Adrenal tumors

Jason Wilson

INTRODUCTION
            Adrenal tumors occur rarely in childhood, but neuroblastoma accounts for more than 90% of these tumors.  In the United States, the incidence of neuroblastoma was recently reported as 1:1/100,000 person-years.1  The adrenal cortex accounts for 6% of adrenal cancers in children, and adrenocortical carcinoma (ACC) constitutes 0.2% of malignant neoplasms in white children less than 15 years of age.2,3  Furthermore, adrenal chromaffin cells contribute to pediatric neoplastic processes in the form of pheochromocytoma (PCC).  In this chapter, discussion is limited to the adrenal cortical tumor (ACT) and PCC.

Epidemiology
            The most commonly encountered pediatric adrenocortical tumors (ACT) are adrenocortical carcinoma (ACC) and adrenocortical adenoma (ACA).  Because of the relative infrequency of occurrence and difficulty in distinguishing ACC from ACA, the two are often reported under the broader term of ACT in the literature.  Lack et al reported thoroughly on ACT in 1992 and estimated a total of 19 new cases of ACC and 6 new cases of ACA each year for persons less than 20 years of age in the United States.3  The annual incidence is estimated, from the same data, to be 3 per million persons under age 20 years.3  Worldwide incidence is reported to be between 0.3 and 0.38 per million children below 15 years of age.4  In southern Brazil, the incidence is reported to be as high as 4.2 per million children less than 15 years of age,5 with another report suggesting an incidence equal to that of Wilms’ tumor, neuroblastoma and non-Hodgkin’s lymphoma.6
            A review of several case series suggests a mean age of presentation to be 6 years3,4,6-14 with a female to male ratio of 1.6 to 1.35,6,8-14  There have also been a reports of antenatally diagnosed ACA and ACC.15,16

Embryology and Genetics
            The adult adrenal gland is composed of three zones and the inner medulla.  The adrenal cortex arisies from intermediate mesoderm and the medulla arises from neuroectoderm.  The cortex from outer to inner is divided into three biologically distinct zones: zona glomerulosa, zona fasciculata and zona reticularis.
            In the fetal adrenal gland, one finds a large inner zone (fetal zone) and a small outer zone (definitive zone).  The fetal zone will disappear by 6 months of age, while the definitive zone will undergo maturation into the zona glomerulosa and zona fasciculata by 3 years of age.  The reticularis begins development after 4 years of age and may not fully mature until age 15.  The mechanism responsible for zonal differentiation within the adrenal gland is not fully understood.  It is generally believed that there are intra/subcapsular and/or zone specific stem cells responsible for differentiation.17-19
            Within the developing fetus, the formation of the adrenogonadal primordia (AGP) marks the first of several distinct events that result in the formation of the fetal adrenal gland.17  The cells of the adrenal cortex are present in the AGP along the urogenital ridge and can be identified as early as week 4 of development by staining for steroidogenic factor 1 (Sf1).17 The bilateral AGP divide to form the adrenal and gonadal primordia, a process dependent upon expression of Sf1. Sf1 expression is encouraged, in part, by WT-1 and Pbx1.  Further definition of the adrenal primordia occurs with mesenchymal encapsulation, after which time the definitive zone becomes evident between the capsule and fetal zone. It is proposed that the capsular formation creates an environment that both recruits and directs stem cell development toward unique zonal steroidogenic potential.  Kim et al presented a comprehensive review of their data and the available literature regarding adrenocortical stem cell biology.17  These authors also commented on the possibility of cancer stem cells and dysregulation possibly associated with mutations of IGF-II, p53 and APC genes in Beckwith-Wiedemann, Li-Fraumeni and familial adenomatous polyposis respectively.  These specific examples could serve as models for development of adrenocortical neoplasms.  By 28 weeks gestational age, the adrenal gland, from outer to inner, is composed of the capsule, definitive zone, (possibly) small “transition” zone, the large fetal zone and the medulla.18  It is at around the 9th week of gestation that neuroectodermal cells migrate to become the center of the adrenal primordia at the same time that encapsulation is occurring.  At birth, the adrenal glands are about twice as large as an adult adrenal.  With involution of the fetal zone by 6 months of age, they decrease in size, while the definitive zone actually enlarges to become the glomerulosa and fasciculata.18  Human adrenal development remains marginally understood.  Kempna and Fluck described the differentiation of the adrenal primordia as “encoded by a specific sequence of genes which are expressed in a spatio-temporal exact fashion, and by paracrine factors.”18  Unique, steroidogenic zonation may be regulated by a paracrine effect of the manufactured hormones and their expression regulators.  Kim et al allude to this “capsular niche” as a self-regulating and developing environment wherein aberrations at the molecular level may lead to disorders of function and/or neoplastic processes.17 

Etiology and Pathophysiology
            Since initial reports of adrenocortical tumors in siblings and their association with Beckwith-Weidemann and Li-Fraumeni syndromes, it has been suspected that there is a genetic explanation for ACT.  As is the case with many neoplastic processes, oncogenes and tumor suppressor gene mutations have been investigated as potential culprits.  Although specific etiology is unknown, there are several genomic areas that deserve consideration (Table 1).20,21

Table 1. Syndromes associated with increased incidence of ACT and reported genetic aberrations.

Beckwith-Weidemann

Paternal isodisomy (11p15), IGF-II overexpression

Li-Fraumeni

TP53 germline mutations (17p13)

MEN-1

Inactivating germline mutation (11q13)

Familial adenomatous polyposis coli

APC germline mutations, Wnt signaling pathway activated

            Much of the work in the field is not specific to pediatric ACT as most are observed in adults with the incidence of incidentally discovered adrenal masses increasing from 0.06 (0-9 years) to 6.9% (70 and over) over eight decades of life.21  Additionally, when considering adult age groups, the prevalence is 4 to 12 per million.22  That said, after years of inexplicably increased incidence of pediatric ACC (10-15 times higher) in southern Brazil, investigators reported an R377H (Arg337His) mutation in exon 10 of the p53 gene in nearly all children with ACC (77-97%).23,24  It may be hypothesized that the occurrence of childhood ACT implies a TP53 germline mutation, but animal, knockout models suggest other factors.  When considering ACT occurrence in other syndromes, it is evident that there are many factors contributing.  Matzuk et al reported an investigation in which inhibin-alpha knockout mice were observed to develop ACT by 5 weeks of age.25  Loss of heterozygosity at 2q33 is a mutation of inhibin-alpha that has been observed in human pediatric ACT’s(8 of 9 patients analyzed), suggesting its function as a suppressor gene.26  West et al presented the first series of childhood ACT gene expression profiles in 2007.27  Some significant aspects of that series included underexpression of major histocompatibility class II genes in ACC compared to ACA, overexpression of FGFR4 and IGF-II in ACT compared to normal cortex and conspicuous underexpression of KCNQ1, CDKN1C and HSD3B2 in ACT samples.
            Establishing clonality in a population of tumor cells has and can provide insight as to the cellular origin of ACT.  It has been demonstrated that ACC are made up of monoclonal populations, suggesting an intrinsic genetic mutation as we have seen in cases of ACC with TP53 germline mutations; ACA can be monoclonal or polyclonal (local or systemic stimuli).28
Complete illumination of the etiology in childhood ACT may be possible in the future with comparative genomic hybridization (CGH), microsatellite markers and genetic engineering—for example, CGH has shown that 28% of ACA carry chromosomal alteration and microsatellite markers have shown loss of heterozygosity (LOH) at 11q13, 17p13 and 2p16 in ACC.29-33  CGH and microsatellite markers have suggested the presence of currently unmapped tumor suppressor genes and/or oncogenes.  With development of cell line cultures and knockout animal models, it may be possible to direct therapy toward specific areas within the genome that are discovered to suppress/encourage tumorigenesis.  It is within this that a hope for earlier diagnosis and targeted therapies for aggressive ACC exists with continued development of registries, tissue repositories and collaborative studies.

 

 

 

Presentation and Diagnosis
            Most antenatally detected suprarenal tumors are attributed to neurobalstoma.  It is important to note that fetal adrenal hemorrhage will lack arterial flow, distinguishing the entity form solid tumors.34  Sauvat et al reported a multicenter investigation in which 30 prenatal suprarenal lesions were either attributed to neuroblastoma, regressed or were benign35; however, there have been reports of maternal sonography detecting ACT’s.15  In 2008, Sherer et al described the first reported case of antenatally detected ACA.15  The authors described the sonographic appearance of the 3 x 3 x 3 cm suprarenal mass as heterogeneous containing cystic and solid elements, similar to well described appearance of neuroblastoma in fetal sonographic imaging.  The differential diagnosis should include neuroblastoma , adrenal hemorrhage, adrenal cysts, ACT, macrocyst associated with Beckwith-Weidemann, sub-diaphragmatic extra-pulmonary sequestration, renal lesions/anomalies, congenital cystic adenomatoid  malformation and mesenteric/enteric duplication cysts.15,35,36  Hishiki et al shared a case report in which a solid suprarenal lesion demonstrated antenatally was proven to be ACC.16  Despite its infrequency, ACT should be included in the differential diagnosis for antenatally detected suprarenal masses.
            ACT most commonly presents with signs of virilization (hirsutism, penile or clitoral enlargement) and/or hypercortisolism (Cushingoid features).  One hundred twenty of 134 patients (89.5%) from 5 different case series presented with signs of virilization, with or without Cushingoid features.6,8,14,27,37  Ten percent of children presented without signs of endocrine dysfunction in a large series of children with ACT reported by Michalkiewicz et al; the children (presumptively) presented with constitutional symptoms and/or an abdominal mass.38 
            In the child with presenting signs or symptoms, it is paramount to establish a diagnosis early.  ACC is, indeed, rare, but in its advanced stages it is insurmountable.  Early diagnosis increases the possibility of curative treatment.  As most ACT in children are hormonally active, ACT should be considered in the evaluation of a child presenting with abnormal hair growth, penile or clitoral enlargement, acne, hypertension, and, rarely, unexplained constitutional symptoms.  Obtainable objective data includes laboratory and radiologic investigations.

Laboratory   With older reports stating as many as 95% of ACT as hormonally active39, it is useful to recall the distinct steroidogenic zones of the cortex.  Most commonly, the clinician will encounter signs of virilization with or without Cushingoid features.  Measurement of androgens and metabolites is necessary to establish or rule out ACT.  Measurement of serum testosterone, serum dihydroepiandrosterone (DHEA) and the adrenal-specific DHEA-sulfate (DHEA-S) and urinary 17-ketosteroids will often return elevated values.  Hypercortisolism may be suspected in presence of classic features such as central obesity, “moon facies,” muscle atrophy, striae and hirsutism; however, younger children may present with generalized obesity.7  A variety of laboratory tests are available in diagnosing hypercortisolism, including daily urinary cortisol levels, basal ACTH, basal cortisol, 17-hydroxycorticosteroid and dexamethasone suppression tests.  Adrenal-dependent hypercortisolism can also be diagnosed by recording an elevated midnight cortisol with failed high dose dexamethasone suppression.40  In rare cases of feminization and mineralocorticoid producing ACT, estradiol and a plasma aldosterone/renin ratio can be utilized.  Laboratory values can also be used in follow-up as complete excision of ACT should result in normalization of these values within 7 days.  If evaluating a small, androgen secreting adrenal mass, dexamethasone suppression of DHEA-S, androstenedione and testosterone suggests against the diagnosis of ACT.41  Table 2 lists useful measurements in different clinical settings.

Table 2. Serum and urine measurements for clinical presentation.

Presentation

Value

Cushingoid features

24 hour urine cortisol
Midnight cortisol level
High dose dexamethasone suppression

Virilization

Urine 17-ketosteroids
Testosterone
DHEA
DHEA-S
17-Hydroxyprogesterone
Deoxycorticosterone

Hypertension, hypokalemia

Aldosterone
Renin

Feminization (breast development, advanced bone age, premature isosexual development)

Estradiol


            Radiology   Available modalities for adrenal imaging include radiography, ultrasonography (US), intravenous pyelography (IVP), computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and meta-iodobenzylguanadine (MIBG) scintiscan.41  According to Ozturk et al, with support from other authors, CT is most useful in evaluating the adrenal gland.41  These authors recommend a detailed CT protocol for evaluating adrenal lesions consisting of 2.5-3 mm collimation, oral and intravenous contrast and 1.5-3 mm  reconstruction through the adrenal region. CT evaluation of adrenal adenomas can be expected to demonstrate a round or nodular lesion less than 4 cm in diameter with a homogenous, low-density  (<10 Hounsfield units) appearance.  In adult adenoma, as many as 30% will not contain sufficient lipids to appear as low-density lesions.42,43  Considering significant cross-over between pediatric ACC and ACA histopathologically, it seems unlikely that CT could reliably distinguish between the two.  Additionally, the difficulty in distinguishing the two virtually assures that all ACT detected in children will be excised after appropriate workup to ascertain a diagnosis (i.e. ACT, PCC, NB).  However, more recent reports regarding nonfunctional adrenal masses in adults (“incidentalomas”) virtually assure the presence of adenoma if the enhanced tumor is <10 Hounsfield units.44
            MRI and PET are potentially useful and have been utilized in the workup, again, of the “incidentaloma,” attempting to differentiate between benign and malignant lesions in adults.  MRI may be very useful for determining extent of ACT extension and local invasion, but really has no practical application for differentiating between ACC and ACA in the pediatric patient.  PET or PET/CT could be potentially useful in postoperative evaluation for recurrence, but there is, at current, scarce literature about its use in this specific clinical scenario.  NP-59 has a high positive predictive value for ACA, but is not currently approved by the United States Food and Drug Administration for that use.44  Most case series report the use of US and CT for diagnosis; however, perhaps with more pediatric specific prospective trials, immunohistochemical and clinical correlation, imaging will prove more useful in differentiating ACC from ACA.  It seems appropriate and necessary to currently employ US, CT and possibly MRI for preoperative evaluation of the child for staging and planned anatomic approach in excision.   It may be preferable in the case of questionable local invasion to use a finer collimating modality such as MRI.

Treatment and Staging
            As previously noted, complete surgical excision is the only curative method of treatment in pediatric ACT.  Preoperative staging is dependent upon whether local invasion or distant disease is radiologically demonstrable.  Biopsy should be avoided, if only to avoid tumor rupture.41  In the appropriate surgical candidate, the approach largely depends on tumor size, presence of local invasion, surgeon experience and technological availability.  It seems logical that if complete surgical resection is the best chance for cure, one should use an approach that would allow wide dissection, delicate tumor manipulation and the possibility of en bloc resection of adjacent structures if necessary.  In that regard, Ribeiro and Figueiredo advocate an ipsilateral, subcostal approach that may easily be extended to a chevron incision if necessary.41  They also emphasize the friable and necrotic nature encountered in ACT and actually recommend against a laparoscopic approach to excision of the pediatric ACT. Although laparoscopic surgery has proven safe and effective for benign, adult adrenal tumors, other investigators have also proposed open adrenalectomy over a laparoscopic approach to minimize the risk of peritoneal tumor-cell dissemination.  Several recent publications stress the need for extreme caution and a very low threshold for conversion to an open procedure if an attempted laparoscopic procedure requires tumor manipulation for exposure or removal.46-48  Until better preoperative tools are developed to detect ACC vs. ACA, it is prudent to approach all pediatric ACT with open adrenalectomy.
            Intraoperative manual palpation of the vena cava should precede tumor manipulation, as should assessment of regional lymph nodes.  A cardiothoracic surgeon may assist in the rare need for thoracoabdominal approach if there is suspicion of supradiaphragmatic tumor thrombus.  Lymph node dissection inferior to the ipsilateral renal vein and superior to the iliac bifurcation has been advocated in large tumors or in the presence of lympadenopathy, although its effect on outcome has not been formally evaluated.41  Aggressive resection of distant disease is recommended when it can be safely undertaken, as it is generally espoused that complete excision can achieve remission.41,49-50
            Staging ACT in children has been modified by some authors to include tumor size, as it is considered to be an independent variable in predicting disease control.  The adult staging system for ACT is usually the modified MacFarlane which is based on tumor size, lymph nodes and metastasis.51  Michalkiewicz et al38 used a modified staging system for pediatric ACT as reported in 2004:

Chemotherapy   A recent retrospective report in adult ACC suggested improved survivability in patients who received adjuvant mitotane therapy.52  Most preceding reports had published partial response rates between 15% and 60% in the adult population.  Ribeiro and colleagues treated 32 pediatric patients between 1990 and 1995 with mitotane as adjuvant therapy.41  About 50% of the children relapsed after surgical therapy.  The authors noted significant toxicity with the agent and emphasized the need for control of the iatrogenic adrenal insufficiency created with mitotane therapy. In 2006, Zancanella and associates reported the use of mitotane with cisplatin, etoposide and doxorubicin.53  There were 5 reported partial responses and 2 cases of remission in 11 patients with only three patients alive at time of report. There is an ongoing international trial (FIRM-ACT) (www.firm-act.org) to determine the efficacy of mitotane, etoposide, doxorubicin, cisplatin vs. streptozotocin and mitotane in adult ACC.  A review of the current literature revealed no formal trials of chemotherapeutic agents in pediatric ACT.  Use of mitotane with or without cytotoxic agents has been reserved for unresectable or endstage disease in the pediatric population with response rates ranging from 11% to 30%.54  Largely, there has been no report of significant effect on tumor size or survivability in the pediatric population.

Radiotherapy   Radiotherapy has been used effectively for palliation, especially with bony metastases, but has not been demonstrated to reliably control disease or affect survival.  There has been some suggestion in the pediatric and adult literature that radiotherapy to the site of resection in high-risk patients (incomplete resection, microscopic residual disease) may improve survival.55,56  While certainly feasible, the evidence that radiotherapy affects survival does not exist in substantial numbers.  It is unlikely that properly designed clinical trials will illuminate the role of radiotherapy any further, secondary to the small number of cases and indications for its use in pediatric ACT.

Prognosis and Outcome
            In general, there is a 49-73% 5-year survival rate in pediatric ACC.9,38,57  When considering all ACT that meet pathologic criteria of malignancy, the survivability increases.  It has been reported in several series that some ACT that meet pathologic criteria for malignancy, do not behave clinically as a malignancy.  This calls into question the value of histopathologic tumor staging in pediatric ACT altogether.  When considering preoperative tumor staging in relation to tumor size and local or distant metastases, stage IV ACT have a dreadful prognosis, with some series reporting survival rates of 0%.  Tucci et al used a preoperative staging classification wherein tumors less than 5 cm with no evidence of metastases were stage I, tumors >5 cm and no metastases were stage II, evidence of local extension but no invasion or regional nodes were stage III and any tumor with distant metastases or local invasion was stage IV.  Using this classification, tumor stage was the single most important factor in prognosis with 5-year survival overall of 59% (20/34), stage I 100% (5/5n=5) and stage IV 0% (n=10). 58 
Ahmed recently proposed presenting age as the predominate prognostic factor.59  It was hypothesized from author data that the infant with an ACC may have the best overall prognosis when considering all age groups.  Other series had reported age as a significant factor in multivariate analysis of outcome.  Wienecke et al found that an age of <5.4 years was associated with a more favorable outcome9 and Sabbaga et al reported an 82% survival for <2 years of age compared with 29% in older children.6 
Sabbaga and colleagues did not detect a significant association of tumor size and outcome; however, the patient population from Weineke’s group was broken down into three groups: group A, clinically and pathologically benign; group B, clinically benign and pathologically malignant; group C, clinically and pathologically malignant (Table 3).  Average group ages were 10.6 years, 5.4 years and 10.9 years, respectively.  The proposed pathologic criteria for malignancy included tumor weight >400 grams, tumor size >10.5 cm, extracapsular extension or invasion, presence of tumor necrosis and greater than 15 mitoses per 20 high-power fields.

Table 3. Summary of data from Weineke et al, 2009.9

Group

Macroscopic (mean)

Outcome

A

4.7 cm, 82 g

100% survival, mean follow-up 14.7 years

B

7.8 cm, 268 g

100% survival, mean follow-up 16.7 years, 7 of 49 required adjuvant therapy at diagnosis

C

12.2 cm, 631 g

12.5% survival, mean follow-up 3 years

Weineke and coauthors concluded that both tumor size and weight correlated with patient outcome and suggested that malignant criteria include a tumor size of greater than 10.5 cm and a tumor weight of greater than 400 grams.9  Additionally, in the series presented by Ahmed, the average specimen weight was 30.8 grams (10-59 grams).59  No specimens exhibited periadrenal extension and all patients were alive without evidence of disease with follow-up ranging from 5 months to 9.5 years.  Age, tumor size and weight seem to all contribute, if not independently, to prognosis.  Hanna and colleagues noted significant prognostic benefit with tumor size and negative margins.12

Summary
            Postoperative molecular analysis may prove useful in prognosis as the genome is further elucidated, but currently it seems wise to treat pediatric ACT as possessing an entire spectrum of malignant potential with close postoperative follow-up including monthly laboratory evaluation in the first year.  Until more reliable predictive factors are discovered and clinically confirmed, every pediatric ACT should be treated as malignant.

PHEOCHROMOCYTOMA
            The term pheochromocytoma is used generally to classify both intra-adrenal and extra-adrenal tumors that arise from chromaffin cells that may be located anywhere along the sympatho-adrenal system, including the adrenal medulla, Zuckerkandl body, paravertebral chain, hilum of the kidney and liver, aortic bifurcation, bladder and mediatinum.60-62  Paraganglioma (PGL) has been used by some investigators as a term designating extra-adrenal PCC.61,62  Herein, PCC shall designate tumor arising from the chromaffin cells within the adrenal medulla and PGL shall designate a tumor of chromaffin cell origin at an extra-adrenal site.  Discussion shall proceed primarily within the scope of PCC.
            The incidence of PCC is estimated at 0.8 per 100,00063 with 10-20% occurring in children.64,65  This would make the estimated pediatric incidence 0.8 to 1.6 per million and this includes paraganglioma and PCC, making the pediatric PCC a rarely encountered tumor.  There is a slight male preponderance of almost 2:1.61,62,65,66  About 80% arise from the adrenal medulla (PCC) and both PCC and paragangliomas (extr-adrenal PCC) produce catecholamines accounting for the high rate (60-90%) of children presenting with sustained hypertension (HTN) and PCC or paraganglioma.62  It is reported that approximately 40% of PCC and paragangliomas in children are associated with known genetic mutations and 19-38% are bilateral adrenal.62

Genetics
            PCC is known to occur with increased frequency in the syndromes of multiple endocrine neoplasia type 2(MEN-2), Von Hippel Lindau (VHL) and can occur in 0.1-5.7% of patients with neurofibromatosis type (NF-1).60  Studies continue to implicate and elucidate germline mutations in genes encoding subunits of succinate dehydrogenase as precursors for increased malignancy, pediatric occurrence and familial aggregations of PCC and PGL.60  Although not pediatric specific, Erlic and Neumann submitted a comprehensive review on familial pheochromocytoma.67  Table 4 is an adaptation from data presented in this review, illustrating gene and genomic location, tumor occurrence and likelihood of malignancy with each syndrome.

Table 4. Genetic mutations and associated tumors.67

 

MEN-2

VHL

NF-1

PGL-1

PGL-3

PGL-4

Gene

RET

VHL

NF1

SDHD

SDHC

SDHB

Chromosome

10q11.2

3p25-26

17q11.2

11q23

1q21

1p36

PCC %

30-60

15-20

3-5

34

Insufficient data

37

Malignancy rate %

3

4

12

< 1

Insufficient data

24

PCC/PGL %

97/3

92/17

94/6

86/57

Insufficient data

42/58

The characteristics of PCC and PGL may be different, depending on which genetic alterations are present; therefore, it seems prudent for every case of PCC and PGL to undergo genetic consultation, testing and familial screening.  As much as 40% of PCC may have a hereditary basis including the paraganglioma syndromes, which, as the table illustrates, are associated with a higher frequency of PGL.61,62,67  Genetic characterization may become more useful in predicting tumor behavior such as bilateral synchronous or metachronous lesions, likelihood of malignancy and recurrence.  As such, continued research with collaborative, multi-institutional databases and repositories may allow patient stratification into different risk groups. 

Presentation, Diagnosis and Treatment Outcomes
            In a child with a known syndrome (Table 4) or with children in whom there is a known familial predisposition, biochemical screening should be performed.  Approximately 1% of hypertensive pediatric patients will have PCC or PGL62  Average age of presentation is 11 years and 60-90% of childhood PCC and PGL may present with HTN.62  Recognized clinical signs and symptoms include wide variability in 24-hour blood pressure monitoring, palpitations, headache, sweating, nausea, vomiting, weight loss, polyuria, visual disturbances and anxiety. One recent publication listed common presentations in children: HTN, 64%; palpitation, 53%; headache, 47%; mass-related effects, 30%.68 
            Diagnosis is based on biochemical testing and imaging.  In appropriate patients for screening, urinary or plasma, fractionated metanephrines (metanephrine, normetanephrine) is considered most accurate with 100% sensitivity reported in children.62  Specificity approaches 97% when considering plasma and urinary fractionated metanephrines, which will be elevated as a result of the chromaffin cell cytoplasm.62,69  It has been suggested that the physician consider plasma metanephrines in working up the pediatric patient for PCC or PGL, as 24-hour urine collection poses problems, specifically with potential under-collection.  Age appropriate reference values for plasma metanephrines, plasma catecholamines and urinary metanephrines have been established and recommended for use in workup of the male and female pediatric patient.70  There seems to be some debate about whether plasma or urine testing is preferred.  Considering the 100% sensitivity previously mentioned and a negligible difference in specificity, either or both can be utilized.  It is recommended by at least one group of authors to obtain blood samples in the supine position.71  In cases of minor and persistent elevations, appropriate endocrine consultation for direction of more specific biochemical testing is warranted.  Imaging in suspected PCC is usually completed after collection of sufficient biochemical, objective data to suggest a neoplastic process.  Strong familial tendencies may lower the threshold for radiologic localization.  Whether to proceed with CT or MRI is debated and one must consider the radiation dose with CT and the likely need for general sedation with the MRI.  As previously noted, MRI may be more useful in evaluating local or regional disease as there is potential for finer collimation.  There is no risk of hypertensive crisis with the use of intravenous nonionic contrast (CT) and the presence of PCC or PGL.45  As many as 70% of PCC cases will demonstrate high signal intensity on T2-weighted images (MRI).45  I123 or I131 – MIBG scintigraphy has nearly 100% specificity and is particularly useful in cases of strong clinical suspicion without CT or MRI demonstrable disease, work up of multifocal or metastatic disease.45,62  Limited use of [18F] fluorodopamine and carbon 11-hydroxyephedrine PET has been reported in adult series and may be further utilized as it is mAs noted with ACT, the treatment and cure of PCC is dependent upon complete surgical resection.  Successful surgical treatment hinges upon localization of the PCC and perioperative medical optimization of the patients hemodynamic status.  Preoperative alpha-blockade has been the primary means by which complications have been reduced.  In a published nearly five-decade experience, Goldstein and colleagues noted a decrease in complications from 69% to 3% when adding preoperative treatment with an alpha blocker.72  Protocols for treatment have not been specified for pediatric patients but, in general, the use of phenoxybenzamine or doxazosin to achieve age, size and sex adjusted normotension 7 to 14 days preoperatively. 
There are currently no official guidelines regarding when to start or which agents should be started to achieve normotension and volume expansion.   Regarding phenoxybenzamine in children, maximum dose is 25 mg daily in twice daily dosing and adolescents may take 40 to 100 mg/day.  With pediatric HTN, the dose is usually 2.5 mg twice daily and titrated to side effects or normotension.  It may be useful to consider a switch to an alpha-1- blockade 2-3 days before surgery as these agents (e.g., doxazosin) are short-acting and may decrease risk of postoperative hypotension. Beta-adrenoceptor blockade should be used after adequate alpha blockade has been established to avoid the risk of hypertensive crisis from further vasoconstriction and is useful for prevention of tachyarhythmias.  If HTN is poorly controlled,  calcium channel blockers may be considered.   Inadequate preoperative expansion of blood volume may result in sudden postoperative hypotension so some have recommended pre-operative hydration and high-salt and high-fluid diets.  Inhibition of catecholamine synthesis is not routinely recommended in children but may be considered when other agents are inadequate at achieving normotension.  Intraoperative use of agents such as nitroprusside and norepinephrine may be needed and should be available.61,62,73 ore available in the workup of the select pediatric patient.  In most cases, CT or MRI with MIBG is adequate for localization and characterization. 
Resection should be undertaken after medical therapy and control has been optimized and is directed toward complete resection of local and regional disease where possible and is used in debulking for unresectable cases when feasible.  The use of laparoscopic cortical sparing tumor resection has been advocated, especially in cases of bilateral PCC.61  Ludwig et al suggested this as the preferred method of surgical resection noting feasibility, safety, decreased length of hospital stay, time to oral intake and ambulation and 87% of patients experiencing total resection of disease with 6 of 13 having been performed laparoscopically.61 
Staging is usually categorized by radiologic and surgical localization with local, regional, metastatic designations.  There are no reliable histologic criteria to establish malignancy and it is unequivocally present only in the presence of metastatic disease with rates varying from as low as 2% to as high as 47%.62  Bone, liver and lung represent the most common sites of metastasis. 
Systemic therapy may be undertaken with MIBG or with conventional chemotherapy, most commonly with cyclophosphamide, vincristine and dacarbazine.  With limited experience, chemotherapy should be reserved for symptom relief or in attempt to achieve partial response to allow resection of previously unresectable mass.  Although there is a favorable long-term survival rate, case series such as presented by Ciftci and colleagues emphasize the importance of resection.65  Two of three patients with malignant PCC or PGL were able to undergo incisional biopsy only and ultimately succumbed to the disease, whereas the remaining patients had a 16-year mortality rate of 19%.  Ludwig and associates reported a 100% overall survival with 93% 5-year disease-free survival, attributing the positive outcome to a low (7%) rate of malignancy and negative margins of resection in all patients (n=15).61  Long-term surveillance is mandated by the reports of recurrence as many as 14 years after successful treatment.

Summary
            PCC or PGL in the pediatric patient is rarely encountered and is almost always associated with characteristic signs and symptoms or a familial predisposition.  Preoperative preparation consists of tumor localization and reversal or control of the physiologic effects of catecholamine excess.  Further genetic characterization and classification may allow patient stratification into low and high risk categories for malignancy and recurrence.  Surgical resection with negative margins is the cornerstone of curative treatment and should be undertaken by experienced surgeons employing laparoscopic or conventional open approaches.

 

 

 

REFERENCES