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AJR FOCUS ON:
Adrenocortical Carcinoma: The Range of Appearances on CT and MRI
Nishat Bharwani1 Andrea G. Rockall1 Anju Sahdev1 Maria Gueorguiev2 William Drake2 Ashley B. Grossman2 Rodney H. Reznek1
Keywords: adrenal gland, adrenal neoplasms, adrenocortical carcinoma, CT, MRI
DOI:10.2214/AJR.10.5540
Received August 11, 2010; accepted after revision November 2, 2010.
1Imaging Department, St. Bartholomew’s Hospital, King George V Wing, Ground Fl, Room 3 West Smithfield, London EC1A 7BE, United Kingdom. Address correspon- dence to N. Bharwani.
2 Department of Endocrinology, Barts & The London NHS Trust, London, United Kingdom.
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AJR 2011; 196:W706-W714
0361-803X/11/1966-W706
@ American Roentgen Ray Society
OBJECTIVE. Adrenocortical carcinoma (ACC) is a rare, aggressive tumor arising from the adrenal cortex that typically presents late with a large mass. The increased use of cross- sectional imaging for unrelated reasons has led to a greater number of ACCs being detected incidentally at an earlier stage. Recognition of the typical clinical, biochemical, and imaging findings is imperative for rapid diagnosis, prompt intervention, and early use of the appropri- ate therapy.
CONCLUSION. Cross-sectional imaging with CT and MRI is essential for determining the extent of local and distant tumor spread. Complete surgical resection is currently the only potentially curative treatment of ACC, and the information attained from CT and MRI is im- portant to guide surgery and further patient management.
A drenocortical carcinoma (ACC) is a rare, aggressive tumor aris- ing from the adrenal cortex that typically presents late with a large mass. The increased use of cross-sec- tional imaging for unrelated reasons has led to a greater number of ACCs being detected incidentally at an earlier stage. Recognition of the typical clinical, biochemical, and im- aging findings is imperative for rapid diagno- sis, prompt intervention, and early use of the appropriate therapy. Cross-sectional imag- ing with CT and MRI is essential for deter- mining the extent of local and distant tumor spread. Complete surgical resection is cur- rently the only potentially curative treatment of ACC, and the information attained from CT and MRI is important to guide surgery and further patient treatment.
Epidemiology
ACCs account for only 0.05-0.2% of all cancers [1, 2] or 1-2 patients per 1 million population per year [3]. The age distribution of the affected population is bimodal, with an increased incidence in infants and chil- dren younger than 5 years old and in indi- viduals in their fourth and fifth decades of life [4, 5]. A female preponderance has been noted [2, 3], and women are more likely than men to present with more well-differentiated tumors that tend to be functional [6].
Cause
Most ACCs are sporadic; however, they also can be associated with several complex genetic syndromes.
Li-Fraumeni Cancer Syndrome
Li-Fraumeni cancer syndrome results in a familial susceptibility to a variety of can- cers including adrenocortical tumors (car- cinomas, adenomas), sarcomas, leukemias, breast, brain, lung, and laryngeal cancers be- cause of a germline TP53 mutation.
Carney Complex
Carney complex consists of primary pig- mented nodular adrenal dysplasia, cardiac myxomas, cutaneous myxomas, testicular tumors, and other endocrine neoplasms.
Beckwith-Wiedemann Syndrome
Beckwith-Wiedemann syndrome is a con- genital disorder characterized by pre- and postnatal overgrowth, macroglossia, and an- terior abdominal wall defects (most com- monly exomphalos).
Familial Adenomatous Polyposis Coli
Familial adenomatous polyposis coli causes multiple adenomatous polyps and cancer of the colon and rectum, thyroid tumors, hepa- toblastoma, and adrenocortical tumors (car- cinomas, adenomas).
CT and MRI of Adrenocortical Carcinoma
Multiple Endocrine Neoplasia, Type 1
Multiple endocrine neoplasia, type 1, causes pituitary, parathyroid, and pancreatic tumors; adrenocortical adenomas or hyperplasia; and, very rarely, adrenocortical carcinomas.
Clinical and Biochemical Features
ACCs are functional in approximately 60% of cases [4, 5, 7, 8], more commonly in children (~ 85%) than in adults (15-30%) [4, 7]. Unlike adrenal adenomas that pre- dominantly secrete cortisol, ACCs secrete a variety of hormones including androgens, cortisol, estrogens, and aldosterone [1]. In adult patients with functioning tumors, 30% present with Cushing syndrome, 20% with virilization, and 10-20% with a combina- tion of the two [1, 8]. Feminization and hy- peraldosteronism are much rarer, each ac- counting for approximately 2% of ACC cases [8]. The rapid onset of Cushing syn- drome, often with virilizing features, is characteristic of ACC in adults [9]. Al- though benign adrenocortical tumors tend to secrete a single class of steroid, ACC can secrete various types; cosecretion of corti- sol with androgens is a frequent combina- tion and is highly suggestive of malignancy [3, 10-12]. In children, ACCs can present with virilization, Cushing syndrome, femi- nization, or Conn syndrome [1].
Approximately 65-85% of ACCs in adults are nonfunctioning, and patients present with a large mass and symptoms related to mass effect (e.g., abdominal or flank pain in 55%) [7] or with a palpable mass (40-50%) [1, 7]. Some ACCs are discovered inciden- tally (0-25%) when they tend to be smaller [2, 13]. Due to the late presentation of non- functioning tumors, a significant proportion (~ 30% of ACC cases) presents with meta- static disease to the regional and paraaortic lymph nodes, lung, liver, and bone [7, 12].
Pathologic Features
Separating benign from malignant adrenal cortical neoplasms is not always possible on the basis of histologic findings alone, partic- ularly from biopsy specimens [2, 14]; how- ever, there are macroscopic and microscopic criteria that favor malignancy [14-17].
Macroscopic Criteria
The macroscopic criteria that favor malig- nancy are tumor wet weight of greater than 500 g; a tumor with a grossly lobulated cut surface; and the presence of necrotic areas, calcification, or hemorrhage in the tumor.
Microscopic Criteria
The microscopic criteria that favor malig- nancy are architectural disarray, mitotic rate, marked nuclear pleomorphism, nuclear atyp- ia, hyperchromasia, capsular invasion, and venous or sinusoidal invasion. The mitotic rate is also important for predicting tumor aggressiveness.
Staging
The most widely used staging system for ACC was proposed by the American Joint Committee on Cancer and the International Union Against Cancer (UICC) and uses the TNM principle [18, 19] (Tables 1 and 2). This system is based largely on earlier clas- sification systems proposed by MacFarlane [20] and modified by Sullivan and colleagues [21]. In recent evaluations, authors have sug- gested that there are significant limitations in the prognostic accuracy of the UICC system [22, 23], and a new system, the European Network for the Study of Adrenal Tumors (ENSAT) classification, has been proposed [22]. According to the ENSAT system, stage III disease is defined as the presence of posi- tive lymph nodes, infiltration of the surround- ing tissues, or venous tumor thrombus, and stage IV disease is restricted to patients with distant metastases.
Imaging Appearances
The presence of metastatic disease is defini- tive of malignancy [24]. However, several im- aging features should increase the suspicion of
ACC within an adrenal mass [1, 25-27]: tumor size greater than 4 cm, irregular tumor mar- gins, central intratumoral necrosis or hemor- rhage, heterogeneous enhancement, invasion into adjacent structures, venous extension (renal vein or inferior vena cava [IVC]), and calcification. Using a logistic regression model, Hussain et al. [25] found tumor size of greater than 4 cm and heterogeneous en- hancement to be the most important discrim- inators of malignancy.
ACCs are usually large at presentation, ranging from 2 to 25 cm (average size, approx- imately 9 cm). Approximately 70% of ACCs are larger than 6 cm [24] (Figs. 1-3). They are bilateral in 2-10% of cases [2] and are slightly more common on the left than on the right [4].
Tumors are frequently hemorrhagic (Fig. 1) and necrotic [24, 28] (Fig. 2) and may con- tain small areas of intracytoplasmic lipid or fatty regions [29, 30] (Fig. 3). The existence of intracytoplasmic fat in ACCs has been at- tributed to the presence of cortisol and relat- ed fatty precursors in hormonally active tu- mors [30]. On occasion, pockets of fat may be seen within the mass, indicating coexis- tent myelolipomatous tissue.
IVC invasion has been reported in 9-19% of ACC cases at presentation [5] (Figs. 4 and 5).
CT
The typical appearance of ACC on unen- hanced CT is of a large, inhomogeneous but well-defined suprarenal mass that displaces adjacent structures as it grows [24]. Regions
| TNM Stage | Description |
|---|---|
| Primary tumor (T) | |
| Tx | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| T1 | ≤ 5 cm in greatest dimension, extraadrenal invasion absent |
| T2 | > 5 cm in greatest dimension, extraadrenal invasion absent |
| T3 | Tumor of any size with local invasion, but not invading adjacent organsª |
| T4 | Tumor of any size with invasion of adjacent organsª |
| Regional lymph nodesb (N) | |
| Nx | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph node metastasis |
| N1 | Positive regional lymph nodes |
| Distant metastases (M) | |
| M0 | No distant metastases |
| M1 | Distant metastases present |
aAdjacent organs include kidney, diaphragm, great vessels, pancreas, and liver. bThe regional lymph nodes are hilar, abdominal paraaortic, and paracaval nodes.
| Surgical Stage | Imaging Feature | Percentage at Presentation | 5-year Survival (%) |
|---|---|---|---|
| I | Tumor ≤ 5 cm without local invasion, nodal or distant metastases | 2.2-6.3 | 65 |
| II | Tumor > 5 cm without local invasion, nodal or distant metastases | 21.7-49.8 | 65 |
| III | Tumor with local invasion or positive lymph nodes | 17.9-22.5 | 40 |
| IV | Tumor with local invasion and positive lymph nodes or distant metastases | 21.3-34.7ª | 10 |
aPresence of metastases.
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of low attenuation correspond to necrosis pathologically (Fig. 2); in one reported se- ries, necrosis was invariably present when tumors reached 6 cm in size [24]. However, smaller lesions may be homogeneous on un- enhanced CT [31]. After the administration of IV contrast material, there is inhomoge- neous enhancement of the tumor, typically with greater enhancement seen peripherally and relatively little enhancement seen cen- trally, because of central necrosis [24, 32].
Measurement of the attenuation of adrenal lesions on unenhanced CT is of great value in distinguishing between benign and ma- lignant masses. Cumulative data obtained for the identification of adrenal adenomas indicate that ACCs rarely have an attenu- ation value of less than 10 HU. The speci- ficity of this threshold for the identification of benign adenomas is approximately 98% [33]. Equally, ACCs retain IV contrast ma- terial and have absolute and relative percent- age washout of less than 60% and less than 40%, respectively, at 15 minutes after con- trast administration [26, 34] or less than 50% and less than 40%, respectively, at 10 min- utes [34-36] (Fig. 6).
Calcification, either microcalcification or coarse calcification, is seen on CT in approxi- mately 30% of patients with ACC and is usu-
ally centrally located [24, 32] (Fig. 3). Cal- cification is rare in adenomas, although it is present in approximately 10% of pheochro- mocytomas [37].
Tumor thrombus extending into the IVC at presentation is not rare [28] and is more fre- quently seen in right-sided tumors. A tumor thrombus within a vein is usually well encap- sulated and can often be withdrawn intact from
the vein [38]. The presence and cephalad ex- tent of tumor thrombus can be identified on contrast-enhanced CT or MRI (Fig. 4 and 5).
CT is also of value in showing the local and distant spread of an ACC. Preservation of fat planes around the tumor indicates that there is no local invasion. Where there is a paucity of retroperitoneal fat, it may be im- possible to determine whether tumor has in- vaded adjacent organs.
Metastases are frequently found at presen- tation: Regional and paraaortic lymph nodes (25-46%), lungs (45-97%), liver (48-96%), and bone (11-33%) are the common sites [1, 5, 28]. Hepatic metastases tend to be hyper- vascular and are best seen on arterial phase imaging after IV contrast administration.
MRI
ACC is typically heterogeneous in signal intensity on MRI because of the presence of hemorrhage and/or necrosis [30]. On T1- weighted imaging, ACC is typically isoin- tense or slightly hypointense to normal liver parenchyma. However, high T1 signal inten- sity is often seen because of the presence of hemorrhage (Fig. 1). On T2-weighted imag-
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ing, ACC is usually hyperintense to liver pa- renchyma and has a heterogeneous texture because of the presence of intratumoral cys- tic regions and hemorrhage [39] (Fig. 2).
A functioning ACC can contain small re- gions of intracytoplasmic lipid resulting in small nonuniform areas of loss of signal on chemical shift imaging (< 30% of the lesion) [26, 29, 30] (Fig. 7). Although similar small nonuniform loss can occur in lipid-poor ad- enomas, the significant uniform signal loss seen in lipid-rich adenomas does not occur.
Schlund et al. [30] described the presence of peripheral mural-based enhancing nod- ules in seven of eight ACCs reviewed. This feature has not been described elsewhere in the medical literature.
Enhancement after the administration of IV contrast material is generally avid with slow washout [3].
MRI has been shown to be superior to CT in the delineation of the presence and extent of IVC invasion [40, 41] (Fig. 5).
The results of early studies suggested that proton MR spectroscopy may be useful in differentiating adrenal adenomas and pheo- chromocytomas from adrenal metastases and ACC [42]. Faria et al. [42] looked at the spec- tral traces obtained from 60 patients with ad- renal masses. Adenomas and pheochromo- cytomas could be differentiated from ACCs and metastases using choline-creatine ratios of greater than 1.20 (92% sensitivity and 96% specificity) and choline-lipid ratios of great-
er than 0.38 (92% sensitivity and 90% speci- ficity). ACCs and pheochromocytomas could be differentiated from adenomas and metasta- ses using a 4.0-4.3 ppm/creatine ratio greater than 1.50 (87% sensitivity and 98% specific- ity). By combining these two spectral analy- ses, they were able to divide adrenal mass lesions into one of four distinct groups: adeno- ma, pheochromocytoma, ACC, or metastasis [42]. Although some criticisms of this study have been raised, the technique appears to of- fer potential in helping to distinguish among adrenal mass lesions [43].
Functional Imaging
FDG PET can identify some malignant adre- nal masses by virtue of their increased metabol- ic activity; however, when FDG uptake is only modest, the likelihood of benign versus malig- nant is about equal [44]. FDG PET combined with contrast-enhanced CT has a sensitivity of 100% and specificity of 87-97% for identify- ing malignant adrenal masses. The lower speci- ficity is because a small number of adenomas and other benign lesions mimic malignancy [45, 46]. The novel PET tracer 11C metomidate, a marker of 11ß-hydroxylase, is used as tracer for adrenocortical tissue and is taken up by ad- enomas and ACCs. This marker differentiates adrenal cortical lesions from pheochromocyto- mas and metastases, which are uptake-negative [47]. However, the most valuable aspect of PET is its ability to detect distant metastases (Fig. 8); it is important to remember that one third of pa-
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tients with ACC will have metastatic disease at presentation [7, 12, 48].
Differential Diagnosis and Distinguishing Features
Adenoma
Adenomas may be diagnosed with a sensi- tivity of 75-98% and specificity of 92-100% using CT washout characteristics [49] and chemical shift imaging [50]. However, in some cases, it can be difficult to distinguish benign from malignant lesions. If they measure 3-4 cm in diameter, the pathologic label of “in- determinate malignant potential” is often ap- plied, and if they are larger than 4 cm, they are generally managed as malignant lesions.
Pheochromocytoma
Pheochromocytomas may be benign or malignant. Small pheochromocytomas are usually homogeneous in appearance with a density of 40-50 HU on unenhanced CT [26], whereas larger pheochromocytomas can be inhomogeneous with areas of hemor- rhage and necrosis [51] (Fig. 9A). There is no correlation between tumor size and ma- lignancy [52]. On MRI, pheochromocyto- mas are typically described as isointense or hyperintense to liver on T1 and hyperintense to fat on T2 [51]. However, appearances can be variable. For example, Jacques et al. [52] reported in 2008 that only 11% of pheochro- mocytomas showed “typical” T2 hyperinten- sity and that pheochromocytomas that were only mildly hyperintense to the spleen (34%) or that were heterogeneous on T2 (39%) were more common. Increasing heterogeneity was
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seen to correlate with increasing amounts of hemorrhage, necrosis, and fibrosis.
After IV contrast administration, pheochro- mocytomas enhance avidly and have a pro- longed washout phase, although exceptions do exist [53]. Ninety-one percent of pheochromo- cytomas are functioning and biochemical mark- ers are important in establishing the diagno- sis [54]. Nonfunctioning pheochromocytomas (9%) pose more of a diagnostic dilemma; al- though many will be differentiated from ACC using 123I-metaiodobenzylguanidine (MIBG) scintigraphy, some nonfunctioning pheochro- mocytomas will not be MIBG-avid [54].
Dominantly inherited succinate dehydro- genase (SDH) gene mutations account for most familial paraganglioma syndromes in which patients have an increased incidence of adrenal and extraadrenal paragangliomas. In patients with SDH-B gene mutations,
there is an increased risk of malignancy, which is reported as between 34% and 97%, and paragangliomas usually show intense uptake on FDG PET [55, 56].
Lymphoma
The primary pathologic type that involves the adrenal glands is non-Hodgkin diffuse large B- cell lymphoma [57, 58]. Disease is usually bilat- eral with enlarged adrenal glands [57, 58] that maintain their normal “adeniform” shape.
Metastases
Adrenal metastases are found in up to 27% of patients with malignant epithelial tumors at autopsy [59]. This diagnosis should be consid- ered when bilateral adrenal lesions are present and there is a known primary malignancy else- where or there is evidence of other metastases. The most common primary site is the lung.
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Composite or Collision Tumors
Composite or collision tumors are rare tu- mors that consist of two contiguous but his- tologically different tissues within a single mass [60]. A collision tumor is composed of independently coexisting neoplasms without significant tissue admixture, whereas a com- posite tumor contains coexisting neoplasms with considerable admixture of the two dif- ferent cell types such as a ganglioneuroma and pheochromocytoma (Fig. 9B) or myelo- lipoma and Cushing adenoma.
Ganglioneuroma
Ganglioneuromas are benign neoplasms arising from the sympathetic ganglia. Gen- erally, they are large solid lesions on CT with homogeneous to mildly heterogeneous
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enhancement after IV contrast administra- tion (Fig. 9C). On MRI they are typically hypointense on T1 and heterogeneously hy- perintense on T2 depending on the content of their myxoid stroma [61, 62].
Infection
The imaging appearances of infection within the adrenal gland are generally non- specific and can be seen as soft-tissue masses and cystic changes with or without calcifica- tion. Tuberculosis and histoplasmosis tend to be bilateral but can be asymmetric and give the appearance of unilateral disease [63].
Neuroblastoma
Neuroblastomas occur most frequently in children and are rare in the adult population. Calcification is a hallmark of neuroblasto- ma in children but is rarely seen in adults. Adults with neuroblastoma tend to show a higher rate of metastatic disease at presenta- tion than children do [64, 65].
Adrenal Hemangioma
Adrenal hemangiomas are well-defined soft-tissue masses with inhomogeneous en- hancement after contrast administration. They are often calcified because of either in- tratumoral phleboliths or previous hemor- rhage. On MRI, adrenal hemangiomas are typically hypointense to liver on T1 and may exhibit central hyperintensity due to hem- orrhage. On T2, lesions are hyperintense. Foci of low signal intensity on T1 and T2 are caused by calcification. Characteristically, they show persistent peripheral enhancement on delayed imaging [66, 67].
All the diagnoses discussed can present a diagnostic challenge in trying to differenti- ate them from an ACC. In practice, however, it is most frequently adenomas that can pres- ent the greatest difficulty, partly because of the frequency with which they occur. Indeed, on occasion, pathologists also find it difficult to make this distinction [2, 14, 15]. Thus, al- though most benign cortical adenomas can now be confidently diagnosed on the basis of the criteria mentioned, some lesions remain indeterminate. When biochemical testing shows these lesions to be functioning, most endocrinologists would advocate removal of the mass. Surgery may also be indicated if doubt exists about the true nature of a non- functioning lesion.
A detailed clinical history and biochemi- cal testing can often distinguish between a pheochromocytoma and an ACC without the need for diagnostic imaging tests, although imaging is still often required for surgical planning. The distinction between large non- functioning pheochromocytomas and ACCs can be problematic, particularly when the le- sion is not 123I-MIBG-avid. Once again, sur- gery is sometimes required to resolve the di- agnostic dilemma.
Treatment Planning Role of Biopsy
There is controversy concerning the role of biopsy in indeterminate adrenal lesions. On one hand, percutaneous biopsies of sus- pected ACC may not be justified in light of the risks of inducing tumor capsule break- down and tumor spread along the needle track [68]. The difficulty arises with suspect- ed adrenocortical lesions that are borderline in size (3-4 cm) in patients at high surgical risk. In some of these cases, biopsy may be justified, but decisions need to be made for each patient individually.
Surgery
The definitive treatment of all stages of ACC is en bloc resection of the tumor with or without adjacent invaded organs. If en bloc re- section is not possible because of local exten- sion into adjacent structures, maximal tumor debulking surgery is indicated. This surgery decreases the amount of hormone-secreting tissue present and also reduces complications due to mass effect.
IVC invasion is not rare, and surgery is performed even when tumor extends the en- tire length of the IVC and into the right atri- um; cardiac bypass techniques may be used
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in these cases. Delineation of IV tumor is par- amount in surgical planning because venous control must be established distal to the tumor thrombus and may require bypass procedures for venotomy or tumor thrombectomy.
Surgery can be open or laparoscopic for small tumors without local invasion or tumor thrombus depending on the tumor extent and the expertise of the local surgical team [69]. However, open adrenalectomy is currently the preferred option because of the high rate of re- currence and peritoneal carcinomatosis asso- ciated with laparoscopic procedures [70, 71].
There are no published guidelines regard- ing postsurgical imaging follow-up of patients with ACC. At our institution, the interval and modality are decided on an individual patient basis and include CT, MRI, and PET/CT.
More recently, less invasive techniques have been introduced whereby both adreno- cortical tumors and adrenal metastases have been treated successfully by radiofrequency ablation [72].
Chemotherapy
Treatment with the adrenolytic drug mito- tane may improve survival or at least control symptoms [3, 7, 12] and is used in both pri- mary and adjuvant therapy. It also plays a role in metastatic and recurrent disease. There is currently no agreement about the possible role of other forms of cytotoxic chemotherapy, but large-scale trials are under way to assess dif- ferent chemotherapeutic regimens.
Radiotherapy
Radiotherapy is indicated in patients with a high risk for local recurrence including those with advanced locoregional disease and incomplete or indeterminate resection; radiotherapy may be helpful in treating the symptoms from bone metastases [73].
Prognosis
Patients with unresectable stage IV ACC have a median survival of 3 months [20]. When treated aggressively with surgery, pa- tients with stage I and II tumors have an ap- proximately 65% 5-year survival, whereas patients with stage III and IV disease have 40% and 10% 5-year survival, respectively [74]. The overall 5-year survival rate for all patients with ACC is 38% [8, 75].
Recurrence (Fig. 10) and metastatic dis- ease (Figs. 4 and 8) are common in patients with ACC. Of the patients undergoing appar- ent complete resection, 35-85% will develop recurrent or metastatic disease [5, 76].
Conclusions
The imaging appearances of ACC are di- verse because of the variable presence of ne- crosis, hemorrhage, calcification, and intra- cellular lipid content. As illustrated, other diseases can simulate ACC, and familiarity with both typical and atypical appearances on cross-sectional imaging taken in conjunction with clinical information helps to suggest the accurate diagnosis and appropriate treatment.
Imaging is also used to plan the extent of and surgical approach for ACC resection.
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