Current Update on Cytogenetics, Taxonomy, Diagnosis, and Management of Adrenocortical Carcinoma: What Radiologists Should Know
Dhakshina Ganeshan1 Priya Bhosale2 Vikas Kundra2
Keywords: adrenocortical carcinoma, CT, FDG PET/CT, MRI DOI:10.2214/AJR.11.8282
Received November 23, 2011; accepted after revision April 18, 2012.
1Body Imaging Section, Division of Diagnostic Imaging, The University of Texas M. D. Anderson Cancer Center, Unit 1476, 1515 Holcombe Blvd, Houston, TX 77030-4009. Address correspondence to D. Ganeshan (drdakshin@yahoo.co.in).
2 Division of Diagnostic Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
AJR2012; 199:1283-1293
0361-803X/12/1996-1283
@ American Roentgen Ray Society
OBJECTIVE. A multimodality imaging spectrum of adrenocortical carcinoma, with an emphasis on both anatomic and functional imaging, will be reviewed. Recent advances in the molecular cytogenetics of this tumor and its impact on diagnosis, prognosis, and development of newer targeted therapy will be discussed in this article.
CONCLUSION. Adrenocortical carcinomas are rare aggressive tumors associated with a poor prognosis. Awareness of the molecular behavior and spectrum of imaging features of this tumor can help in appropriate patient treatment.
A drenocortical carcinoma (ACC) is a rare neoplasm with an annu- al incidence of 1-2 cases/1 mil- lion population [1, 2]. It is slight- ly more common among female patients (1.5:1) and has a bimodal age distribution, with one peak in children younger than 5 years and another peak between ages 30 and 50 years. Pediatric ACCs are more common in children younger than 4 years and tend to be relatively less aggressive compared with ACCs in adults. In a study involving 254 pe- diatric ACCs, three fourths were early-stage tumors (44.1% stage I and 31.5% stage II tu- mors) [3]. The 5-year survival rate is also better for pediatric ACCs than for adult ACCs (54% vs 38%) [3]. Differentiating be- tween adenomas and ACC in children may sometimes be difficult by imaging, resulting in delays in diagnosis [3].
The proportion of secreting tumors among ACC varies in the literature, from 17% to 79% [2, 4-7]. It is possible that this may be a reflection of increased sensitivity of the newer hormonal assay tests. However, re- cruitment bias in these studies may also be contributing to the wide range in hormonally active ACC tumors. For example, more hor- monally active tumors are likely to be seen in endocrine centers, whereas nonfunctional tumors may be more common in oncology centers [6, 7]. Also, studies including pedi- atric ACCs are likely to have a higher inci- dence of functional tumors [3].
Cushing syndrome is the most common hor- monal abnormality seen in functional ACCs
and is seen in 30-45% of the hormonally ac- tive tumors [8]. Cushing syndrome combined with androgen excess is seen in 25% of cases. Virilization due to androgen excess is seen in only 10% of adult patients with ACC, but this is the most common presentation of pediatric ACCs [9]. Other hormonal abnormalities seen in ACC include hyperaldosteronism and femi- nization due to estrogen excess [8, 9].
The nonfunctional ACCs may be much larger at presentation, and patients often pres- ent with nonspecific abdominal pain [10, 11]. Such ACCs may also be discovered inciden- tally on imaging done for unrelated reasons [12-14] (Fig. 1). In a study involving 387 pa- tients with ACC, 16% of the ACCs were iden- tified as incidentalomas [14]. ACCs are typi- cally large tumors measuring more than 6 cm. However, it is important to realize that they may present as masses smaller than 5 cm (T1 stage), particularly those discovered as inci- dentalomas [1]. For example, in a series in- volving 38 patients with ACCs, Barnett et al. [15] reported that five of 38 ACCs (13%) were smaller than 5 cm. In another series involving 20 patients with ACCs, the tumor was smaller than 5 cm in seven patients (35%) [16]. Hence, other clinical and imaging criteria must be ap- plied to evaluate the lesion further.
In this article, we illustrate the multimodal- ity imaging spectrum of ACC, with an empha- sis on both anatomic and functional imaging. Furthermore, recent advances in the molecular cytogenetics of this tumor and its impact on di- agnosis, prognosis, and development of newer targeted therapy will be discussed in this article.
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Taxonomy, Pathology, and Molecular Cytogenetics of ACC
Adrenocortical tumors include adrenal ade- nomas, ACC (Fig. 2), adrenocortical tumors of unknown malignant potential, and other rare tumors, such as oncocytomas, primary adrenal lymphoma, sarcomas, and composite tumors [17-20]. Standard histopathologic examination for determining the presence of malignancy in adrenocortical tumors is based on certain mor- phologic features. Several scoring systems are currently used widely for this purpose, includ- ing the Weiss criteria [19], Hough classification [21], and van Slooten criteria [22]. The most commonly used method is the Weiss criteria, which scores tumors from 0 to 9 according to features such as Fuhrman nuclear grade, num- ber of mitoses, percentage of clear cells, degree
of diffuse architecture, presence or absence of atypical mitoses, confluent necrosis, venous in- vasion, sinusoidal invasion, and capsular infil- tration. A Weiss score equal to or greater than 3 suggests malignancy [19] (Table 1).
Histopathology
ACCs are yellow-orange-colored tumors with a lobulated surface. They are typically bulky tumors and usually weigh more than 100 g [23]. Necrosis, hemorrhage, and calcification are frequent. Intratumoral hemorrhage has been shown to be associated with a poor prognosis [24]. Furthermore, ACCs larger than 5 cm have a relatively worse prognosis than do smaller ACCs, a fact that is reflected in the TNM clas- sification, wherein tumors smaller than 5 cm are staged as T1 and those larger than 5 cm
are staged as T2. Also, Harrison et al. [24] reported that ACCs larger than 12 cm have a significantly poorer 5-year survival rate of 22%, compared with 53% seen in tumors smaller than 12 cm.
Microscopically, ACC is characterized by large compact pleomorphic cells with abun- dant eosinophilic cytoplasm organized in a trabecular pattern [17]. Necrosis and broad fi- brous bands are frequently seen [17, 19]. Nu- clear pleomorphism is often prominent. Mi- toses are found with difficulty, and their rate is quite variable. When atypical mitoses are present, it is thought to be a characteristic fea- ture of malignancy. Other features favoring malignancy include capsular infiltration and venous or sinusoidal invasion. Of all these mi- croscopic criteria, a mitotic count of more than 6 per 10 high-power fields has been reported as an independent prognostic factor associated with a poor 5-year survival rate [24].
Although the standard histopathologic sys- tem using Weiss score is useful in most cases, there are situations in which it becomes impos- sible to say whether a tumor is benign or ma- lignant on the basis of the microscopic features alone [25, 26]. This may be particularly prob- lematic in pediatric ACCs. However, mislabel- ing an early ACC as benign can have devastat- ing consequences-from a potentially curable early stage, the tumor may quickly progress into an advanced metastatic cancer with dismal prognosis. When dealing with such difficult cases, evaluation of the cytogenetics and mo- lecular pathology of the tumor is turning out to be useful in guiding management.
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Cytogenetics, Taxonomy, Diagnosis, and Management of Adrenocortical Carcinoma
| Weiss Criteria | Score | |
|---|---|---|
| Present | Absent | |
| Nuclear grade: Fuhrman nuclear grade III and IV | 1 | 0 |
| Mitotic rate: greater than 5 per 50 high-power fields | 1 | 0 |
| Atypical mitotic figures: presence of abnormal distribution of chromosomes or an excessive number of mitotic spindles | 1 | 0 |
| Presence of ≤ 25% clear cells within cytoplasm | 1 | 0 |
| Diffuse architecture of tumor: if more than one third of the tumor formed patternless sheets of cells, tumor was defined as having diffuse architecture | 1 | 0 |
| Necrosis | 1 | 0 |
| Venous invasion | 1 | 0 |
| Sinusoid invasion | 1 | 0 |
| Invasion of tumor capsule | 1 | 0 |
Note-Each criterion is scored as 0 when absent and 1 when present. Tumors with a score of more than 3 are classified as ACC.
| Familial Syndrome | Genetic Alteration | Clinical Manifestations |
|---|---|---|
| Li-Fraumeni syndrome | Mutation in TP53 gene (17p13) | Breast cancer, brain tumors, leukemia, soft-tissue and bone sarcomas, and ACC |
| Multiple endocrine neoplasia type 1 | Mutation in Menin gene (11q13) | Parathyroid, pituitary, and pancreas (islet cell) tumors, carcinoid tumors, benign adrenal adenomas, and diffuse hyperplasia (20-40%); ACC rarely |
| Carney syndrome | Mutation in PRKARIA gene (17q22-24) | Primary pigmented nodular adrenocortical disease, cutaneous manifestations such as lentigines and blue nevi, myxomas of the heart and other sites, psammomatous melanotic schwannoma, pituitary adenoma, testicular tumors, thyroid tumors, and ductal adenoma of the breast |
| Beckwith-Wiedemann syndrome | Mutation in IGF-II locus at 11p15 | Large tongue, omphalocele, macrosomia, organomegaly, hemihypertrophy, Wilms tumors (5-20%), and ACC |
Note-IGF = insulinlike growth factor.
Cytogenetics of ACC
Awareness of the molecular mechanisms and genetic abnormalities in ACC provides better understanding of tumor biology, imag- ing findings, and prognosis and can help the radiologist and the clinicians in providing optimal care [27-36]. For example, ACCs with a loss of heterozygosity in 17p13 have a higher chance of recurrence and may require more-frequent imaging follow-up. Similarly, if an adrenal lesion is suspected to be ACC on cross-sectional imaging but standard his- topathologic analysis is inconclusive, further evaluation with molecular classification can help to confirm the diagnosis [25, 26].
Recent advances in the molecular cytoge- netics of ACCs have substantially enhanced understanding of the pathophysiology of this rare tumor [27-31]. Specific genetic altera- tions have been identified in hereditary ACCs. For example, germ-line mutations in TP53 (17p13) are seen in Li-Fraumeni syndrome, a familial cancer syndrome that can predispose to various cancers, such as sarcomas, leuke- mia, breast, and lung tumors, as well as benign and malignant adrenocortical tumors. Similar-
ly, other hereditary cancer syndromes associ- ated with ACC also have characteristic genetic alterations (Table 2).
What has been particularly useful is that the advances made in molecular cytogenet- ics of the hereditary cancer syndromes asso- ciated with ACCs have facilitated progress in the research in sporadic forms of ACC [33]. Indeed, similar genetic aberrations seen in fa- milial forms have since been identified as so- matic alterations in sporadic tumors [27, 33]. As a result of these major advances in the past decade, molecular classification is now being used more often in clinical practice, especially in the specialist centers.
For example, loss of heterozygosity in 17p13 is seen in more than 85% of ACCs, and insulinlike growth factor (IGF)-II is overexpressed in 90% of ACCs [32]. Hence, testing for IGF-II overexpression or loss of heterozygosity in 17p13 may be a useful di- agnostic test in cases where standard histo- pathologic evaluation is indeterminate. Com- bining this with immunohistochemistry, such as overexpression of Ki-67 proteins, increas- es the diagnostic sensitivity further [30].
Moreover, it is now possible to predict prognosis with these molecular markers [33- 35]. For example, increases in DGL7 and de- creases in PINK1 (both are cell-cycle regula- tor genes) have been shown to be associated with a poorer prognosis [34]. Similarly, so- matic mutations in TP53 are associated with a more-aggressive outcome [36]. On the basis of a prospective study involving 114 patients with ACC, Gicquel et al. [29] showed that loss of heterozygosity in 17p13 was an inde- pendent variable predictive of recurrence after complete surgical removal of localized ACC. Hence, molecular classification has gained both diagnostic and prognostic significance in the overall management of ACCs.
Advances in the knowledge of molecular mechanisms of ACC have also helped to de- velop potential newer targeted therapies for ACC. For example, it has been shown that IGF-signaling-pathway upregulation is one of the cardinal events in the pathogenesis of ACC [32]. This has led to the introduction of clinical trials using inhibitors of IGF-I re- ceptor in ACC (National Cancer Institute tri- al no. NCT00924989). Similarly, preclinical
studies using immunotherapy, gene therapy, and treatment with antiangiogenic substances are currently being researched [37].
Imaging Features of ACC
The intention of this review article is not to comprehensively describe the imaging fea- tures of the various adrenal lesions. Rather, we aim to describe the imaging features of ACC in detail and then to show how to differentiate it from other adrenal lesions, where relevant.
Ultrasound
Ultrasound is not used as a first-line im- aging method when adrenal tumors are sus- pected because it is quite difficult to sono- graphically assess the adrenal glands in adults. However, occasionally an ACC is first identified on an ultrasound, because most nonfunctional ACCs present as nonspecific abdominal pain, and patients may undergo ultrasound as the initial diagnostic test [14].
ACCs are typically seen as large hetero- geneous tumors (Fig. 1) lying immediately adjacent to the posterior surface of the liver and posterolateral to the inferior vena cava (IVC) (right side) or anteromedial to the su- perior pole of left kidney (left side). When present, invasion into renal veins or IVC is a definitive feature of malignancy. However, there are no specific ultrasound features of ACC [38]. For example, pheochromocyto-
mas can also present as large heterogeneous masses, though they are usually more vascu- lar. Hence, once a mass is identified on ul- trasound, further evaluation should be per- formed with CT or MRI.
CT
Although various different CT techniques have been described in the literature for eval- uating adrenal masses, including CT densi- tometry, CT histogram, CT perfusion im- aging, and washout scans, the underlying principles are simple, as follows: first, up to 70% of benign adrenal adenomas contain in- tracellular lipid, whereas malignant lesions rarely do [39-42]; and second, after admin- istration of IV contrast agent, benign adre- nal adenomas tend to wash out much faster, as early as 3 minutes, whereas malignant le- sions tend to show delayed washout [43-45].
Capitalizing on these two principles, a standard protocol for adrenal mass evalu- ation should contain an unenhanced scan, an IV contrast-enhanced scan obtained at 45 seconds, and a delayed scan obtained at 15 minutes after administration of contrast agent [42-45]. Because most benign ade- nomas contain intracellular lipid, they will have relatively low attenuation values on un- enhanced CT. When 0 HU is used as the cut- off value for differentiating benign from ma- lignant masses, a specificity of 100% can be achieved, but the sensitivity is poor, at only 47% [40]. When the cutoff value is increased to 10 HU, it is still possible to achieve 98% specificity and increase the sensitivity to 71% [46]. However, because 30% of the ad- renal adenomas are lipid poor, it is not possi- ble to say that all lesions with an attenuation value greater than 10 HU are malignant on the basis of unenhanced CT alone [46].
Hence, adrenal masses with attenuation val- ues greater than 10 HU on unenhanced scans should be considered indeterminate. Because most of these adrenal incidentalomas are like- ly to be benign, it is neither realistic nor cost effective to evaluate all of these lesions. Clini- cal correlation can help to decide as to which of these lesions can be ignored and which will require follow-up or further evaluation. By performance of a contrast-enhanced scan at 45 seconds and then again at 15 minutes after ad- ministration of IV contrast, the washout char- acteristics of the lesion can be evaluated by the following simple formulas: absolute percent- age washout = [(E - D) / (E-U)] x100, and relative percentage washout = [(E - D) / E] x 100, where E is early attenuation value (after
45 seconds), D is delayed attenuation value (after 15 minutes), and U is unenhanced atten- uation value (in the unenhanced scan).
The CT scan percentage washout values that would strongly support a benign adenoma include an absolute percentage washout great- er than 60% and a relative percentage wash- out greater than 40%. Conversely, malignancy is highly likely if absolute percentage washout is less than 60% or relative percentage wash- out is less than 40% [40, 46]. The sensitivi- ty, specificity, and accuracy of these washout characteristics in differentiating benign ade- nomas from malignant lesions is reported to be 89-98%, 92-95%, and 91-96%, respec- tively [41, 44, 47-49]. However, an adrenal mass with absolute percentage washout less than 60% or relative percentage washout less than 40% is not specific and simply suggests a malignancy such as an ACC, a metastasis, a pheochromocytoma, or, rarely, a primary ad- renal lymphoma [41, 44, 47-49]. Although correlation with clinical and biochemical findings might help to exclude pheochromo- cytoma, biopsy will often be required to dif- ferentiate between the other lesions.
The next most important feature is the size of the lesion; an adrenal mass larger than 4 cm has a 40% chance of malignancy and one larger than 6 cm has an 85% chance of ma- lignancy [13, 50]. Although the size criteria
Cytogenetics, Taxonomy, Diagnosis, and Management of Adrenocortical Carcinoma
are useful for differentiating ACC from adre- nal adenoma, the same may not apply for dif- ferentiating ACC from adrenal myelolipoma, because the latter can frequently present as large tumors [51, 52]. The presence of macro- scopic fat is a characteristic feature of adrenal myelolipoma [51]. However, there have been
few case reports of ACC containing fat, and, in such cases, it may be extremely difficult to differentiate between the extremely rare fat-containing ACC and a large myelolipoma [53] (Fig. 3). The presence of features such as hypertension, signs and symptoms of adrenal hormone excess, and CT features of hetero-
geneous mass with significant peripheral het- erogeneous enhancement are more sugges- tive of ACC but not diagnostic, because these may also be seen in myelolipoma coexisting with other adrenal tumors (collision tumors). Adrenal biopsy may be required for defini- tive diagnosis in such cases [54].
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C
A, Contrast-enhanced axial CT of abdomen shows large heterogeneous mass (arrow) in right abdomen. It is difficult to determine whether mass is arising from kidney or adrenal gland.
B, Coronal CT of abdomen shows thin claw of normal renal parenchyma (arrows) along margin of tumor. Presence of normal renal parenchyma cupping or abutting mass is called “claw sign” and is useful for confirming renal origin of mass.
C, Three-dimensional reformation shows renal artery (arrow) supplying mass. Pathologic examination confirmed clear cell renal cell carcinoma.
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C
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3
4
Fig. 6-66-year-old man with metastatic adrenocortical carcinoma who presented with hypertension; biochemical tests revealed hypercortisolism and hyperaldosteronism.
A, Contrast-enhanced axial CT image of abdomen shows large heterogeneous left adrenal mass (arrow) invading pancreas. B, Axial CT image shows liver metastases (arrows).
C, Axial CT image of thorax reveals lung metastases (arrows).
D, Coronal CT reformation of lumbar spine shows sclerotic bone metastasis (arrow). E, Sagittal ultrasound image of right forearm shows heterogeneous echogenic subcutaneous mass (arrow), which was biopsy-proven to be metastasis.
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E
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C
Sometimes, large pheochromocytomas can be difficult to distinguish from ACCs. How- ever, careful attention to clinical presentation and biochemical evaluation, such as plasma and urinary metanephrines and urinary vanil- lylmandelic acid, will usually help to diag- nose pheochromocytoma correctly in most cases. Other CT features of ACC include het- erogeneity, necrosis, hemorrhage, and calci- fication [55] (Fig. 4). Sometimes, when the tumor is very large, it may be difficult to as- sess the correct site of origin [51]. Because many nonfunctional ACCs are large at dis- covery, the major tumors that might lead to confusion in imaging are large upper pole
exophytic renal cell carcinoma and large pri- mary malignant retroperitoneal tumors of other cell types, such as sarcomas. If the ad- renal glands are not identified on imaging, these tumors can mimic ACC. In such cases, multiplanar reformations in coronal and sag- ittal planes may be helpful in identifying the tumor origin or identifying the vascular sup- ply to the tumor [51, 56] (Fig. 5).
Features of malignant adrenal masses in- clude local invasion into vessels or the pres- ence of distant metastases. Invasion of the IVC is seen in 9-19% of cases of ACC [57]. When there is IVC invasion, it is important for the radiologist to comment on the cranial ex- tent of the IVC invasion by the tumor on im- aging examinations, because this influences the surgical approach. Metastases are seen in up to one third of the cases and most frequent- ly involve the regional lymph nodes, lungs, liver, and bones (Fig. 6). However, they may be encountered in various other locations, in- cluding brain and subcutaneous tissues.
MRI
MRI can be very useful in assessing ad- renal masses. Imaging features of ACCs on MRI complement those seen on the CT scan, and the signal intensity on different sequenc- es depends on the pathologic state. On T1- weighted images, ACCs are usually isoin- tense to liver, but a necrotic tumor may be hypointense and a hemorrhagic tumor may be hyperintense on such images. Heteroge- neous high signal intensity on T2-weighted images implies necrosis [58] (Fig. 7). Irreg- ular heterogeneous enhancement is seen on contrast-enhanced scans.
The multiplanar capability of MRI is very helpful to decide the site of origin. MRI is very sensitive and accurate in assessing in- vasion into the IVC [58, 59] (Fig. 8). Tradi- tionally, MRI has been the reference standard for assessing IVC invasion, although there is mounting evidence that modern MDCT per- forms equally well in assessing the presence of tumor thrombus and in estimating the up- per limit of thrombus, with a sensitivity of 84- 100% and an accuracy of 78-96% [60-63]. Furthermore, dynamic contrast-enhanced liv- er MRI can be performed at the same exami- nation, which is useful in equivocal cases of suspected hepatic metastases. The liver metas- tases from ACC may be either hypervascular or hypovascular.
Chemical-shift imaging by MRI is common- ly used for assessment of adrenal lesions [59]. In the out-of-phase image, fat and water pro- tons in the same voxel cancel each other out, re- sulting in a decrease in signal intensity. This signal drop is seen only in lesions containing microscopic or intracellular fat in the same voxel as fluid, such as adrenal adenomas. Al- though qualitative assessment of signal loss us- ing spleen as a reference is used commonly in routine practice, it has been shown by some au- thors that quantitative analysis of signal loss can significantly increase the sensitivity and speci- ficity of diagnosing adenomas to almost 100% [64-66]. The most common method of quanti- tative analysis for signal loss is the adrenal-to- spleen chemical-shift ratio, which is defined as the adrenal-mass-to-spleen signal-intensity ra- tio on the opposed-phase images divided by the adrenal mass-to-spleen signal-intensity ratio on the in-phase images [66]. An adrenal-to-spleen
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chemical-shift ratio of less than 0.71 is highly sensitive for adrenal adenoma.
Although chemical-shift imaging is an ex- tremely useful and simple way of diagnos- ing lipid-rich adenomas, it should be kept in mind that, very rarely, ACCs may also con- tain microscopic fat, especially the function- al tumors, and these would also show signal drop on out-of-phase images [59, 67-71]. The presence of fat in this lesion is because these tumors arise from the adrenal cortex. The signal drop in the ACCs is usually het- erogeneous and to a much lesser degree com- pared with the adenomas. However, it may be extremely difficult to distinguish the rare fat-containing ACC from a myelolipoma on imaging or according to clinical characteris- tics alone. Hence, these cases may warrant an adrenal biopsy.
MR spectroscopy has been reported in ex- perimental studies to be useful in differenti- ating among ACC, pheochromocytoma, ade- noma, and metastases [72]. It is beyond the scope of this article to discuss the technique of proton MR spectroscopy in depth, and there are many excellent resources describ- ing this in great detail [73, 74]. In short, the diagnostic utility of proton MR spectroscopy is based on the fact that choline is a marker of active neoplasm and, hence, elevated levels of choline compounds would be expected in tumors. The creatine levels are also measured in MR spectroscopy because they provide in- formation on cell energy status and are used as a standard metabolite.
In the evaluation of adrenal masses by MR spectroscopy, measurement of the choline- to-creatine ratio has been reported to be the most useful [72]. A choline-to-creatine ratio greater than 1.20 strongly favors malignancy, such as carcinoma or metastasis, whereas a value less than or equal to 1.20 would suggest pheochromocytoma or adenoma (92% sensi- tivity, 96% specificity, 86% positive predic- tive value, and 95% accuracy) [72]. Other values that have been explored by MR spec- troscopy include choline-to-lipid ratio, lipid- to-creatine ratio, and 4.0-4.3 ppm/creatine ratio [48, 72]. Although MR spectroscopy is not used as a standard test for diagnosing ACC and is still in experimental stages, this technique holds promise.
18F-FDG PET and PET/CT
The diagnostic value of FDG PET is based on increased glucose uptake by malignant le- sions. Apart from qualitative visual analysis, quantitative assessments, including maximum standardized uptake value (SUVmax) and ad- renal-to-liver SUV max ratio, have been used to predict malignancy in adrenal masses. High sensitivity (94-100%) and specificity (88- 91%) have been reported for detecting adre- nal malignancy with FDG PET/CT [75-79].
There are well-known pitfalls in FDG PET/ CT. First, FDG PET/CT has reduced sensi- tivity and specificity in diagnosing lesions smaller than 1 cm [76, 77]. Furthermore, it is known that even benign adenomas and pheo- chromocytomas may show FDG uptake [78,
79] (Fig. 9). However, adrenal adenomas usu- ally show mild FDG uptake and only rarely show avid FDG uptake, which is a more typi- cal feature of ACCs.
In a study involving 30 patients with 35 in- determinate adrenal lesions, an SUV max cut- off value of 2.5 corresponded to a sensitivity of 89%, specificity of 94%, accuracy of 91%, positive predictive value of 94%, and negative
| Classification | Description |
|---|---|
| Primary tumor (T) | |
| T1 | Tumor ≤ 5 cm in greatest dimension and confined within the adrenal gland |
| T2 | Tumor > 5 cm in greatest dimension and confined within the adrenal gland |
| T3 | Tumor extending outside adrenal gland into adjacent fat |
| T4 | Tumor invading adjacent organs |
| Regional lymph nodes (N) | |
| N0 | No regional lymph node metastasis |
| N1 | Regional lymph node metastasis |
| Distant metastasis (M) | |
| M0 | No distant metastasis |
| M1 | Distant metastasis |
predictive value of 88% [80]. The tumor-to-liv- er SUV max ratio was 1.0 ± 0.2 for adrenal be- nign lesions and 4.5 ± 3.0 for adrenal malignant lesions. Using a tumor-to-liver SUV max ratio cutoff value of 1.8, the authors reported a sensi- tivity of 85%, specificity of 100%, accuracy of 91%, positive predictive value of 100%, and negative predictive value of 83% [80]. In an- other prospective study involving 77 patients, Groussin et al. [81] reported a 100% sensitiv- ity and 88% specificity to distinguish adenomas from ACCs, using a cutoff value above 1.45 for adrenal-to-liver SUV max ratio.
Given the higher cost involved, FDG PET/ CT should be reserved for the challenging and difficult cases, rather than used in the ini- tial evaluation of an adrenal mass. Further- more, there are preliminary reports that FDG PET/CT may be useful in preoperative stag- ing and postoperative surveillance and plays a complementary role to CT [82] (Fig. 10). In a study involving 22 patients with ACC and a total of 269 metastatic lesions in 57 organs, Leboulleux et al. [82] reported that 18% of the metastatic organs were diagnosed only with PET/CT. However, further research is needed to validate this finding before PET/ CT can become a routine staging tool in ACC. Furthermore, small metastases can be missed by PET/CT because they may be be- low the resolution of PET, as was also high- lighted in the study by Leboulleux et al. [82]. As of now, PET/CT plays a complementary role to CT, especially in those cases where curative surgery is being considered. Sim- ilarly, it may be useful in the early postop- erative surveillance because there is a high rate of recurrence in ACCs [82-84]. Leboul- leux et al. reported that 38% of the local re- currences were seen only with PET/CT [82].
FDG PET/CT can help further to differenti- ate between postoperative fibrosis and recur- rent tumor [56]. FDG PET/CT may also be potentially useful in monitoring response to therapy. Currently, the utility of 11C-metomi- date as an adrenocortical tissue specific trac- er is being explored and may further improve specificity [1].
Role of Other Imaging Modalities
As a result of the advances in MDCT and MRI technology, conventional angiography is now rarely used in the initial evaluation of adrenal masses but can be useful if selective adrenal venous sampling is required for bio- chemical evaluation. Also, angiography may be used occasionally in large ACCs for pre- operative embolization to reduce vascularity before surgery [85]. Apart from PET/CT, nu- clear medicine has a limited role in the work- up of adrenal masses, with the notable excep- tion of 131I and 123I-metaiodobenzylguanidine scanning [86, 87]. This test can be very use- ful in the diagnosis of pheochromocytomas, especially in ectopic or metastatic cases or situations where there is strong biochemical evidence suggesting this disease but no ab- normality is visualized in cross-sectional im- aging. However, an important pitfall is that, occasionally, nonfunctional pheochromocyto- mas may not be avid on an 123I-metaiodoben- zylguanidine scan [88].
Role of Biopsy
When patients with a known malignancy present with an adrenal lesion and diagnos- tic imaging cannot exclude a metastasis, bi- opsy of the adrenal mass is often performed. However, most surgeons currently do not fa- vor percutaneous biopsy of a mass suspected
to be an ACC, especially when it is potential- ly resectable [85]. This is because of the po- tential theoretic risk of seeding along the nee- dle track, although this is an exceedingly rare complication, with only anecdotal reports seen in the literature. In a study involving 31 adrenal biopsies performed on malignant ad- renal lesions (27 metastasis and four ACCs), only one biopsy resulted in malignancy along the needle track, and this, too, was seen in a case of adrenal metastasis [89]. Habscheid et al. [90] also reported that this was a very rare complication, with an estimated incidence of 1 case/100,000 biopsies.
Another argument against the routine use of biopsy in these cases is that negative re- sults in routine histopathology from biopsy cannot definitely exclude malignancy [91]. However, recent reports have described that genetic testing can facilitate the differenti- ation of malignant from benign adrenal le- sions [25, 26, 30, 32, 92]. From a practical point of view, large nonfunctional tumors may warrant biopsy, because it is doubtful that they can be identified by imaging alone.
Management
Surgery remains the standard treatment of ACC. Even for advanced stage IV tumors, surgical debulking is performed as a pallia- tive procedure to control hormonal effects. In general, open surgery is recommended for large tumors. Smaller tumors may be dealt with by laparoscopic adrenalectomy, but this is best done by expert surgeons, preferably in specialist centers, because there have been several reports of recurrence following lapa- roscopic removal of tumors [93, 94]. Imaging is important to correctly stage the disease so that an appropriate decision can be made re- garding curative resection or palliative treat- ment. The 2004 TNM classification for ACC is summarized in Table 3 [95, 96].
Depending on the local practice, adjuvant treatment may be carried out with mitotane, which is anadrenocorticolytic drug [97]. Mi- totane inhibits 11-ß-hydroxylase and there- by blocks cortisol synthesis. In a retrospec- tive trial involving 177 patients, Terzolo et al. [97] showed that adjuvant use of mitotane reduces the risk of recurrence and death and prolongs recurrence-free survival. Radiothera- py is another useful adjuvant treatment in pa- tients with ACC following surgical resection. Sabolch et al. [98] reported that adjuvant ra- diotherapy can significantly reduce the risk of recurrence of ACC following surgery. Che- motherapy may also be used as an adjuvant
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Cytogenetics, Taxonomy, Diagnosis, and Management of Adrenocortical Carcinoma
therapy in ACC, and the commonly used treat- ment regimen includes etoposide, doxorubicin, and cisplatin and mitotane or streptozotocin and mitotane [99]. Newer targeted therapies such as IGF-I receptor inhibitor, ß-catenin an- tagonist, and mammalian target of rapamycin inhibitors are currently under evaluation in the treatment of ACC [37].
Prognosis
ACCs are very aggressive tumors with a poor prognosis. Tumor staging at initial pre- sentation is the most important factor affecting survival. The 5-year survival rates are 66% for patients with stage I tumors, 58-65% for stage II, 24-40% for stage III, and 0-10% for stage IV [100, 101]. In a large study involving 3982 patients diagnosed with ACC, Bilimoria et al. [102] reported that the 5-year survival for all patients who underwent resection was 38.6%. Factors associated with a poor prognosis in- cluded age older than 55 years, positive resec- tion margins, lymph node-positive disease, resection of a contiguous organ, poorly differ- entiated tumors, and distant metastatic disease; also, certain pathologic features and molecular markers are associated with a worse prognosis, as described earlier in this article [24, 33-35].
Conclusion
ACCs are rare and complex tumors. Al- though diagnosing the larger lesions may not be difficult, correctly identifying the smaller lesions as ACCs may be more challenging. Thorough understanding of the wide spec- trum of the clinical, molecular, and patho- logic behavior of this tumor will help the ra- diologist to diagnose these tumors accurately and play a more active role in the multidisci- plinary management of this condition.
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