INTERNATIONAL JOURNAL OF UROLOGY
Review Article
Clinical and imaging overview of functional adrenal neoplasms
Gavin Low and Kamal Sahi
Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, Edmonton, Alberta, Canada
Abbreviations & Acronyms
17OH = 17-hydroxy 18FDG-PET = 18F-2-fluoro-2-deoxy- D-glucose positron emission tomography ACC = adrenocortical carcinoma ACTH = adrenocorticotropic hormone APW = absolute percentage washout
CA = celiac axis CT = computed tomography DHEA = dihydroepiandrosterone ENST = European Network for the Study of Adrenal Tumors HU = Hounsfield Units I-MIBG = I-metaiodobenzylguanidine INSS = International Neuroblastoma Staging System IVC = inferior vena cava MEN 1 = multiple endocrine neoplasia type 1 MRI = magnetic resonance imaging
MYCN = v-myc myelocytomatosis viral-related oncogene, neuroblastoma derived (avian) NF 1 = neurofibromatosis type 1 RPW = relative percentage washout SDH = succinate dehydrogenase SDHB = succinate dehydrogenase complex, subunit B, iron sulfur (Ip) SDHD = succinate dehydrogenase complex, subunit D, integral membrane protein SI = signal intensity UICC = Union Internationale contre le Cancer VHL = von Hippel Lindau VIP = vasoactive intestinal peptide
Correspondence: Gavin Low M.B.Ch.B., M.R.C.S., F.R.C.R., Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, 2A2.41 WMC, 8440-112 Street, Edmonton, Alberta T6G 2B7, Canada. Email: timgy@yahoo.com
Received 28 December 2011; accepted 6 March 2012.
Abstract: Adrenal adenoma, adrenocortical carcinoma, pheochromocytoma and neuroblastoma are four discrete adrenal neoplasms that have the potential for func- tional activity. Functional adrenal neoplasms can secrete cortisol, aldosterone, sex hor- mones or catecholamines. These heterogeneous groups of tumors show varied biological behavior and clinical outcomes. These neoplasms are encountered with increasing clinical frequency as a result of an expansion in the volume of medical imaging carried out. The clinical presentation, including prognosis and treatment options, and the imaging features of these neoplasms are discussed. The key radiological observa- tions of each of these neoplasms are shown using multimodality images. Familiarity with the clinical and imaging features of these neoplasms improves diagnosis, and facilitates appropriate clinical decision-making and patient management.
Key words: adrenal gland neoplasms, hormones, magnetic resonance imaging, multidetector computed tomography, positron emission tomography.
Introduction
The adrenal glands are responsible for the synthesis and secretion of a variety of physi- ological hormones. The adrenal cortex (comprising 90% of the adrenal gland) has three distinct layers - the zona glomerulosa produces aldosterone, the zona fasciculata produces cortisol and the zona reticularis produces sex hormones DHEA and androstenedione. The adrenal medulla (comprising 10% of the adrenal gland) produces catecholamines: epineph- rine and norepinephrine. Neoplasms that originate from the adrenal cortex or adrenal medulla possess the potential for metabolic activity and autonomous hormone secretion. The functional status of these adrenal neoplasms is determined by biochemical evaluation (Table 1).1 Functional adrenal neoplasms include adrenal adenomas, adrenocortical carci- nomas, pheochromocytomas and neuroblastomas. These are a diverse collection of neo- plasms with varied clinical and imaging findings, prognosis, and treatment options. These neoplasms are encountered with increasing clinical frequency given the escalating use of cross-sectional imaging. An incidental adrenal mass is detected in approximately 4-6% of CT examinations.2 Therefore, a clinical understanding of adrenal neoplasms is essential. In the present review, we discuss these functional adrenal neoplasms with particular attention devoted to their clinical findings and imaging features.
Search strategy
An electronic database search was carried out on PUBMED using the following keywords: “adrenal adenoma”, “adrenocortical carcinoma”, “adrenal cortical carcinoma”, “pheochro- mocytoma” and “neuroblastoma”. Articles were selected on the basis of the abstracts, before examining the full text. Only articles in English were included. The reviewers were not blinded to the journals, authors or institutions. The electronic search was last updated on 14 February 2012.
Adrenal adenoma
Adrenal adenomas are benign adrenal cortical neoplasms representing 50-80% of all adrenal neoplasms.2 An age- related incidence is recognized with adenomas found on CT in 0.2% of patients aged 20-29 years and 7-10% of elderly patients.2,3 Autopsy prevalence is 9%.4 Approximately 70-90% of adenomas are non-functioning, 6% are overtly functioning (5% cortical secreting, 1% aldosterone or sex- hormone secreting) and the rest show subclinical hormone dysfunction.2,5
Clinical findings
Non-functioning adenomas are clinically silent. Functioning adenomas are symptomatic as a result of excess secretion of cortisol, aldosterone or sex hormones. Cortisol is the most common hormone produced, leading to Cushing’s syn- drome or subclinical Cushing’s syndrome. Features of Cushing’s syndrome include truncal obesity, facial round- ing, muscle wasting, diabetes, hypertension, osteoporosis and neuropsychiatric disorders. Aldosterone secretion leading to Conn’s syndrome is the most frequent cause of primary aldosteronism (80%).6 Clinical findings include hypertension, hypokalemia, hypernatremia, metabolic alka- losis, muscle cramps, headaches and polyuria. Androgen secretion causes female virilization with hirsutism, acne, male pattern baldness, deepened voice, breast atrophy and oligomenorrhoea. Estrogen secretion causes male feminiza- tion with gynecomastia, testicular atrophy and low libido.
Adenomas have an excellent prognosis because of their benign nature. In general, small non-functioning adenomas can be managed conservatively. Imaging follow up at 6 months and 12 months can be carried out if clinically appropriate to confirm interval stability and for reassurance that the working diagnosis is correct. Imaging surveillance beyond this period is not required for stable lesions. Large (>4 cm) non-functioning adrenal lesions (presumed to be adenomas) should be considered for surgical resection. The rationale for this is twofold. First, adenomas rarely present with a large size, whereas the risk of malignancy is higher (up to 70%) in adrenal lesions >4 cm.2 Thus, it is difficult to be completely confident of the diagnosis of a large adenoma based on imaging findings alone. Second, large adrenal lesions (irrespective of whether these are benign or malig- nant) are far more likely to be symptomatic and therefore surgery is generally an appropriate option. With advances in surgical techniques, even large adrenal masses can be treated successfully by minimally invasive procedures, such as laparoscopic adrenalectomy.7 In contrast to non- functioning adenomas, functioning adenomas as a whole are generally treated by surgical resection, with laparoscopic adrenalectomy the procedure of choice. Furthermore, bilat- eral functioning adenomas should be separately considered
| Hormones | Biochemical tests |
|---|---|
| Cortisol (minimum of 3 of 4 tests) | Dexamethasone suppression |
| test, 1 mg | |
| 24 h urinary free cortisol | |
| Basal cortisol | |
| Basal ACTH (plasma) | |
| Aldosterone | Aldosterone/renin ratio |
| Serum potassium | |
| Sex steroids and | Serum DHEA |
| steroid precursors | Serum 17OH-progesterone |
| Serum testosterone | |
| Serum 17ß-estradiol | |
| Catecholamines | |
| Pheochromocytoma | 24 h urinary fractionated |
| metanephrines | |
| Plasma fractionated | |
| metanephrines | |
| Neuroblastoma | Urinary metabolites (homovanillic |
| acid, vanillylmandelic acid, | |
| dopamine) |
for adrenal-sparing laparoscopic bilateral partial adrenalec- tomy rather than bilateral total adrenalectomy.7 Preservation of normal adrenal tissue is essential for preventing adreno- cortical insufficiency and the requirement for life-long medical treatment with glucocorticoid and mineralocorti- coid replacement.
Imaging findings
Adenomas are typically well-circumscribed ovoid shaped neoplasms.2 Most measure 1-3 cm (Cushing’s adenomas are generally >2 cm and Conn’s adenomas generally <2 cm, with 20% <1 cm).6 A Cushing’s adenoma might cause con- tralateral adrenal atrophy as a result of ACTH suppression.8 A homogeneous CT attenuation is characteristic (87% homogeneous precontrast, 58% homogeneous postcon- trast).8 As adenomas are benign, no significant size change is seen on 6-monthly interval imaging. In contrast, adrenal malignancies show significant growth on interval imaging. Rarely, adenomas can show larger size (4-6 cm), irregular margins and heterogeneous attenuation as a result of hem- orrhage or cystic change.8 These features can overlap with other adrenal neoplasms, including malignancies. Approxi- mately 10-20% of adenomas are bilateral.9
Adenomas can be categorized as lipid rich (70%) or lipid poor (30%), depending on the intracellular fat content. Lipid-rich adenomas have a low attenuation on unenhanced CT (Fig. 1a,b). In a pooled analysis of 10 studies, Boland
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# Pix 1653
Perim 70.4 mm
Area 387.9 mm2
Avg 0.151 HU
Dev 20.49
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et al.10 found that a threshold of 10 HU had a sensitivity and specificity of 71% and 98% in diagnosing adenomas. This 10 HU threshold is now widely used for differentiating lipid-rich adenomas from other adrenal neoplasms. Chemi- cal shift imaging is a lipid sensitive MRI technique that exploits the differences in resonant frequencies of fat and water in tissues. On chemical shift imaging, lipid-rich adenomas show signal loss on opposed-phase images as a result of signal cancellation of fat and water (Fig. 1c,d). The adrenal SI index, ([SIIn Phase - SIOpposed Phase]/SIIn Phase) × 100%, is used to calculate the degree of signal loss.2 A measure- ment of ≥16.5% is considered diagnostic for an adenoma. Alternatively, the adrenal-to-spleen chemical shift ratio might be calculated instead, with a value of <0.71 indicative of a lipid-rich adenoma.2 This is carried out by dividing the lesion-to-spleen signal intensity ratio on the in-phase images by the lesion-to-spleen signal intensity ratio on the opposed-phase images. Chemical shift imaging has a sensitivity and specificity of 81-100%, and 94-100% in diagnosing adenomas.2 Chemical shift MRI and unen- hanced CT perform comparably for diagnosing lipid-rich adenomas, but chemical shift MRI might be superior for lipid poor adenomas with attenuations between 10-30 HU.11-13
Adenomas (regardless of lipid status) show characteristic rapid contrast washout, a differentiating feature from adrenal malignancies. The adrenal CT washout (Fig. 2) is calculated using the following equations:14
RPW =([enhanced HU 60 s - delayed HU 15 min ]/ enhanced HU60s)×100
APW = ([enhanced HU 60 s-delayed HU 15 min ] / [enhanced HU60 s - unenhanced HU])×100
An APW >60% or RPW >40% has a sensitivity and specificity close to 100% in diagnosing adrenal adeno- mas.2,9,13,14 In contrast, an APW <60% or RPW <40% is almost always associated with malignancy. CT washout studies are recognized clinically as the most accurate imaging method for diagnosing adenomas.
ACC
ACC is a rare malignant neoplasm of the adrenal cortex. It has an incidence of 1-2 cases per million annually and accounts for 0.2% of all cancer deaths.15,16 A bimodal distribution is reported with a primary peak in the fourth and fifth decades of
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# Pix 490.1 Perim 51.7 mm Area 212.3 mm2 Avg -1.563 HU Dev 11.47
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# Pix 530.9
Perim 53.8 mm Area 230.0 mm2 Avg 78.11 HU Dev 16.46
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Perim 49.6 mm Area 196.0 mm2 Avg 18.39 HU Dev 11.22
life, and a secondary peak in children <5 years-of-age.16,17 A female preponderance exists with a female to male ratio of 1.5:1.15,16 Most ACC are sporadic, although associations exist with Li-Fraumeni syndrome, Beckwith-Wiedemann syn- drome, Carney syndrome and MEN 1.15,18,19 Smoking and oral contraceptives are risk factors.20
Clinical findings
Approximately 60% of ACC are functional and 40% are non-functional.19,21,22 Functional ACC might secrete single or multiple hormones. Cortisol is the most common hormone produced and causes Cushing’s disease in 30-40%.19,23 Androgen secretion occurs in 20% and is cose- creted with cortisol in 25%.19,23 Androgens cause virilization in females and estrogens cause feminization in males.19,23 Aldosterone secretion causes Conn’s syndrome in 2%.19,23 A total of 90% of childhood ACC are functional, and most secrete androgens leading to virilization and precocious puberty.24 Non-functional ACC generally present late with symptoms of mass effect (e.g. vomiting, early satiety, abdominal distension, weight loss). Presenting symptoms can occasionally be a consequence of metastatic involve- ment.25 The mean time from onset of symptoms to diagnosis is 6-14 months.17
Various staging systems have been developed, such as the Macfarlane classification (1958),26 its modification by Sul- livan (1978),27 the UICC (2004)28 and the ENST (2008).29 The UICC and ENST classifications are as follows:
| Stage I | T1 (<5 cm), N0, M0 |
| Stage II | T2 (>5 cm), N0, M0 |
| Stage III | |
| UICC | T1-2, N1, M0 |
| T3, N0, M0, | |
| ENST | T1-2, N1, M0 |
| T3-4, N0-1, M0 | |
| Stage IV UICC | |
| T1-4, N0-1, M1 | |
| T3, N1, M0 | |
| T4, N0-1, M0 | |
| ENST | T1-4, N0-1, M1 |
Advanced disease is found in 70% of patients at presen- tation.19 At diagnosis, stages I and II account for 32% of cases, and stages III and IV account for 68% of cases.19
Fig. 3 ACC. (a) Coronal postcontrast CT image shows a large heterogeneously enhancing right ACC (arrow) with internal foci of mixed attenuation. The tumor causes extrinsic compression on the adjacent IVC, which is narrowed. (b) Coronal T2-weighted MRI shows heterogeneous intermediate- to high- signal intensity in the ACC. (c) Coronal 18FDG-PET-CT fusion image shows high uptake in the ACC.
Overall 5-year survival rates for ACC range from 35-58%.19,30,31 In a European study of 478 patients, the survival rates were 47% after 5 years and 41% after 10 years (5-year survival per stage: stage I 84%, stage II 63%, stage III 51% and stage IV 15%).32
Surgery is the only definitive treatment. The 5-year sur- vival in surgical patients is 32-48%, with a median survival of 2 years for patients who undergo complete resection as opposed to <1 year for patients with incom- plete resection.19,31-35 Postsurgical recurrence is high at 60-80%.19,32 Open surgery is favored over laparoscopic adrenalectomy, as the latter has a higher risk for incomplete resection and peritoneal tumor spillage. Combined thoraco- abdominal surgery is necessary for vascular extension into the right atrium.
There are several medical options for ACC. Introduced in the 1960s, mitotane (a synthetic derivative of the insec- ticide dichlorodiphenyltrichloroethane) is an adrenal spe- cific agent that induces cytotoxic adrenocortical necrosis.17 A 2005, a meta-analysis found that mitotane treatment for advanced disease induced tumor regression in 25% of patients.36 Limitations of mitotane include a narrow thera- peutic window requiring high serum levels and dose- limiting adverse effects (mainly gastrointestinal and central nervous system related). Mitotane combined with cyto- toxic chemotherapy is a further option in advanced disease. A 2005 phase II study found that mitotane combined with etoposide, doxorubicin and cisplatin resulted in disease stabilization in 28%, treatment response in 49% and com- plete clinical response in 7% of patients.37 Adrenostatic drugs, such as mitotane, metyrapone, ketoconazole and etomidate, can be used to treat symptoms of endocrine excess.19
Imaging findings
ACC are typically large at presentation (92% >6 cm, median size 11-12 cm, range 2-40 cm).22,38 As the risk of malig- nancy is related to size, the National Institute of Health recommends surgical excision for adrenal lesions >6 cm.39 Most ACC are inhomogeneous on imaging, with ill-defined margins and heterogeneous enhancement (Fig. 3a,b).25 Necrosis and hemorrhage are common, and calcifications are found in 30%.25 The left adrenal is more commonly
(a)
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involved than the right, whereas bilateral disease occurs in 2-10%.25,40 ACC typically show >10 HU on unenhanced CT, and generally exhibit slow contrast washout (APW <60% and RPW <40%).41 On MRI, ACC are hypointense on T1- and heterogeneously hyperintense on T2-weigthed images (Fig. 3b). Hemorrhage might appear as a high signal on T1 as a result of methemoglobin. Some functional ACC contain intracellular fat and show signal loss on chemical shift MRI.25,42 MRI has 81-89% sensitivity and 92-99% speci- ficity in differentiating benign from malignant adrenal neoplasms.41
Metastases from ACC generally affect the lungs, liver, lymph nodes and bones (in decreasing order). Vascular invasion can involve the renal vein with extension into the IVC and the right atrium. IVC involvement is seen in 9-19% of patients, and is more frequent with right-sided ACC.25,43 MRI is preferred to CT for vascular assessment, as it has superior soft tissue resolution. 18FDG-PET is a functional imaging modality used for detecting metaboli- cally active neoplasms. When combined with CT, 18FDG PET-CT has a 100% sensitivity and 87-97% specificity in differentiating malignant from benign adrenal neoplasms.25 A study of 77 surgical patients found that 18FDG-PET com- bined with CT had 100% sensitivity and 88% specificity in differentiating ACC from adenomas (Fig. 3c).44 A new radiotracer, metomidate, shows exclusive uptake in adrenocortical neoplasms, such as adenomas and ACC. It has been introduced clinically for PET (“C-metomidate PET) and single photon emission computed tomography imaging (123I iodometomidate).25,41,45,46
Pheochromocytoma
Discovered by Frankel in 1886,47 pheochromocytomas are neuroendocrine neoplasms of chromaffin tissue of the adrenal medulla.48 Furthermore, extra-adrenal neoplasms of chromaffin tissue of the sympathetic paraganglia might be referred to as extra-adrenal pheochromocytomas.48 In 2004, the WHO defined the term “paraganglioma” to include both sympathetic and parasympathetic neoplasms of the extra-adrenal paraganglia.49 Research at the Mayo Clinic from 1950-1979 suggests that pheochromocytomas have an incidence of 0.8 per 100 000 persons annually.5º A prevalence of one in 200 is reported in postmortem stud- ies.48,51,52 Prevalence in hypertensive patients is 0.1- 0.6%.48,53,54 A total of 25% of pheochromocytomas are incidentally discovered on imaging and account for 5% of all adrenal incidentelomas.48,55,56
Pheochromocytomas have become synonymous with the “the 10% rule” since its proposal by Bravo and Gifford in 1984.57 This rule suggests that 10% of pheochromocytomas are familial, 10% are malignant, 10% are bilateral, 10% are extra-adrenal and 10% occur in normotensive patients.57,58 Genetic discoveries have challenged the validity of this
concept.58-61 In 2000, SDH mutations were discovered to be responsible for hereditary pheochromocytoma/ paraganglioma syndromes.59,62-64 SDHB mutations predis- pose to extra-adrenal pheochromocytomas and a 50% risk of malignancy, whereas SDHD mutations predispose to multifocal head and neck paragangliomas, and pheochromocytomas.59,62-64 Other familial causes of pheo- chromocytomas include MEN 2 (RET gene), VHL disease (VHL gene) and NF 1 [NF1 gene]. Pheochromocytomas are found in 30-50% of MEN 2, 15-20% of VHL and 1-5% of NF 1 patients.65 A total of 50-80% of pheochromocytomas in MEN 2 and 40-80% in VHL are bilateral.65 In contrast, bilateral pheochromocytomas are found in 10% of sporadic cases. New knowledge suggests that 15-25% of apparently sporadic pheochromocytomas harbor mutations in the RET, VHL, NF1, SDHB and SDHD genes.48,59,60
Sporadic pheochromocytomas are most frequent in the fourth and fifth decades of life.48,66 Familial pheochromocy- tomas are commonly diagnosed before 40 years-of-age.48,66 A total of 10-20% of pheochromocytomas occur in chil- dren.67,68 A mild female preponderance in adults and a mild male preponderance in children is reported.48,66-69 Childhood pheochromocytomas are commonly familial (<70%), multi- focal and extra-adrenal.66,67,70 A total of 30-43% of childhood pheochromocytomas and 15-18% of adult pheochromocyto- mas are extra-adrenal.66,70 Metastatic involvement (most commonly to the bones, lymph nodes, lungs and liver) is the only reliable criterion of malignancy in pheochromocytomas, as pathological analysis is non-discriminatory. Malignancy is found in 2-11% of sporadic pheochromocytomas, and 26-35% of familial pheochromocytomas in adults and 12% in children.66,67,70 Approximately 20-50% of extra-adrenal pheochromocytomas are malignant.66,71,72
Clinical findings
Most pheochromocytomas are hormonally active, and secrete catecholamines: epinephrine and norepinephrine.65 Very rarely other hormones are produced, such as dopa, dopamine, VIP, parathyroid hormone-related peptide, sero- tonin, gastrin, atrial natriuretic factor, somatostatin, growth hormone-releasing factor and ACTH.61 The clinical triad of catecholamine excess in pheochromocytoma involves head- aches (60-90%), palpitations (50-70%) and diaphoresis (55-75%).48,65,73 This was reported to have 90.9% sensitivity and 93.8% specificity in diagnosing pheochromocytomas in hypertensive patients.65 However, studies suggest that this triad is only found in 15-24% of cases.73-76 Hypertension classically quoted at 90%, was found in just 60-70% of patients in recent studies.73-76 Hypertension is sustained in 50-60%, paroxysmal in 30% and 10-50% have orthostatic hypotension.48 Other findings include pallor, tiredness, nausea, weight loss, psychological symptoms and flushing.48
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Surgery is the mainstay of treatment, with 5-year sur- vival rates of 95% for benign pheochromocytomas and 50% for malignant pheochromocytomas.73,77,78 Even when pheochromocytomas are benign, hypertension persists in 50% after surgery and 16% develop recurrence within 10 years.79 Preoperatively, patients undergo pharmaco- logical intervention (alpha and beta adrenergic blockade ± calcium channel blockers) and intravenous hydration to prevent hypertensive crises that might be trig- gered by anesthesia or surgery. Laparoscopic surgery is favored for benign pheochromocytomas as this reduces post-operative morbidity. Open surgery is more suitable for malignant pheochromocytomas, as extensive resection might be required. Patients with multifocal or bilateral pheochromocytomas (e.g. MEN 2 and VHL) should receive cortex-preserving surgery to limit tissue loss and prevent glucocorticoid deficiency.
Several medical therapies are available for non-curative malignant disease. 131I-MIBG therapy leads to tumor response in 30%, disease stabilization in 57%, progression in 13% and catecholamine reduction in 45% of patients.80 Combination chemotherapy with cyclophosphamide, vinc- ristine and dacarbazine provides short-term tumor response and symptom improvement in 65%.80 External beam radia- tion is used to treat bony metastases.
Imaging findings
Pheochromocytomas have variable imaging appearances. A study of 44 pheochromocytomas suggested a mean size of 5.5 cm, with a size range of 1.2-15 cm.81 Functional pheo- chromocytomas are generally smaller than non-functional pheochromocytomas.82 Smaller pheochromocytomas are commonly homogeneous, and larger pheochromocytomas are heterogeneous in appearance.81 On MRI, pheochro- mocytomas are classically described as showing low-signal intensity on T1- and high-signal intensity equivalent to cere- brospinal fluid on T2- weighted images - “light bulb” bright (Fig. 4a,b). This classical appearance is found in 34% of cases.81 Overall, 65% of pheochromocytomas show interme- diate or high-signal intensity on T2-weighted images. In contrast, 35% of pheochromocytomas show low-signal intensity on T2 weighted images.83 Liquefactive necrosis and hemorrhage might be found in larger neoplasms. Pheo- chromocytomas with abundant liquefactive necrosis might appear cystic.84 Hemorrhage in a pheochromocytoma is visualized as high T1 signal intensity on MRI. Calcifications are reported in 10-20% of pheochromocytomas. Rarely, pheochromocytomas contain fat and can be misdiagnosed as adenomas showing <10 HU on unenhanced CT, and signal loss on chemical-shift MRI.83 Intravenous iodinated CT con-
@ 2012 The Japanese Urological Association
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trast media were initially thought to precipitate hypertensive crises in patients with pheochromocytomas.85 However, recent reports suggest that non-ionic CT contrast media are not associated with an increased risk of adverse reactions.86 Most pheochromocytomas show avid contrast enhancement and slow contrast washout (Fig. 4c).86 This pattern overlaps with that of adrenal cortical carcinomas and adrenal metastases.86 Rarely, pheochromocytomas can show APW >60% and RPW >40% similar to adenomas.83
123/131I-MIBG scintigraphy is widely used in imaging pheochromocytomas (Fig. 4d). Whole-body MIBG imaging permits detection of multifocal pheochromocytomas, extra- adrenal pheochromocytomas and metastatic disease. 123I- MIBG is superior to 131I-MIBG, with sensitivities and specificities of 83-100% and 95-100% versus 77-90% and 95-100%, respectively.87 Pheochromocytomas can also be evaluated by PET imaging utilizing novel tracers, such as 18F-flurodopamine, 18F-flurodopa or 11C- hydroxyoephe- drine. 18F-flurodopa PET is reported to outperform 123I- MIBG scintigraphy in diagnosing pheochromocytomas.88 Unlike MIBG, 18F-flurodopa PET is not taken up by the normal adrenal glands.
Neuroblastoma
Neuroblastoma is a malignant embryonal neural crest- derived neoplasm of the sympathetic nervous system. It is most frequently located in the adrenal medulla (35%), but
can be found anywhere along the sympathetic chain. It is the most common solid extra-cranial neoplasm of childhood, representing 8-10% of all pediatric neoplasms and 15% of pediatric cancer mortality.89 It has an incidence of 10.5 cases per million children younger than 15 years-of-age.89 A mild male preponderance exists, with a male to female ratio of 1.2:1.89 At diagnosis, 50% of cases are under the age of 2 years, 75% are under the age of 4 years and 90% are under the age of 10 years.90 Familial neuroblastomas occur in 1-2%, with a mean age of 9 months at diagnosis.90 Associations exist with neural crest disorders, such as Hirschsprung’s disease, NF 1 and congenital central hypoventilation syndrome.91
Clinical findings
Neuroblastomas are heterogeneous neoplasms with a broad spectrum of biological behavior. Clinical presentation is influenced by the location of the neuroblastomas, their size and aggressiveness, and the presence or absence of cat- echolamine secretion and paraneoplastic syndromes.89 An asymptomatic palpable mass in the abdomen is the most common clinical finding. Metastatic disease is present in 50-60% at diagnosis, and might be the cause of the initial clinical complaint (e.g. liver metastasis might cause gross hepatomegaly and respiratory insufficiency in newborns; bony metastases might cause pain, limping and irritability; orbital metastases might cause periorbital ecchymoses).90
Catecholamine secretion can cause hypertension, tachycar- dia and flushing. Neuroblastomas are associated with para- neoplastic syndromes, such as Kerner-Morrison syndrome (intractable diarrhea with electrolyte disturbance) from VIP secretion and opsoclonus myoclonus ataxia syndrome (rapid eye movements with involuntary limb spasms) from anti- body cross-reaction with cerebellar tissue.89
The INSS, formulated in 1986 and revised in 1988, is the foundation of disease staging.92-94
INSS
Stage 1 Localized tumor with complete gross resection. No regional lymph involvement.
Stage 2 Localized tumor with incomplete gross resection or ipsilateral lymph node involvement.
Stage 3 Tumor crossing midline or tumor with contralat- eral lymph node involvement.
Stage 4 Tumor with distant metastases.
Stage 4S Patients younger than 12 months-of-age with localized tumor and metastases confined to liver, skin and/or bone marrow.
Prognosis is stratified by the Children’s Oncology Group into low-, intermediate- or high-risk categories based on age at diagnosis, INSS stage, histopathology, DNA ploidy and MYCN amplification status.89,92,95 Data suggests that neuro- blastomas occurring younger than 15-18 months-of-age have a more favorable prognosis than neuroblastomas occur- ring at an older age.92 Other poor prognostic factors include advanced INSS stage, unfavorable histology, near-triploid DNA and MYCN amplification. Low-risk patients have a >90% survival rate with surgery.92 In a minority of cases, spontaneous regression without treatment or maturation into ganglioneuroma is reported. Intermediate-risk patients have a >90% survival rate with surgery and chemotherapy.92 High-risk patients have a 30-40% survival rate despite intensive multimodality therapy involving chemotherapy, radiation treatment and stem-cell transplantation.92
Imaging findings
An invasive suprarenal mass in a young child is the classic imaging finding. Unlike Wilms’ tumor, which arises from the kidney, adrenal neuroblastomas displace the ipsilateral kidney inferiorly. Stippled calcifications are found in 30% of neuroblastomas on plain radiographs and in 85% on CT (Fig. 5a). CT and MRI typically show a lobulated heteroge- neous enhancing mass with internal hemorrhage and necro- sis. Aggressive features are commonly seen, such as invasion of adjacent organs, engulfment of surrounding vessels (e.g. celiac axis, superior mesenteric artery or aorta) and distant metastases (most commonly to the liver or bone; Fig. 5b-d). MRI is superior to CT in assessing tumor
encroachment into the neural foramen and spinal canal. Neuroblastomas show high uptake on MIBG scintigraphy with 88-93% sensitivity and 83-92% specificity reported.92 Because of its whole-body imaging capabilities, MIBG facilitates tumor localization, assessment of metastases and disease staging (Fig. 5d). In MIBG-negative neuroblastomas (10%), 99Tc-diphosphonate scintigraphy might be used for detecting bony metastases, and 18FDG-PET might be used for detecting soft-tissue metastases.
Conclusion
Functional adrenal neoplasms are a heterogeneous group of tumors with a wide spectrum of biological behavior, clinical features and imaging findings. The clinical variability of these neoplasms poses significant medical challenges. A clinical understanding of these neoplasms facilitates appro- priate diagnosis and clinical management.
Conflict of interest
None declared.
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