Molecular Imaging in the Management of Adrenocortical Cancer A Systematic Review

Ka Kit Wong, MBBS, ** Barbra S. Miller, MD,¿ Benjamin L. Viglianti, MD, PhD,f§ Ben A. Dwamena, MD, ¡ Paul G. Gauger, MD,# Gary J. Cook, MD, || Patrick M. Colletti, MD,1 Domenico Rubello, MD, ** and Milton D. Gross, MD **

Abstract: Adrenocortical cancer (ACC) is an uncommon primary neoplasm of the adrenal cortex with dismal prognosis. It often presents with symptoms and signs of adrenal cortical hormone hypersecretion and abdominal mass effect or is incidentally detected as an adrenal mass on imaging performed for other indications. Endocrine evaluation, comprehensive staging, and me- ticulous resection are crucial to ensure the best possible outcome. Despite extensive initial surgical resection, local and distant metastases are not un- common with disappointing 5-year survival, although progress is being made at high-volume centers. Accurate restaging of recurrent disease is im- portant to guide further management. Mitotane, external beam radiation and chemotherapy, and newer anticancer systemic treatments are used as adjunc- tives for inoperable disease and distant metastases. Contrast-enhanced CT and MRI are first-line imaging modalities for evaluation of ACC to charac- terize adrenal masses and to determine tumor resectability. Emerging litera- ture supports 18F-FDG PET/CT use to determine the malignant potential of adrenal masses. In patients with a diagnosis of ACC, FDG PET/CT is sen- sitive for detecting metastatic disease, and its tumor accumulation has been correlated to pathology, Weiss scores, and prognosis. Metomidate, labeled with 11C for PET or with 123I for SPECT/CT, allows characterization of an adrenal mass as being of adrenocortical origin with high specificity. Taking advantage of its adrenocortical avidity, metomidate has been labeled with 131I for radionuclide therapy in a subset of ACC. In this review, we describe how nuclear medicine imaging, and specifically PET, can assist surgical management of ACC.

Key Words: adrenal “incidentaloma”, adrenocortical adenoma, adrenocortical cancer, prognosis, 18F-FDG, metomidate

(Clin Nucl Med 2016;41: e368-e382)

A drenocortical cancer (ACC) is an uncommon primary malig- nancy of the adrenal cortex with an incidence of 1 to 2 cases per million per year. By contrast, other adrenal lesions are com- mon, occurring in 3% to 10% of the population; the majority of

Received for publication November 10, 2015; revision accepted November 13, 2015.

From the *Nuclear Medicine/Radiology Department, University of Michigan Hospital; ¡ Nuclear Medicine Service, Department of Veterans Affairs Health System; ¿ Endocrine Surgery/General Surgery Department, University of Michigan Hospital; and §Radiology Service, Department of Veterans Affairs Health System, Ann Arbor, MI; ||Division of Imaging Sciences and Biomed- ical Engineering, Department of Cancer Imaging, King’s College London, St Thomas’ Hospital, London, United Kingdom; [Department of Radiology, University of Southern California, Los Angeles, CA; and ** Department of Nuclear Medicine, Radiology, NeuroRadiology, Medical Physics, Labora- tory, Microbiology, Pathology, Santa Maria della Misericordia Hospital, Rovigo, Italy.

Conflicts of interest and sources of funding: none declared.

Correspondence to: Ka Kit Wong, MBBS, Department of Nuclear Medicine/ Radiology, University of Michigan, 1500 E Medical Center Dr, B1G505 UH, Ann Arbor, MI 48109. E-mail: kakit@med.umich.edu.

DOI: 10.1097/RLU.0000000000001112

these are small, benign, nonfunctioning adrenocortical adenomas.2 Adrenocortical cancer has a slight female preponderance,1,2 bi- modal age distribution with a childhood peak of less than 5 years,3 and a second peak in the fifth to sixth decades of life.2,4 It is a bio- logically aggressive neoplasm, with a dismal prognosis that has remained essentially unchanged over the last 2 decades with 5-year survival between 25% and 40%.5,6

Adrenocortical cancers are monoclonal tumors associated with multiple somatic mutations that include overexpression of growth factors and loss of tumor suppression genes.7 Mutations causing loss of p53 tumor suppressor genes account for 50% to 80% of childhood ACC.2 This inherited germline mutation explains the 10 to 15 times more frequent rate of ACC in Brazilian children.3 Adrenocortical cancer has reported associations with Li-Fraumeni syndrome (autosomal dominant p53 mutation on 17p13), multiple endocrine neoplasia type 1, Lynch syndrome, Beckwith-Wiedemann syndrome, familial adenoma polyposis, Carney complex, and neuro- fibromatosis type I.2,3,8

There is no consensus regarding whether ACC develops from preexisting adenoma or de novo.1º Sporadic ACC has been linked to overexpression of insulin growth factor (IGF) gene; excess IGF-2 is seen in 90% of ACCs.10 As both IGF-1 and IGF-2 are in- volved in normal adrenal growth, overexpression is hypothesized to cause dedifferentiation of cortical cells. However, despite that Wnt/ B-catenin and IGF-2 are frequently altered signaling pathways, these appear insufficient for malignant transformation, and thus, mechanisms of adrenal tumorigenesis are still not fully understood.10-12 Adrenocortical cancer warrants a careful family history to reveal he- reditary syndromes13 and consideration of genetic counseling par- ticularly in younger patients. 13,14

Surgical management remains the cornerstone of manage- ment of ACC at initial diagnosis and selectively in patients with re- current disease.15 Mitotane, external beam radiation treatment, chemotherapy, and newer anticancer systemic treatments are re- served for inoperable disease and distant metastases and are consid- ered palliative treatment options.1,2 Despite adequate initial surgical resection, recurrent disease locally or at distant sites is common with consequent poor 5-year survival rates. Treatment in specialized cancer centers should be considered given the rarity of ACC and its poor prognosis.2 Careful endocrine evaluation, accurate staging and restaging of disease, and meticulous surgical resection are crucial to ensure the best possible outcomes. Imaging with CT and MRI is es- tablished for ACC for characterization of the lesion, staging, deter- mining locoregional extent (involvement of adjacent structures), and for distant staging of metastases to liver, lung, and other sites.16-18 There is emerging evidence that PET imaging with 18F-FDG and 11C metomidate (MTO) can provide important func- tional information that can assist staging and surgical and medical planning and guide management of ACC and incidentally discov- ered adrenal masses.

We performed an OVID/MEDLINE search for relevant arti- cles in March 2015 using the search terms adrenal cortical cancer and the MESH terms adrenal cortex neoplasms. These were

combined with search terms fluorodeoxyglucose, metomidate, and etomidate and Mesh terms, imidazoles, PET/CT, PET-CT and PET, and Weiss. The purpose of this review article is to describe how PET and nuclear medicine imaging can assist the management of ACC.

Presentation, Diagnosis, and Staging of ACC

Typically, ACC presents in 3 clinical settings: (1) symptom- atic hypersecretion of adrenal cortical hormones (40%-60%), (2) mass effect with abdominal discomfort or pain (~33%), or (3) as an incidentally discovered adrenal mass (20%-30%).2 Func- tional ACC tumors most commonly hypersecrete cortisol, which in 50% to 80% of patients leads to adrenocorticotropic hormone (ACTH)-independent Cushing syndrome.1,2 Hypersecretion of ad- renal androgens occurs in 40% to 60%, which in women causes male pattern baldness, hirsutism, virilization, and menstrual irregu- larities,2 whereas feminization is seen in males.3 Concurrent corti- sone and androgen excess occurs in more than half of the cases. By contrast, mineralocorticoid excess is rare.1,7 Endocrine activity may vary over the course of the disease, with endocrine inactive tu- mors becoming active and vice versa.

The endocrine workup of hypercortisolism is composed of the 1 mg overnight dexamethasone suppression test, midnight salivary cortisol measurement, or 24-hour urinary free cortisol level.2,3,11,12 Adrenocorticotropic hormone measurement is also key to differentiate adrenal- or non-adrenal-dependent forms. Malignant adrenal masses secrete a higher ratio of dehydroepian- drosterone sulfate than benign adenomas; therefore, this is a useful discriminatory test.3 Other tests that may be considered include aldosterone-to-renin ratio, testosterone, estrone, 17ß-estradiol, 17-OH- progesterone, androstenedione, and 24-hour urinary 17-corticosteroids measurements.7,11,12 Measurement of plasma metanephrine and normetanephrine or fractionated 24-hour urinary metanephrine is critical to preoperatively exclude a clinically silent pheochromocy- toma.19 Urinary steroid profiling is another strategy for the evalua- tion of patients with an adrenal incidentaloma. One study found 18 urinary steroid metabolites that were excreted in higher concentra- tions in ACC compared with adrenocortical adenomas and particu- larly THS (tetrahydro-11-deoxycortisol) at a threshold of 2.35 umol over 24 hours could differentiate ACC from other adrenal disorders with 100% sensitivity and 99% specificity, a potentially useful diag- nostic test.20

Patients at elevated likelihood of having ACC are those pre- senting with a palpable or radiologically large (>4 cm) mass, youn- ger age (<20 years), weight loss, fever, feminization or virilization, lack of high-dose dexamethasone suppression of cortisol, or in- creased urinary 17-ketosteroids.3 Standard imaging of suspected ACC is performed with adrenal protocol abdominal CT or MRI.2,21 Preoperative FDG PET/CT scanning is emerging as an ad- ditional modality to predict malignancy in indeterminate adrenal masses as a supplemental imaging test.1,19 In general, ACCs are large, on average measuring 10 to 13 cm in cohorts studied with CT and MRI, with the minority less than 6 cm (9%-20%) and only 3% smaller than 4 cm in diameter.2 4 Using size thresholds, an ad- renal mass measuring greater than 6 cm has sensitivity of 91% and specificity of 80% for being an ACC2; greater than 5 cm has a sen- sitivity of 93% and specificity of 63%7; and greater than 4 cm has sensitivity of 97% and specificity of 52%.2

Advanced stage at diagnosis is common with ACC. Nodal metastases are present on imaging in 10% to 26% and as high as 68% at autopsy.4 Metastases from ACC are seen most frequently in lungs (45%), liver (42%), or lymph nodes (24%) and less commonly in bone, pancreas, spleen, diaphragm, and peritoneum.3 Brain metas- tasis is very rare, occurring in 6 of 500 patients (1%-2%) in 1 series,

most often detected in advanced ACC long after the initial diagno- sis.22 Adrenocortical cancers demonstrate heterogeneity on CT and MRI, with irregular borders, central necrosis, hemorrhage, and inter- nal calcifications. CT density in Hounsfield units (HU) is greater than 10, and they often display heterogeneous contrast enhancement.2,7 A minority (~2%) of ACCs present as cystic neoplasms because of pseudocyst formation.” The diagnoses of myelolipoma, cysts, and hemorrhage of the adrenals are easily established with characteristic imaging findings.7 Differential diagnosis of ACC on imaging in- cludes adrenocortical adenoma, pheochromocytoma, granulomatous disease, metastases, and adrenal hemorrhage.3 Extension into the ad- renal and renal veins and inferior vena cava (IVC) and surrounding structures occurs in approximately 25% of ACCs on CT, mainly with right-sided adrenal masses.4

Guidelines recommend staging at initial diagnosis to plan surgical resection19,23 performed with the European Network for the Study of Adrenal Tumors (ENSAT) system24 or the Interna- tional Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC seventh edition), which are based on the earlier work by Macfarlane25,26 and Sullivan et al25,26 (Table 1). Both sys- tems distinguish disease confined to the adrenal gland (stage I ≤5 cm and stage II >5 cm) and disease extending beyond the gland (stage III local invasion or locoregional nodes and stage IV distant disease); ENSAT differs from UICC/AJCC in that it considers only M1 disease as stage IV and is preferred at many tertiary centers as it may be more predictive of outcome.24,28 Only 21% of patients pres- ent with stages 1 and 2, and unfortunately, of these, less than 2% are at stage I, whereas the majority (61%) present with stage IV and 18% with stage III disease.3 In a study of 330 patients treated at M. D. Anderson Cancer Center, 5-year survival rates reported were 24.1%, 6%, 3.5%, and 0.89% for AJCC stages I, II, II, and IV, respectively.

Management of ACC at Initial Presentation

Complete resection of the primary ACC tumor and involved nodes or soft tissue extension is the only chance for potential cure and is crucial to optimizing outcomes.29-32 In the hands of experi- enced surgeons, morbidity and mortality are low for adrenalec- tomy.31 In the United States, the majority of adrenalectomies for ACC are performed at community hospitals by low-volume

TABLE 1. TNM Staging Systems for Adrenocortical Cancer
	ENSAT24	UICC/AJCC27
Stage I	T1, N0, M0	T1, N0, M0
Stage II	T2, N0, M0	T2, N0, M0
Stage III	T1, N1, M0	T1, N1, M0
	T2, N1, M0	T2, N1, M0
	T3, N1, M0	T3, N0, M0
	T4, N1, M0
	T3, N0, M0
	T4, N0, M0
Stage IV	Any T, Any N, M1	T3, N1, M0
		T4, N1, M0
		T4, N0, M0
		Any T, any N, M1

T0: no evidence of primary tumor; T1: tumor 5 cm or less in greatest dimension, no extra-adrenal invasion; T2: tumor greater than 5 cm, no extra-adrenal invasion; T3: tumor of any size with local invasion, but not invading adjacent organs; T4: tumor of any size with invasion of adjacent organs; Nx: regional lymph nodes cannot be assessed; N0: no regional lymph node metastasis; N1: metastasis in regional lymph node(s); M0: no distant metastasis (use clinical M to complete stage, no pathologic M0 category); M1: distant metastasis.

surgeons inexperienced with adrenalectomy specifically for ACC.2 Referral to a tertiary center could potentially improve survival by having primary resection with expertise from a multidisciplinary team.13 Hypercortisolism is associated with poor wound healing, and endocrine control with inhibitors of steroidogenesis, such as ketoconazole, metyrapone, and aminoglutethimide can be initiated preoperatively.” Imaging must be obtained close to the planned op- eration date. Imaging provides important information regarding the size, extent, involvement of adjacent structures, vascular invasion, and overall resectability of the mass. However, at least 25% of stage III ACCs are initially thought to be stage II by imaging criteria, be- cause of unrecognized microscopic tumor extension through the tu- mor capsule.2 This supports the concept of systematic en bloc resection of these tumors to include periadrenal soft tissue and lymph nodes.

Routine lymph node dissection is controversial as to its utility aside from accurate staging, and it is not currently known whether lymphadenectomy improves disease-specific and recurrence-free survival. N1 staging is common, varying between 26% and 68% in some series, and as N1 stage does confer worse prognosis, lymph node dissection may provide better staging, and upstaging may guide more appropriate use of radiation or chemotherapy.2 Surgical debulking can be performed even for stages 3 and 4 disease as a pal- liative strategy to reduce tumor load and control endocrine hyperac- tivity,31 but these are highly selected situations as other nonsurgical treatments can control excess hormone secretion and tumor size in a situation where survival is unlikely to be positively impacted given a long recovery period after surgery.15 Preoperative identification of involvement of the IVC with tumor has implications for surgical re- section. If there is invasion of the IVC, surgery may still be per- formed, although appreciation of the superior-most extent is necessary while performing thrombectomy to avoid pulmonary em- bolism. Alternatively, IVC stents can be considered for inoperable cases.2 The data on treatment of M1 disease are sparse.13 In ENSAT stage IV tumors, decisions to operate versus treatments with chemo- therapy or radiation are highly individualized. In unresectable tu- mors, a combination of chemotherapy with etoposide and mitotane should be considered as palliative treatment. 19,33

The surgically resected specimen provides important infor- mation that can guide management,10,34-37 and therefore, it should not be morcelated during extraction. The Weiss criteria are com- monly used with a score of 3 or more, of 9 parameters, as being sug- gestive of ACC. First introduced in 1984, the Weiss system was developed from observation of 43 adrenocortical tumors followed for 5 years38 (Table 2). The Weiss score has sensitivity of 100%

and specificity of 96% for prediction of ACC,34 and importantly tu- mors considered negative by Weiss scoring (<3) have been corre- lated to excellent outcome.34 It has been widely adopted because of its reliability, simplicity, and reproducible performance.1º Lack of reproducibility on several parameters led to a proposal of modi- fied Weiss scoring. Other limitations include application to border- line tumors with Weiss scores of 2 or 3 and inapplicability to rare variants such as tumors with oncocytoma, myxoid, sarcomatoid fea- tures, and pediatric adrenal tumors.1º The pathologist can classify ACC as low-grade (mitoses <20 per 50 high-power field) versus high-grade tumors with implications for prognosis.39 The Ki-67 in- dex is an important indicator of tumor proliferation, which is being investigated to determine its ability to predict clinical tumor behav- ior.11,12 Furthermore, the pathologist is able to define margin status designated as RO (complete resection), R1 (microscopic margins), or R2 (gross margins), and these guide decisions regarding adjuvant treatments.4 Prognosis is worse for 5-year survival based on surgi- cal margin, R2 (10%), R1 (21%), and RO (49%).2 R1 and Rx, stage III ACC may have consideration of mitotane. Those with high-risk features (Ki-67 >10) may also benefit from mitotane, whereas R1 and Rx surgical beds may have consideration of ra- diation therapy (RT).19

Management of ACC at Follow-up

Despite R0 resection, there is a high rate of locoregional re- currence between 19% and 24% with associated morbidity and mortality. Close follow-up is required with imaging at 3 monthly in- tervals during and after treatments. The tumor bed, the liver, and the lungs all require close imaging surveillance for both locoregional recurrence and distant metastases. After 2 to 3 years, the interval may be increased to 6 months until 5 years at which time the recur- rence rate is less than 3%.2 In the setting of recurrent disease, reop- eration may improve symptoms, with some studies demonstrating a 5-year survival of 27% to 57% after a debulking surgical proce- dure, compared with 0% to 8% when treated with chemotherapy alone.1,40 Because of the rarity of this disease, such studies are often prone to selection bias. The decision to reoperate on patients with ACC is often very difficult, and consideration of apparent tumor bi- ology is critical. The morbidity from surgery needs to be balanced against any modest improvement in disease-free progression and survival, and decisions remain highly individualized. Disease-free intervals have been found to be a predictor of mortality in the setting of complete resection of disease at reoperation, with a disease-free in- terval of more than 12 months associated with improved outcomes compared with recurrence of less than 1 year after metastasectomy.”

TABLE 2. Weiss System for Assessing Malignant Potential of Adrenocortical Neoplasms
	Weiss38		Modified Weiss
1	Histological features
2	Diffuse architecture (>1/3 of the tumor)
3	Clear cells ≤25% of the tumor	1	Cytoplasm (clear cells ≤25% of the tumor)	x2
4	High nuclear grade (Fuhrman grade 3 or 4)
5	Mitotic rate ≥6 per 50 high-power fields	2	Mitotic rate ≥5 per 50 high-power fields	x2
6	Atypical mitotic figures	3	Abnormal mitoses	x1
7	Necrosis	4	Necrosis	x1
8	Venous invasion
9	Sinusoidal invasion
10	Capsular invasion	5	Capsular invasion	x1

Weiss system: the presence of 3 or more criteria highly correlates with malignant behavior.

Modified Weiss system: a score of 3 or more highly correlates with malignant behavior NB. Weiss system is not applicable for evaluation of pediatric adrenal tumors or myxoid, sarcomatous, oncocytic subtypes of adrenocortical neoplasms.

This observation speaks to the importance of tumor biology and behavior in decision making. A study of operative resection in 57 patients found those having a disease-free interval of more than 1 year derived a survival benefit, although this could have been due to selection of patients with less aggressive tumor biology.3º Recur- rences within 6 months of surgery require aggressive medical treat- ment and are associated with extremely short survival. Before a decision is made to surgically address recurrent or oligometastatic disease, thorough imaging and clinical restaging should be per- formed, and FDG PET/CT is very helpful in this setting.

Adjuvant Treatment Options for ACC

Mitotane (Lysodren, 1,1-dicholoro-2(o-chlorophenyl)-2-(p- choloroiphenyl)ethane) is given as adjunctive treatment of ACC with documented improvement in survival.7 It is the only Food and Drug Administration approved drug for ACC.2 Mitotane is an isomer of pesticide, o,p’-DDD, and is directly toxic to adrenal cells; accumulation in the zona fasciculata and reticularis leads to mitochondrial disruption and necrosis, although the mechanism is poorly understood.3 Mitotane inhibits cholesterol side-chain cleavage and 11-ß hydroxylation (side-chain cleavage enzymes CYP11A1 and CYP11B1), and the cytotoxic effects on steroid- producing tissue lead to necrosis of vulnerable normal and tumor tissues.41,42 Mitotane has an overall response rate of 14% to 36%, although not all studies showed significant survival benefit. Adju- vant mitotane improved outcomes for patients with resected stages I, II, and III ACCs in a retrospective analysis of 177 patients in Italian and German centers,13 although this study did not control for tumor grade or adjunctive treatments, and recurrences are ex- pected.2 Discrepancies in the literature may lie in the time course of treatment and dosage. Mitotane is given more frequently for hormone-secreting tumors and those with Ki-67 of greater than 10,13 whereas it is given less commonly after apparent complete resection without concern about margins. It requires a loading dose followed by adequate monitoring of serum levels.13 Dose-dependent adverse ef- fects are common, including vomiting, nausea, diarrhea, anorexia, central nervous system symptoms, somnolence, vertigo, and skin lesions. Adrenocortical insufficiency occurs invariably and should be treated preemptively.2 Currently recruitment is ongoing for the ADIUVO trial, a prospective international randomized multicenter trial that aimed to test the efficacy of adjuvant mitotane treatment.2,13

Chemotherapy is reserved for unresectable tumors with in- sufficient response to mitotane.43 46 Cisplatin and etoposide mono- therapy or combination with doxorubicin has some efficacy in the treatment of ACC.” Combination chemotherapy and mitotane has synergistic benefits13 as established by the FIRM-ACT trial of high- risk locally advanced or metastatic disease treated with mitotane in monotherapy or in combination chemotherapy.42 In a compar- ison of combination mitotane and chemotherapy, treatment with mitotane + (etoposide, doxorubicin, and cisplatin) had significantly better rates of response and progression-free survival than with mitotane plus streptozocin as first-line therapy.33 There were similar rates of toxic events, although no significant difference in overall survival was found.

Historically, external beam radiation (RT) is not preferred for adrenal masses because of the proximity of the adrenals to radiosen- sitive tissues such as kidney, stomach, intestine, and spinal cord, al- though older techniques used wide ports. Intensity-modulated RT is a refinement of the 3-dimensional treatment planning that may al- low better target definition and limited toxicity to normal tissues.4 Radiation therapy could be used palliatively, although patients rarely receive it in this setting, and although radiation may control symptoms in stages 3 and 4 disease,31 there is no proven survival benefit.47 There is a potential role for adjuvant RT in patients with

positive surgical margins with small retrospective series of contem- porary RT in ACC, showing that it could reduce the rates of locoregional recurrence and improve local control.47 After complete resection (RO), RT is not recommended. Promising molecular tar- gets for chemotherapy48 and targeted and salvage therapies are un- der investigation.11,12 Another exciting area for future study is based on the observation that some rare patients have exceptional responses to chemotherapy given for disease judged to be border- line resectable such as in patients with extensive vena caval involve- ment or oligometastatic disease. Neoadjuvant chemotherapy could potentially render lesions in some patients resectable, but the long-term impact or even the applicability of this strategy is unclear.

Radiopharmaceuticals for Adrenocortical Scintigraphy and PET

18F-FDG is an analog of glucose, preferentially accumulated by malignant tumors compared with benign and/or normal cells. This is based on the overexpression of glucose transporters (Glut 1-7) by malignant cells, a phenomenon first described by Warburg49 in 1956. FDG taken up in cancer cells is phosphorylated by hexoki- nase, where it remains intracellularly trapped because of the lack of significant glucose phosphatase activity. Interpretation of FDG PET/CT is based on identification of hypermetabolic FDG activity within abnormal structures, qualitatively comparing FDG uptake to background glucose metabolism by visual inspection. Semiquantita- tive evaluation is performed with SUVs within a region of interest. This is a measure of the activity concentration within the region of in- terest compared with the injected radioactivity of FDG, corrected for the patient’s body weight, commonly expressed based as the maxi- mum pixel value (SUVmax), peak 1-cm3 volume of pixel values (SUVpeak), or mean pixel values (SUVmean) within an organ or tu- mor mass. The adrenal glands have a unique shape likened to a lambda or an inverted T, Y, or V shape on axial CT or MRI images, with thin limbs having a normal maximum diameter of 6 mm for the right and 8 mm for the left adrenal gland.5º Normal adrenal glands demonstrate mild FDG uptake at or below that of liver, with SUVmax ranging from 0.95 to 2.46.51 A study of aging normal organs on PET reported that the left adrenal gland had an SUVmax of 1.39 ± 0.34 (0.76-2.64), and the right adrenal gland had an SUVmax 1.68 ± 0.48 (0.86-3.26).52 Glucose is used as an energy substrate within normal tissues such as the brain, liver, spleen, and variably in the heart. Therefore, adrenal SUV measurements are often normalized to liver and reported as an adrenal-to-liver SUV ratio, the most commonly used parameters being adrenal SUVmax-to-liver SUVmax and adrenal SUVmax-to-liver SUVmean. Limitations of FDG PET/CT include physiological excretion of FDG into the renal collecting system of the kidney and bladder, high metabolic uptake in inflammatory and infectious processes (including in posttreatment settings leading to false-positive results), and spatial resolution in the order of 7 to 8 mm. Furthermore, there is overlap between benign and malignant processes, particularly when metabolic activity is ob- served to be low in the range similar to background activity.33 An- other pitfall relevant to adrenal imaging is increased FDG uptake occurring in benign pheochromocytoma, recognized as a potential false-positive adrenal mass.54

Adrenal-specific radiotracers are also available for ACC im- aging. Metomidate is a selective inhibitor of 11ß-hydroxylase (CYP11B1, P45011B), an enzyme involved in adrenocorticotrophin- regulated biosynthesis of cortisol and aldosterone. This radiotracer is specific for imaging tumors of adrenocortical origin.55-58 Origi- nally developed as a PET imaging agent radiolabeled with “C, more recently it has been labeled with 18F, and it has also subsequently been labeled with 123I, allowing SPECT and SPECT/CT imaging with an Anger gamma camera.59 Another radiotracer specific to the

adrenal cortex is 131I-ß-iodomethyl-19-norcholesterol (NP-59), which is an analog of cholesterol, the precursor of the corticosteroid syn- thesis pathway, which was initially developed in 1975.60 NP-59 is bound to low-density lipoprotein in the circulation and taken up into adrenocortical cells where it is esterified and intracellularly trapped. NP-59 uptake is regulated by ACTH and suppressed by dexamethasone, concentrating in hyperfunctioning cortisol- and aldosterone-secreting adenomas, with decreased uptake in the con- tralateral normal adrenal gland because of suppression of ACTH. In contrast, malignant ACC will typically not show increased up- take of NP-59 because of the inefficient concentration of radiotracer by malignant tissues, even if they are endocrinologically func- tional.º Following Lugol solution or saturated potassium iodide so- lution drops to protect the thyroid, 13 I-NP-59 studies are performed with early 3 to 5 days’ and late more than 6 to 7 days’ imaging for suspected ACTH-independent Cushing syndrome (20% of cases) (Fig. 1). When performed for primary aldosteronism (PA), a dexa- methasone suppression protocol is required to reduce uptake in the normal adrenals as the ACTH axis is not suppressed in PA.62

An alternative radiotracer that may have a selective role in imaging incidentally discovered adrenal masses is MIBG, a pseudoanalog of norepinephrine, used to image tumors of chromaf- fin origin (pheochromocytoma and paraganglioma). Although MIBG is the most widely used catecholamine analog for radionu- clide imaging of pheochromocytomas, other catecholamine precur- sors radiolabeled with positron emitters have been developed including 11C-labeled HED, 18F-DA, and 18F-DOPA. 63 Other major radiotracers include the somatostatin receptor analogs for imaging of neuroendocrine tumors (NETs). The most widely used is 111In- DTPA-pentetreotide (Octreoscan), a somatostatin analog with high affinity for somatostatin receptors, particularly somatostatin recep- tor type 2, which are overexpressed in NETs. 68Ga-DOTA peptides

such as 68Ga-DOTA-TATE, 68Ga-DOTA-TOC, and 68Ga-DOTA-NOC are positron-emitting somatostatin analogs that allow PET/CT imaging with even greater sensitivity than Octreoscan scintigraphy. 64,65

PET and Nuclear Medicine Imaging for ACC

FDG PET/CT is emerging as an adjunctive imaging modality for characterization of the malignant potential of adrenal masses and for staging and restaging of ACC (Table 3). Because of the rar- ity of the disease, the number of ACC patients studied with FDG PET/CT is small. In 2001, a series of 10 patients with ACC underwent FDG PET/CT imaging, 8 for detection of recurrent dis- ease, and the other 2 were for preoperative tumor staging.69 This study reported that ACC metastases were intensely FDG-avid and that FDG PET/CT had a sensitivity of 100% (22 lesions) and spec- ificity of 95% (1 false positive) compared with CT sensitivity of 89% (20 lesions) and specificity of 100%. Similarly in 10 ACC pa- tients undergoing restaging, FDG PET/CT had a sensitivity of 83%, with metastatic disease demonstrating high metabolic activity.6 These findings were confirmed in a study from France looking at 28 patients with ACC (21 with metastatic disease and 7 in remis- sion) comparing FDG PET/CT to contrast-enhanced CT (CECT).68 FDG PET/CT detected 53 metastatic organs (sensitivity of 93%) and 243 metastatic lesions (sensitivity of 90%), compared with CECT finding only 47 metastatic organs (sensitivity of 82%) and 237 metastatic lesions (sensitivity of 88%).68 The metabolic activity of ACC metastases correlated significantly to prognosis, 6-month survival, and also with the tumor size and mitotic rate. More re- cently in a study of 37 patients with ACC (14 M1 and 23 M0), FDG PET/CT was used for preoperative staging of ACC. Adreno- cortical cancer lesions demonstrated increased metabolic activity. However, sensitivity and specificity of FDG PET/CT were not

FIGURE 1. A 55-year-old woman with Cushing syndrome underwent 1311-NP-59 SPECT/CT scan for localization of Cushing adenoma. Planar posterior (A) abdominal image on day 5 after injection of 1311-NP-59 SPECT/CT demonstrates focal uptake in the left adrenal region (arrow). Transverse SPECT (B), CT images (C), and fused SPECT/CT (D) localize activity to a 1.5 x 1.8-cm nodule arising from the left adrenal gland (arrows). Findings are compatible with a hyperfunctioning left adrenal adenoma. Imaging courtesy of Wong KK, et al. "Adrenal Cortical Imaging With 131| NP-59 SPECT-CT." Clin Nucl Med. 2010;35:865-869 (with permission).

TABLE 3. 18F-FDG PET/CT Imaging of Adrenocortical Cancer and Incidentally Discovered Adrenal Masses
Reference	Year	Design	Population	Patients	ACC	Age, y	Metabolic Criteria	Modality	Analysis	Sensitivity	Specificity
Tessonnier et al66	2013	Retro	ACC	37	37/37	52 ± 15	SUVmax, SUVratio tumor/liver	FDG PET/CT	Survival analysis (DFS, OS)	NA	NA
Mackie et al67	2006	Retro	ACC	12	12/12	34.7 (5-71)	Visual, SUVmax, SUVratio tumor/liver	FDG PET, FDG PET/CT	Patients	83.3%	NA
Leboulleux et al68	2006	Retro	ACC	28	28/28	49 (22-73)	SUVmax, tumor glycolytic volume	FDG PET/CT	Lesions (n = 269)	90%	NA
								CE-CT	Lesions (n = 269)	88%	NA
							SUVmax, tumor glycolytic volume	FDG PET/CT	Organs (n = 57)	93%	NA
								CE-CT	Organs (n = 57)	82%	NA
Becherer et al69	2001	Retro	ACC	10	10/10	48 (38-74)	SUVmax	FDG PET	patients	100%	100%
								FDG PET	Lesions (n = 23)	100%	95%
								CT	Lesions (n = 23)	89%	100%
								FDG PET	Organs	100%	97%
								CT	Organs	88%	100%
Takanami70	2014	Retro	Lipid-rich adenoma	28	0	NA	SUV ratio (adrenal-to-liver SUVmax) >1	FDG PET/CT	Functioning vs nonfunctioning	46%	100%
Takanami70	2014	Retro	Lipid-rich adenoma	28	0	NA	SUV ratio (adrenal-to-liver SUVmax) >0.8	FDG PET/CT	Functioning vs nonfunctioning	69%	81%
Kim et al71	2014	Retro	Indeterminate	52	4/52	56.4 ± 12.7	Size >4.5 cm	CT	Malignant vs benign	44.7%	100%
Kim et al71			or secretory adrenal mass
			or secretory adrenal mass
							SUVmax >5.0	FDG PET/CT	Malignant vs benign	60.5%	92.9%
							SUV ratio (adrenal-to-liver SUVmax) >1.2	FDG PET/CT	Malignant vs benign	78.9%	78.6%
							TLG>12	FDG PET/CT	Malignant vs benign	92.1%	78.6%
							Size and SUV peak	FDG PET/CT and CT	Malignant vs benign	92.1%	64.3%
Gust et al72	2012	Retro	Adrenoma	51	22/51	54 (27-80)	SUV ratio (adrenal-to-liver SUVmax) >1.7	FDG PET/CT	Malignant vs benign	95%	97%
Gust et al72	2012	Retro	Adrenoma		22/51	54 (27-80)	SUV ratio (adrenal-to-liver SUVmax) >1.7	FDG PET/CT	Malignant vs benign	95%	97%
Nunes et al73	2010	Retro	Adrenaloma	23	2/23	54.1 ±14.9 (26-79)	SUV ratio (adrenal-to-liver SUVmax) >1.6	FDG PET/CT	Malignant vs benign	100%	90%
		Retro	Adrenaloma			54.1 ±14.9 (26-79)	SUV ratio (adrenal-to-liver SUVmax) >1.6	FDG PET/CT	Malignant vs benign	100%	90%
Groussin	2009	Pros	Indeterminate or secretory adrenal mass	77	22/77	(32-81)	SUV ratio (adrenal-to-liver	FDG PET/CT	Malignant vs benign	100%	88%
et al74						(32-81)	SUV ratio (adrenal-to-liver
et al74							SUVmax) >1.45

reported. In this study, the authors did not demonstrate an associa- tion between SUVmax and prognosis, disease-free interval, and overall survival at 20 months median, nor was correlation found with Weiss scores.66 The authors recommended against manage- ment decisions based on preoperative ACC SUV.

The appearance of ACC on FDG PET/CT is an intensely FDG-avid mass, demonstrating FDG uptake above liver back- ground, with subsequent elevated SUVmax, SUVpeak, and high tumor-to-liver SUV ratios. The primary adrenal mass on the CT portion of the study often shows heterogeneity, irregular margins, and central necrosis with calcification (Fig. 2). There is often re- gional metastasis to abdominal (generally retroperitoneal) nodes. When performed for restaging after resection, FDG PET/CT may show not only locoregional recurrence in the surgical bed, but po- tentially elsewhere within the peritoneum and retroperitoneum.” Distant metastatic disease is commonly seen in the liver, lungs, and bones. FDG PET/CT may provide critical information, which precludes reoperation for recurrence.

An important imaging finding is invasion into the renal veins, or in the case of right-sided tumors into the IVC, with several cases reported documenting proximal extension into the right atrium with potential for tumor pulmonary embolism based on FDG PET/CT findings, further impacting or precluding surgical management.79 MRI and magnetic resonance venography are useful in these cases to evaluate IVC involvement and the proximal tumor extent. False- positive findings with FDG PET/CT used for restaging of ACC are uncommon and usually related to posttreatment surgical changes and inflammation. An important false-positive finding in the setting of FDG PET/CT for detecting recurrence is the observation of FDG uptake in the remaining contralateral adrenal following adre- nalectomy. In 62 patients with ACC having serial FDG PET/CT, postsurgical uptake in the contralateral adrenal occurred in 14% to 29% of the patients with normal adrenal gland morphology.82 This uptake resolved spontaneously within 24 months of follow-up and is believed related to an effect of concurrent mitotane treatment83 and possible functional endocrine compensation. 79-81

Therefore, FDG PET/CT is a useful surveillance imaging modality to evaluate for recurrent disease, because of the biologi- cally aggressive nature of ACC.84 Currently, there is little evidence for a routine role of preoperative FDG PET/CT for staging of ACC, with only case reports and small series.85 90 However, when cross- sectional imaging raises the suspicion of distant metastatic disease, the additional information can be useful for determining the appro- priate treatment course. Although it would theoretically be useful for preoperative staging of ACC, an emerging indication is for char- acterization of incidentally discovered adrenal lesions, in part be- cause fine-needle aspiration biopsy (FNAB) is not routinely performed in this clinical setting in patients without a previous his- tory of cancer, but mostly because of the importance of selection of the appropriate surgical approach (ie, laparoscopic vs open adrenal- ectomy) as discussed below.

Adrenocortical PET has also been used to evaluate ACC using C-MTO (Fig. 3 and Table 4). In 2002, a prospective study in 11 patients with ACC (7 preoperative and 6 restaging) reported that 11C-MTO PET (sensitivity 86%) performed similarly to CT (sensitivity 90.5%) for detection of metastatic lesions.99 However, subsequent studies of C-MTO PET in the setting of adrenal masses noted that “C-MTO PET, while having excellent sensitivity of 89% and specificity of 96% in 75 patients with histopathologic proof for distinguishing adrenocortical versus noncortical origin of adrenal masses,97 was not able to distinguish benign adenomas from malignant ACC. Furthermore, a significant number of ACCs demonstrated decreased MTO uptake, believed in part to be related to central tumor necrosis. This study noted that false-positive results were relatively rare with C-MTO PET, and decreased sensitivity

TABLE 3. (Continued)
Reference	Year	Design	Population	Patients	ACC	Age, y	Metabolic Criteria	Modality	Analysis	Sensitivity	Specificity
							Adrenal SUVmax >3.4	FDG PET/CT	Malignant vs benign	100%	70%
Tessonnier et al66	2008	Pros	Indeterminate adrenal mass	37	3/37	58	Visual (>liver background)	FDG PET/CT	Malignant vs benign	100%	86%
							SUV ratio (adrenal-to-liver SUVmax) >1.8	FDG PET/CT	Malignant vs benign	100%	86%
Tenenbaum et al7	2004	Retro	Adrenaloma	13	3/13	(27-70)	Visual (>liver background)	FDG PET	Malignant vs benign	100%	100%
Maurea et al76	2001	Pros	Adrenaloma	54	6/54	50 ± 16	Adrenal SUV > background	FDG PET/CT	Malignant vs benign	100%	100%
								MIBG	Pheo vs nonpheo	100%	94%
								NP-59	Cortical vs noncortical	100%	71%
Maurea et al	1999	Pros	Adrenaloma	27	7/27	50 ±17	Adrenal SUV > background	FDG PET	Malignant vs benign	100%	93%

DFS indicates disease-free survival; NA, not applicable/not available; OS, overall survival.

FIGURE 2. Preoperative 18F-FDG PET/CT study in a 33-year-old woman with clinical presentation of Cushing syndrome and a left adrenal mass detected on abdominal CT. MIP image (A) and corresponding axial PET (B), CT (C), and fused PET/CT (D) images demonstrate a large heterogeneous hypermetabolic left adrenal mass measuring 6 cm (arrows). The SUVmax is 13.5 compared with the liver background SUVmean of 2.7, with a tumor-to-liver SUVmean ratio of 5.0, meeting the metabolic criteria for adrenal neoplasm. There were no extra-adrenal sites of abnormal FDG activity. Surgical resection specimen at open adrenalectomy revealed a 9-cm low-grade ACC with capsular and vascular invasion, negative surgical margins, focal extra-adrenal extension, and mitotic rate of 10 (per 50 high-power fields). No metastatic lymph nodes were found. ENSAT staging was T3, NO, MO, stage III. In addition, the Ki-67 proliferation index of the adrenal mass ranged from low (1%) up to 30%.

was seen with small lesions. Therefore, FDG PET/CT would be preferable to C-MTO PET for staging ACC.58,98

Subsequent efforts have been made to radiolabel MTO with 123I, which allows SPECT/CT imaging.59 The physical half-life of I of 13 hours is favorable compared with the positron emitting 11C half-life of 20 minutes. 123I MTO SPECT/CT was used in a pro- spective pilot study of 12 patients with ACC, confirming its low sensitivity as a diagnostic test, although there was a subset of ACC metastases that demonstrated increased MTO uptake.100 This was confirmed in 55 patients with ACC, all of whom had M1 dis- ease, and 22 of whom had functioning disease. 123I MTO SPECT/ CT detected just over a third, 164 of 430 lesions, identified with a combination of MTO, MRI, and CT with a sensitivity of 38%. 123I MTO SPECT/CT was positive in only 34 of 54 patients, for a sensi- tivity of 59%. Planar MTO performed worse than SPECT, with SPECT/CT being the most accurate modality. However, a subset of 21 patients with metastatic ACC, who did have MTO uptake, went on to have 13 I radiolabeled MTO therapy with some encour- aging early results.93 Therefore, 123I MTO SPECT/CT may have a role for confirming MTO avidity in M1 ACC patients with the potential for radionuclide-based systemic therapy. This is similar in concept to radionuclide 13 I MIBG therapy for neuroblastoma

and metastatic pheochromocytoma or paraganglioma, and with 90Y- and 177Lu-DOTA peptide somatostatin analogs for treatment of stage IV NETs.

NP-59 scintigraphy is not indicated in the setting of ACC, which usually does not demonstrate increased uptake in the primary tumor or its metastases, even when hormonally active, resulting in negative NP-59 imaging. This is believed to be due to the low con- centration NP-59 uptake per gram of tissue in ACC that is very inef- ficient compared with hyperfunctioning adrenocortical adenomas.101 Rather, a positive NP-59 study in the presence of hypercortisolism, hyperaldosteronism, or excess hyperandrogenism would favor the di- agnosis of a benign adrenocortical adenoma, the appearance being that of unilateral or lateralizing uptake in the affected adrenal.1 Availability of NP-59 is limited; for example, in the United States, it is no longer commercially obtainable.

Diagnosis and Management of Adrenal “Incidentaloma”

Adrenal lesions greater than 1 cm discovered on cross- sectional imaging performed for indications apart from investiga- tion of the adrenal, so-called “incidentalomas,” have an incidence of 3% to 10% on CT, with the majority representing benign

FIGURE 3. Imaging results after treatment with 20 GBq [13]]]IMTO. A, Planar whole-body scan. B, SPECT/CT 5 days after administration of 20 GBq [13] []IMTO demonstrating high tracer uptake in the lung lesions. C, FDG PET before treatment (left panel) and 13 months after the first treatment dose (right panel). D, CT of lung lesions showing pretreatment images (top) and images 6 (middle) and 13 (bottom) months after first treatment dose. Imaging courtesy of Hahner et al93 (with permission).

t = 0

6 months

1-131 IMTO

F-18 FDG

13 months

nonfunctioning adrenocortical adenomas. 103,104 It is most important to identify malignancy, which is most commonly metastatic disease. Rapid growth of an adrenal mass over a short period is particularly concerning for malignancy.105 Large masses may represent ACC or other rare primary malignant diseases of the adrenals including lym- phoma, melanoma, neuroblastoma, or malignant pheochromocy- toma. The history of a known malignancy versus no cancer history is important as this affects the likelihood of metastatic dis- ease. In cancer patients, an adrenal mass represents a 32% to 73% risk for malignancy, whereas in patients without a cancer history it is on the order of 0% to 21%.101 Identification of an adrenal

incidentaloma may require endocrine workup for hypersecretory syn- dromes.106,107 All incidentally discovered adrenal masses should be investigated for the presence of hormone hypersecretion including cortisol and aldosterone and catecholamines, which are due to adre- nocortical adenomas, ACC, and pheochromocytoma, respectively.”

Imaging workup of incidentaloma is based on likelihood of malignancy, with surgical resection considered for suspected hyper- functioning or malignant adrenal masses. Adrenal tumor size is an important consideration as regarding masses less than 4 cm, 4% to 5% are ACCs; 4 to 6 cm, up to 10% are ACCs; and greater than 6 cm, more than 25% are ACCs. Interval enlargement on follow-up

TABLE 4. Metomidate PET/CT and SPECT/CT Adrenocortical Imaging
Reference	Year	Design	Population	Patients	Age, y	Modality	Interpretation	Sensitivity	Specificity
Kreissl et al91	2013	Pros	ACC	58	52.1 ± 15.8	123 I MTO SPECT/CT	Lesions (n = 430 )	38%	100%
							Patients (n = 58)	59%	NA
Hahner et al92	2013	Pros	Adrenaloma	51	55 (17-88)	123 I MTO SPECT/CT	Cortical vs noncortical	89.6%	65%
							ACC (n = 14)	89%	NA
							Adenomas (n = 16)	100%	NA
Hahner et al93	2012	Pros	MTO-avid ACC	11	NA	123I MTO SPECT/CT	Patients (n =11)	NA	NA
Burton et al94	2012	Pros	Aldosteronoma	44	49.6 ± 6.0	11C MTO PET/CT	Hyperfunctioning	76%	87%
Hennings et al95	2010	Pros	Aldosteronoma	11	52 (30-78)	11C MTO PET/CT	Hyperfunctioning	100%	NA
Hennings et al96	2009	Retro + pros	Adrenaloma	38	(22-81)	11C MTO PET	Cortical vs noncortical	100%	100%
						MRI	Cortical vs noncortical	86%	100%
						CT	Cortical vs noncortical	71%	100%
Hennings et al97	2006	Retro + pros	Adrenaloma	173	55.9± 13.8	11C MTO PET (212 scans)	Cortical vs noncortical	89%	96%
Zettinig et al58	2004	Pros	Adrenaloma	16	56 (29-72)	11C MTO PET	Cortical vs noncortical	100%	100%
						FDG PET	Benign vs malignant	100%	100%
Minn et al98	2004	Pros	Adrenaloma	21	(21-79)	11C MTO PET (21 scans)	Cortical vs noncortical	NA	NA
						FDG PET (19 scans)	Benign vs malignant	NA	NA
Khan et al99	2002	Pros	ACC	11	52 (26-69)	11C MTO PET	Lesions (n = 23)	86%	NA
						CT	Lesions (n = 23)	90.5%	NA
Bergstrom et al55	2000	Pros	Adrenaloma	15	(42-78)	11C MTO PET	Adrenocortical origin	100%	100%

imaging is important as an ominous sign of malignancy.4 Imaging may be able to provide clues to diagnosis. In particular, adrenal cysts and myelolipoma have characteristic appearances that are con- sidered pathognomonic. Some benign conditions such as adrenal inflammation and adrenal hemorrhage are considered based on clin- ical suspicion, whereas other lesions such as_ganglioneuroma, oncocytoma, schwannoma, and others are rare. 7 Serial CT scans can often provide information regarding hemorrhage versus an un- derlying mass. Adenomas tend to have lower mean attenuation than ACC, pheochromocytoma, or metastases. Using a cutoff of less than 10 HU, a homogenous adrenal mass is predictive of a so- called benign “lipid-rich” adenoma. A meta-analysis of 10 studies concluded that on noncontrast CT, masses with less than 10 HU had 71% sensitivity and 98% specificity for benign lipid-rich ade- noma.108 Absolute and relative contrast washout calculated using a dedicated adrenal protocol CECT compares the delayed post- contrast at 10 to 15 minutes with the early postcontrast at 1 minute or unenhanced CT. Using absolute percentage washout of greater than 60% and relative percentage washout of greater than 40%, ad- enomas can be differentiated from nonadenomas with nearly 100% sensitivity and specificity. If the lesions demonstrate absolute per- centage washout of less than 60% and/or relative percentage wash- out of less than 40%, they cannot be characterized confidently as a benign adenoma and require further evaluation or close imaging follow-up to monitor size.1,3,4

MRI characterization of adrenal masses is based on intracel- lular lipid differential between adenomatous and nonadenomatous lesions. Adenomas have a large intracellular lipid component. While ACC is generally isointense on T1-weighted imaging, the high T1 and intermediate T2 signal due to products of hemorrhage can change this. These lesions often display internal hemorrhage, central necrosis, and peripheral enhancement. Chemical-shift MRI (often referred to as in-phase and opposed-phase imaging) for the evaluation of microscopic fat has overall sensitivity of 81% to 89% and specificity of 92% to 99% for benign versus malignant masses.3 MRI with magnetic resonance venography may detect IVC involvement and locoregional disease. In addition, most of these imaging features can be obtained without intravenous con- trast, and evaluation of vascular involvement can also be performed using noncontrast angiographic techniques.

The role of FNAB of adrenal masses differs in cancer patients and those with incidentally discovered adrenal masses and no prior cancer history. In patients with cancer of nonadrenal origin, FNAB has a sensitivity of 80% and specificity of 100% and overall accu- racy greater than 90% for metastases, and when these are solitary, there may be a role for adrenalectomy.11,12 However, in the setting of adrenal incidentaloma and desire to differentiate between adrenal adenoma and ACC, the accuracy of FNAB is only 54% to 86% be- cause of cytological problems with diagnosis of malignancy.3 More importantly, there is a significant risk of seeding from violation of the tumor capsule. Therefore, FNAB is not recommended for diag- nosis of primary ACC because of difficulties differentiating benign adenoma and ACC and possible capsular breach leading to tumor implantation along the needle tract (seeding).23 By contrast, FNAB is indicated in cancer patients (lung, breast, kidney) with no other signs of metastases and a heterogeneous mass with high unenhanced attenuation value after exclusion of pheochromocytoma.23 It is also sometimes used for infectious abscesses or lymphoma.

The treatment of choice and only chance of cure for ACC is complete surgical extirpation of the tumor and adrenal gland. En bloc resection of the involved organs and any periaortic or retroperitoneal lymphadenopathy may be appropriate.” There is controversy regard- ing the surgical approach when adrenalectomy is required.1,109-111 Laparoscopic adrenalectomy was introduced in the early 1990s and has become the operation of choice for almost all adrenal lesions

except tumors concerning for ACC and those that are too large or dif- ficult to resect laparoscopically. A laparoscopic or retroperitoneo- scopic approach is associated with shorter hospital stays, quicker return to normal activity, less postoperative pain, and fewer complications.3,31

However, from an oncologic standpoint, laparoscopic or retroperitoneoscopic adrenalectomy is associated with port-site me- tastases and increased local and peritoneal recurrence.31 Adrenocor- tical cancer may have microscopic tumor on the surface or capsular penetration so direct manipulation of the tumor surface should be avoided, and morcellation should not be performed.2

In a study of 217 patients with stages I to III ACC, 156 pa- tients were included, of whom 110 had open adrenalectomy, whereas 46 had laparoscopic adrenalectomy. Laparoscopic adrenal- ectomy was associated with more frequent positive surgical margins (30% vs 16%) than open adrenalectomy. Progression-free survival was longer in patients with open adrenalectomy, and time to tumor bed recurrence and peritoneal recurrence in stage II ACC was lon- ger with open adrenalectomy.11 This study addressed local and peritoneal recurrences, which are likely affected by surgical tech- nique, rather than analyzing overall survival or all recurrence sites, which may be more reflective of tumor biology. In a systematic re- view of 6 key publications, 673 patients with localized ACC, of whom 112 had laparoscopic adrenalectomy, were examined. Three larger studies concluded that laparoscopic adrenalectomy and open adrenalectomy are oncologically effective, whereas 3 other studies clearly recommended against laparoscopic adrenalectomy approach for ACC.110 All studies agreed that successful surgical outcome re- quires an experienced surgeon and recommended higher surgical volume and experienced surgeons.110

A debate regarding operative approach for ACC enumerates the advantages and disadvantages from an oncologic perspective.” Because the quality of surgical resection is critically important for patients with ACC, it is imperative the surgeon decide prior to oper- ation whether to treat the tumor as benign or malignant. This guides the selection of the most appropriate operative approach with con- sideration for oncologic technique. Preoperative imaging along with the hormonal signature of the tumor is used to help inform the deci- sion for operative approach.15 The specificity of various imaging techniques remains an issue, as an operation could be entirely avoided or approached laparoscopically without hesitation if it were clear the mass was benign. Many adrenal masses are resected be- cause they are indeterminate and concerning for ACC, and the team needs to make sure a resectable ACC is not missed. For these rea- sons and concerns, some patients may ultimately be denied the potential benefits of a laparoscopic procedure in order to pursue the most conservative oncologic principles.

PET and Nuclear Medicine Imaging for Incidentally Discovered Adrenal Masses

There is growing evidence for FDG PET/CT as a useful mo- dality for characterization of adrenal masses as benign versus malig- nant (Table 3). The majority of studies in the literature have been in cohorts composed of cancer patients, usually lung cancer or mixed groups because of the role of FDG PET/CT as an imaging standard for pretreatment oncologic staging. FDG PET was first described in 1995 as having 100% sensitivity and 100% specificity for separat- ing metastases to the adrenal from benign lesions in 24 patients with cancer.113 A large number of subsequent studies have found similar results, although 1 common limitation is that the majority of pa- tients do not have histopathologic proof of disease, relying instead on the diagnosis being made on combined imaging, hormonal, clin- ical, and follow-up data.114-125 Nonetheless, in a recent meta- analysis, pooling results from 21 studies describing 1391 lesions

in 1217 patients reported FDG PET and PET/CT had overall sen- sitivity of 97% and specificity of 91% for characterization of ad- renal masses as benign versus malignant. 14 There was no significant difference in diagnostic performance between differ- ent interpretive criteria, visual interpretation compared with liver background, SUVmax or SUVpeak, SUV ratios (adrenal SUVmax to liver SUVmax or adrenal SUVmax to liver SUVmean), or using the aorta, liver, or spleen as the comparator. Combination of CT criteria HU of less than 10 and histograms modestly improves the diagnostic accuracy, although the complexity of interpretation is increased.116,121,122,126

In these studies composed of cancer patients, ACC is gener- ally not a diagnostic concern, with most malignancies attributed to adrenal metastases, often in the presence of overwhelming extra- adrenal metastatic disease in which an additional site of adrenal me- tastasis may not be of clinical importance. Conversely, if there is a solitary adrenal metastasis, adrenalectomy may be contemplated. Of more relevance to ACC are studies of FDG PET/CT used to in- vestigate incidental adrenal masses, including studies of surgical co- horts with histopathology results.71,73-77,117,127-129 Early studies of patients without cancer history found utility of FDG PET for iden- tifying malignant adrenal masses.76,77,128 In these small cohorts, ACC was seen in 3 of 13 patients,75 7 of 27 patients,77 6 of 54 patients,76 and 1 of 16 patients,58 with FDG having high sen- sitivity and specificity for distinguishing malignant versus be- nign cases. FDG PET compared favorably to imaging with other radionuclide studies using NP-59, MTO, and MIBG for the workup of adrenal masses. 58,76,77,128

Subsequently, 2 larger retrospective studies of adrenal ade- noma studied with FDG PET/CT have confirmed excellent sensitiv- ity of 100% and specificity of 90% in (1 ACC of 15)73 and sensitivity of 95% and specificity of 97% (22 ACCs of 51 patients).72 In these studies, the interpretation of a positive PET scan was based on SUV adrenal-to-liver SUVmax ratios of greater than 1.7 and greater than 1.6, respectively. One of the sce- narios in which FDG PET/CT may be of additional benefit to stan- dard CT and MRI is for adrenal nodules otherwise indeterminate for adenoma. These are usually lipid-poor adenomas that are found in up to 30% of cases and cannot be confidently diagnosed with chemical-shift MRI or CECT. FDG PET/CT performed well for this indication. In 53 patients with indeterminate adrenal masses on CT and MRI (3 with ACC), FDG PET/CT had sensitivity of 100% and 90% for identification of malignancy using an SUV adrenal-to- liver SUVmax ratios of greater than 1.8.66 Ansquer and col- leagues127 reported similar results in 10 of 81 patients with ACC, with FDG PET/CT having sensitivity of 89% and specificity of 76% for identification of malignancy using visual interpretation. The authors noted that lesions with high SUVmax of greater than 10 were highly likely to be malignant, although at lower SUVmax there was overlap between benign adenoma and malignant lesions. In 52 patients with indeterminate masses (4 with ACC), FDG PET/CT had overall sensitivity of 60.5% and specificity of 92.9% using SUVmax of greater than 5.71 The authors studied several dif- ferent metabolic and anatomic parameters and concluded that in this cohort the best diagnostic performance was with total glycolytic volume (TLG), an advanced metabolic parameter requiring soft- ware that allows selection of volumes of interest. A TLG of greater than 12 had sensitivity of 92.1% and specificity of 78.6% and com- bined size and SUVpeak parameters (using both CT and FDG PET/ CT) having sensitivity of 92.1% and specificity of 64.3%.

Two studies have looked at the ability of FDG PET/CT to se- lect patients for surgery, either because of suspected adrenal malig- nancy or hyperfunctioning adrenal masses. In 71 patients of whom 22 had ACC on histopathology, using an SUV ratio (adrenal-to-liver SUV max) greater than 1.45 had sensitivity of 100% and specificity

of 88%, whereas an adrenal SUVmax greater than 3.4 had sensitiv- ity of 100% and specificity of 70%.74 Ansquer and colleagues127 re- ported similarly that a positive FDG PET/CT was predictive of both secreting adrenal masses and malignancy that would require surgi- cal intervention. FDG PET/CT was useful to select surgical candi- dates because either hypersecreting masses or malignancy and a negative FDG PET/CT allow clinically adequate follow-up. There have been 2 studies of FDG PET/CT in cohorts of patients com- prised mainly of adrenocortical adenoma.70,130 One retrospective study of 47 adenomas compared with 12 nonadenomas found 43 of 47 adenomas had HU of less than 10, and 89% had adrenal FDG uptake equal to or less than the liver. All nonadenomas had HU greater than 10, with none displaying FDG uptake less than liver.130 Another study looked at 28 lipid-rich adenomas (13 func- tioning and 15 nonfunctioning) and found FDG PET/CT could dis- tinguish functioning from nonfunctioning lesions with sensitivity of 69% and specificity of 81%, with functioning tumors having higher metabolic activity than nonfunctioning ones.7

False-positive FDG PET/CT results are usually described in cases of adrenocortical adenoma, either functioning or nonfunction- ing, attributed to the overlap in metabolic activity between benign and malignant lesions.63,131-134 This is particularly important in cancer patients with tumors that are not commonly metastatic to the adrenal gland. Other causes of false-positive results are pheo- chromocytoma,63,135-138 adrenal macrohyperplasia,63 inflammation

(sarcoidosis), infection (histoplasmosis, tuberculosis, syphilis),63,139-148 related to para-adrenal brown fat,149,150 hemorrhage,151-155 rare oncocytoma, 156,157 myelolipoma,63,158-161 and postchemotherapy response.68,83 False-negative results have been attributed to small size (<1.0-1.5 cm), tumor necrosis, and tumors with low FDG avid- ity. Neuroendocrine tumors and renal cancer cells have been de- scribed as having low FDG uptake. Therefore, FDG PET/CT could be performed for evaluation of an adrenal incidentaloma with indeterminate findings on CT or MRI, provided that the size greater than 1.5 cm and that size less than 4 to 6 cm (threshold for surgical intervention) or the mass is not growing, no extra- adrenal metastatic disease is present, and there are no classic im- aging findings of myelolipoma or adrenal cyst. A negative FDG PET/CT result may still warrant follow-up imaging out to 2 years. A positive result would need to be interpreted with correlative imaging, hormonal workup, and consideration of surgery or close imaging follow-up.

Other nuclear medicine studies to consider are in the setting of suspected hyperfunctioning adrenal masses, MIBG for suspected pheochromocytoma and neuroblastoma, In-DTPA-pentetreotide, or 68Ga-DOTA peptides for suspected pheochromocytoma or NET and NP-59 or 123I-MTO SPECT/CT,92 if available to determine ad- renocortical origin. These radiotracers have high specificity, greater than CT and MRI, and the positive predictive value helps to confirm the diagnosis. These tests will often be used in combination with CT, MRI, and FDG PET/CT for characterization of adrenal masses.

In a study of 100 131I-NP-59 studies, the accuracy was found to be 71% in PA, 75% in nonhyperfunctioning tumors, and 100% in Cushing syndrome.162 131I-NP-59 scintigraphy is able to lateralize the side of hyperfunctioning abnormality, thereby selecting patients who will benefit from surgery as opposed to those in whom bilateral macrohyperplasia is responsible for their hyperfunction.62,163 The main indication for NP-59 is for hyperaldosteronism. A positive NP-59-SPECT/CT in a 1-cm left adrenal adenoma was reported, with resolution of hypertension and biochemical disturbance after surgical resection.164 In 49 patients with surgery for primary hyperaldosteronism, SPECT/CT semiquantitative parameters, the adrenal-to-liver ratio, and the lesion to contralateral ratio of bilateral glands predicted surgical cure, distinguishing adenoma from macrohyperplasia.16> Similar findings were reported for SPECT/CT

in stage I and atypical hyperaldosteronism.166 123I-MTO SPECT/CT has a similar use for evaluation of hyperaldosteronism.94,95

After initial discovery of an unsuspected adrenal mass, bio- chemical evaluation should be performed to exclude hyperfunction, especially a catecholamine-secreting pheochromocytoma, which occurs in up to 11% of cases. 101 123I-MIBG is sensitive and specific for imaging of chromaffin tumors. A meta-analysis of 123I-MIBG found pooled sensitivity of 96% and specificity of 98% for evaluation of pheochromocytoma. 167 123I-MIBG is more sensitive 131I-MIBG for detection of pheochromocytoma confined to the adrenal rather than extra-adrenal locations. 123I-MIBG SPECT/CT is potentially useful for imaging pheochromocytoma and paraganglioma.168 In 126 adrenal lesions evaluated with 123I SPECT/CT, there was an in- cremental step-up in sensitivity between planar 63.3%, SPECT 86.6%, and SPECT/CT 90%.169 Specificity remained high on all modalities at planar 100%, SPECT 96.8%, and SPECT/CT of 100%. The interobserver variation for SPECT/CT between 2 readers was a Cohen K value of 0.815 for planar, 0.826 for SPECT, and 0.966 for SPECT/CT.

18F-FDG is accumulated by pheochromocytoma, with a sen- sitivity of 58% in benign pheochromocytoma, increasing to 76% in metastatic pheochromocytoma.54 Therefore, when FDG uptake oc- curs in an incidentally discovered adrenal mass, a sympathomedullary NET must be considered as a diagnostic possibility. F-FDG PET is useful for further staging of metastatic pheochromocytoma and paraganglioma particularly in the presence of genetic succinate dehydrogenase-related tumors.170 If there is biochemical evidence for a catecholamine secreting pheochromocytoma, 18F-DA has high sensitivity and specificity for localization of intra-adrenal and metasta- tic pheochromocytoma, with superior sensitivity to that of MIBG.171 1 8F-DA has been used to identify pheochromocytomas in patients with von Hippel-Lindau syndrome, a heritable disorder in patients with neg- ative 123I or 131I-MIBG scans. In a similar fashion, 18F-DOPA may be used to characterize adrenal masses suspected to represent pheochro- mocytoma.172 In this application, the value of these radiopharmaceuti- cals of amine precursor uptake is high specificity for NETs of both enterochromaffin and chromaffin origin. In the presence of a negative 18F-DA or 18F-DOPA PET study, a neoplasm may have undergone ma- lignant dedifferentiation with loss of vesicular uptake mechanisms, and imaging with 18F-FDG PET might be useful to fully depict addi- tional extra-adrenal sites of disease.173,174 68Ga-DOTA peptides may also be used in a problem-solving capacity for adrenal incidentaloma. In the unusual circumstance where other imaging modalities were un- successful for adrenal nodule characterization, 68Ga-DOTA PET could be performed to confirm a tumor of neuroendocrine origin and exclude metastatic or multifocal disease. It has been shown that pheochromo- cytomas will accumulate 68Ga-DOTA peptide.175 In 11 patients with either pheochromocytoma or neuroblastoma, 68Ga-DOTA peptide was compared with MIBG SPECT. 76 PET had a sensitivity of 94.4% compared with 76.9% with 123I SPECT. 68Ga-DOTA peptides are also accumulated by somatostatin receptor-expressing cells; there- fore, infection or chronic granulomatous inflammation processes in- volving the adrenals could lead to potential false-positive studies.

CONCLUSIONS

There is growing evidence that FDG PET/CT can better char- acterize adrenal masses otherwise indeterminate on CT, adrenal pro- tocol CT, and MRI, as benign versus malignant, and selecting optimal patient candidates for surgical management in suspected malignancy or hyperfunctioning adrenal masses. Preoperative eval- uation of malignant potential of adrenal masses may have relevance in selection of the surgical approach, either open versus laparo- scopic adrenalectomy, and the limited role of biopsy in this setting. FDG PET/CT is valuable for restaging ACC patients with suspected

recurrent disease. 11C-MTO PET/CT and 123I-MTO SPECT/CT allow adrenocortical imaging to determine adrenocortical origin of an adrenal mass with high specificity and perhaps promise for radionuclide therapy in a subset of ACC with locoregional metastatic disease.

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