Clinical and imaging overview of functional adrenal neoplasms

Authors


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

Abstract

Adrenal adenoma, adrenocortical carcinoma, pheochromocytoma and neuroblastoma are four discrete adrenal neoplasms that have the potential for functional activity. Functional adrenal neoplasms can secrete cortisol, aldosterone, sex hormones 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 observations 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.

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

Introduction

The adrenal glands are responsible for the synthesis and secretion of a variety of physiological 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: epinephrine 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 carcinomas, pheochromocytomas and neuroblastomas. These are a diverse collection of neoplasms 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.

Table 1.  Biochemical evaluation in suspected functional adrenal neoplasms
HormonesBiochemical tests
Cortisol (minimum of 3 of 4 tests)Dexamethasone suppression test, 1 mg
24 h urinary free cortisol
Basal cortisol
Basal ACTH (plasma)
AldosteroneAldosterone/renin ratio
Serum potassium
Sex steroids and steroid precursorsSerum DHEA
Serum 17OH-progesterone
Serum testosterone
Serum 17β-estradiol
Catecholamines 
 Pheochromocytoma24 h urinary fractionated metanephrines
Plasma fractionated metanephrines
 NeuroblastomaUrinary metabolites (homovanillic acid, vanillylmandelic acid, dopamine)

Search strategy

An electronic database search was carried out on PUBMED using the following keywords: “adrenal adenoma”, “adrenocortical carcinoma”, “adrenal cortical carcinoma”, “pheochromocytoma” 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 syndrome or subclinical Cushing's syndrome. Features of Cushing's syndrome include truncal obesity, facial rounding, 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 alkalosis, 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 feminization 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 malignant) 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, bilateral functioning adenomas should be separately considered for adrenal-sparing laparoscopic bilateral partial adrenalectomy rather than bilateral total adrenalectomy.7 Preservation of normal adrenal tissue is essential for preventing adrenocortical insufficiency and the requirement for life-long medical treatment with glucocorticoid and mineralocorticoid 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 contralateral adrenal atrophy as a result of ACTH suppression.8 A homogeneous CT attenuation is characteristic (87% homogeneous precontrast, 58% homogeneous postcontrast).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 hemorrhage or cystic change.8 These features can overlap with other adrenal neoplasms, including malignancies. Approximately 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 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. Chemical 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 measurement 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 unenhanced 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

Figure 1.

Lipid-rich adrenal adenoma. (a) Axial unenhanced CT image shows an oval-shaped, well-defined, low attenuation right adrenal mass (arrow). (b) Coronal unenhanced CT image shows that the adrenal mass has an attenuation of 0.2 HU (HU <10). (c) Coronal in-phase MRI and (d) coronal opposed-phase MRI shows signal dropout in the adrenal mass (arrow) as a result of signal cancellation of fat and water molecules in the lipid-rich adenoma.

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

image
image
Figure 2.

CT adrenal washout study. The attenuation values of the left adrenal mass are: (a) unenhanced CT image: −1.6 HU; (b) 60 s postcontrast CT image: 78.1 HU; and (c) −15 min postcontrast CT image: 18.4 HU. Based on the data, the adrenal mass has a calculated RPW of 76% (>40%) and an APW of 75% (>60%). These results are consistent with a diagnosis of adrenal adenoma.

An APW >60% or RPW >40% has a sensitivity and specificity close to 100% in diagnosing adrenal adenomas.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 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 syndrome, 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 cosecreted 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 involvement.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 Sullivan (1978),27 the UICC (2004)28 and the ENST (2008).29 The UICC and ENST classifications are as follows:

Stage IT1 (<5 cm), N0, M0
Stage IIT2 (>5 cm), N0, M0
Stage III
UICCT1-2, N1, M0
T3, N0, M0,
ENSTT1-2, N1, M0
T3-4, N0-1, M0
Stage IV
UICCT1-4, N0-1, M1
T3, N1, M0
T4, N0-1, M0
ENSTT1-4, N0-1, M1

Advanced disease is found in 70% of patients at presentation.19 At diagnosis, stages I and II account for 32% of cases, and stages III and IV account for 68% of cases.19 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 survival 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 incomplete 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 insecticide dichlorodiphenyltrichloroethane) is an adrenal specific 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 therapeutic window requiring high serum levels and dose-limiting adverse effects (mainly gastrointestinal and central nervous system related). Mitotane combined with cytotoxic 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 complete 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 malignancy 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 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% specificity in differentiating benign from malignant adrenal neoplasms.41

Figure 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.

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 metabolically 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 combined 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 (11C-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.50 A prevalence of one in 200 is reported in postmortem studies.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 predispose 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 pheochromocytomas 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 pheochromocytomas are commonly diagnosed before 40 years-of-age.48,66 A total of 10–20% of pheochromocytomas occur in children.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%), multifocal and extra-adrenal.66,67,70 A total of 30–43% of childhood pheochromocytomas and 15–18% of adult pheochromocytomas 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, serotonin, gastrin, atrial natriuretic factor, somatostatin, growth hormone-releasing factor and ACTH.61 The clinical triad of catecholamine excess in pheochromocytoma involves headaches (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

Surgery is the mainstay of treatment, with 5-year survival 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 pharmacological intervention (alpha and beta adrenergic blockade ± calcium channel blockers) and intravenous hydration to prevent hypertensive crises that might be triggered 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, vincristine and dacarbazine provides short-term tumor response and symptom improvement in 65%.80 External beam radiation 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 pheochromocytomas are generally smaller than non-functional pheochromocytomas.82 Smaller pheochromocytomas are commonly homogeneous, and larger pheochromocytomas are heterogeneous in appearance.81 On MRI, pheochromocytomas are classically described as showing low-signal intensity on T1- and high-signal intensity equivalent to cerebrospinal 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 intermediate 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. Pheochromocytomas 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 contrast 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

Figure 4.

Pheochromocytoma. (a) Axial T1-weighted MRI and (b) axial fat saturation T2-weighted MRI show an oval-shaped, left adrenal pheochromocytoma (arrow) with signal intensity similar to the cerebrospinal fluid (star). This equates to low-signal intensity on T1 and very high-signal intensity on T2 (“light bulb” bright). (c) A coronal postcontrast CT image shows heterogeneous avid enhancement in the pheochromocytoma (arrow). (d) A coronal 123I-MIBG scintigraphy image shows high uptake in the pheochromocytoma (arrow).

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- hydroxyoephedrine. 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 catecholamine 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, tachycardia and flushing. Neuroblastomas are associated with paraneoplastic 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 antibody 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 1Localized tumor with complete gross resection. No regional lymph involvement.
Stage 2Localized tumor with incomplete gross resection or ipsilateral lymph node involvement.
Stage 3Tumor crossing midline or tumor with contralateral lymph node involvement.
Stage 4Tumor with distant metastases.
Stage 4SPatients 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 neuroblastomas occurring younger than 15–18 months-of-age have a more favorable prognosis than neuroblastomas occurring 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 heterogeneous enhancing mass with internal hemorrhage and necrosis. 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.

Figure 5.

Neuroblastoma. (a) Axial postcontrast CT image shows coarse nodular calcifications (stars) within an adrenal neuroblastoma. (b) Axial postcontrast CT image shows a large right adrenal neuroblastoma that crosses the midline abdomen and displaces the liver anteriorly. The neuroblastoma engulfs and encases the abdominal aorta and the CA. (c) Axial postcontrast MRI shows heterogeneous enhancement in a right adrenal neuroblastoma (arrow). There is associated hepatomegaly and diffuse infiltrating liver metastases that possess similar enhancement as that of the primary tumor. (d) A coronal whole-body 123I-MIBG scintigraphy image shows multifocal high uptake in the calvarium, femora and tibia bilaterally consistent with bony metastases. High uptake is also seen in the right adrenal neuroblastoma.

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 appropriate diagnosis and clinical management.

Conflict of interest

None declared.

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