, Yu JS, Kim JH. Adrenocortical oncocytoma displaying intense activity on 18F-FDG-PET: a case report and a literature review. Ann Nucl Med. 2008;22(9):821-824.
6. . Sato N, Nakamura Y, Takanami K, et al. Case report: adrenal oncocytoma associated with markedly increased FDG up- take and immunohistochemically positive for GLUT1. Endocr Pathol. 2014;25(4):410-415.
7. . Benvenga S. Another case of hypocholesterolemia associated with virilizing adrenal adenoma. J Clin Endocrinol Metab. 1995;80(11):3391-3392.
8. Leichter SB, Daughaday WH. Massive steroid excretion and hypocholesterolemia with an adrenal adenoma. Report of a case. Ann Intern Med. 1974;81(5):638-640.
9. Nakagawa T, Ueyama Y, Nozaki S, et al. Marked hypocholesterolemia in a case with adrenal adenoma-enhanced catabolismof low density lipoprotein (LDL) via the LDL recep- tors of tumor cells. J Clin Endocrinol Metab. 1995;80(1):92-96.
10. Sbiera S, Schmull S, Assie G, et al. High diagnostic and prog- nostic value of steroidogenic factor-1 expression in adrenal tu- mors. J Clin Endocrinol Metab. 2010;95(10):E161-E171.
11. Menegaux F, Chéreau N, Peix JL, et al. Management of adrenal incidentaloma. J Visc Surg. 2014;151(5):355-364.
12. Nieman LK. Approach to the patient with an adrenal incidentaloma. J Clin Endocrinol Metab. 2010;95(9):4106-4113.
13. Kahramangil B, Kose E, Remer EM, et al. A modern assessment of cancer risk in adrenal incidentalomas: analysis of 2219 pa- tients. Ann Surg. Published online June 11, 2020. doi:10.1097/ SLA.0000000000004048.
14. Blake MA, Cronin CG, Boland GW. Adrenal imaging. AJR Am J Roentgenol. 2010;194(6):1450-1460.
15. Papotti M, Libè R, Duregon E, Volante M, Bertherat J, Tissier F. The Weiss score and beyond-histopathology for adrenocortical carcinoma. Horm Cancer. 2011;2(6):333-340.
16. Ciftci E, Turgut B, Cakmakcilar A, Erturk SA. Diagnostic im- portance of 18F-FDG PET/CT parameters and total lesion
glycolysis in differentiating between benign and malignant ad- renal lesions. Nucl Med Commun. 2017;38(9):788-794.
17. Kunikowska J, Matyskiel R, Toutounchi S, Grabowska- Derlatka L, Koperski L, Królicki L. What parameters from 18F- FDG PET/CT are useful in evaluation of adrenal lesions? Eur J Nucl Med Mol Imaging. 2014;41(12):2273-2280.
18. Okada M, Shimono T, Komeya Y, et al. Adrenal masses: the value of additional fluorodeoxyglucose-positron emis- sion tomography/computed tomography (FDG-PET/CT) in differentiating between benign and malignant lesions. Ann Nucl Med. 2009;23(4):349-354.
19. Vos EL, Grewal RK, Russo AE, et al. Predicting malignancy in patients with adrenal tumors using 18 F-FDG-PET/CT SUVmax. J Surg Oncol. 2020;122(8):1821-1826.
20. Tessonnier L, Ansquer C, Bournaud C, et al. (18)F-FDG uptake at initial staging of the adrenocortical cancers: a diagnostic tool but not of prognostic value. World J Surg. 2013;37(1): 107-112.
21. Hofman MS, Hicks RJ. How We Read Oncologic FDG PET/CT. Cancer Imaging. 2016;16(1):35.
22. Rubello D, Rufini V, Casara D, Calcagni ML, Samanes Gajate AM, Shapiro B. Clinical role of positron emission tomography (PET) in endocrine tumours. Panminerva Med. 2002;44(3):185-196.
23. Coppola M, Romeo V, Verde F, et al. Integrated imaging of adrenal oncocytoma: a case of diagnostic challenge. Quant Imaging Med Surg. 2019;9(11):1896-1901.
24. Wiesner W, Engel H, von Schulthess GK, Krestin GP, Bicik I. FDG PET-negative liver metastases of a malignant melanoma and FDG PET-positive Hurthle cell tumor of the thyroid. Eur Radiol. 1999;9(5):975-978.
25. Fenske W, Völker HU, Adam P, et al. Glucose transporter GLUT1 expression is an stage-independent predictor of clinical outcome in adrenocortical carcinoma. Endocr Relat Cancer. 2009;16(3):919-928.
26. Pinheiro C, Granja S, Longatto-Filho A, et al. Metabolic repro- gramming: a new relevant pathway in adult adrenocortical tu- mors. Oncotarget. 2015;6(42):44403-44421.
27. Mills JK, Khalil M, Pasieka J, Kong S, Xu Y, Harvey A. Oncocytic subtypes of adrenal cortical carcinoma: Aggressive in appearance yet more indolent in behavior? Surgery. 2019;166(4):524-533.
28. Wong DD, Spagnolo DV, Bisceglia M, Havlat M, McCallum D, Platten MA. Oncocytic adrenocortical neoplasms-a clinicopathologic study of 13 new cases emphasizing the im- portance of their recognition. Hum Pathol. 2011;42(4):489-499.
29. Harada K, Yasuda M, Nakano Y, et al. A rare case of oncocytic adrenocortical carcinoma clinically presented as an incidentaloma. Endocr J. 2020;67(8):883-888.
30. Fassnacht M, Dekkers OM, Else T, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018;179(4):G1-G46.
31. Renaudin K, Smati S, Wargny M, et al .; for Comete-Cancer Network. Clinicopathological description of 43 oncocytic adrenocortical tumors: importance of Ki-67 in histoprognostic evaluation. Mod Pathol. 2018;31(11):1708-1716.