Rare Tumors of the Peripheral Nervous System

Abstract

The WHO in 2004 reclassified endocrine tumors and redefined pheochromocytoma as intra-adrenal paraganglioma and those tumors of extra-adrenal sympathetic or parasympathetic paraganglia as extra-adrenal paragangliomas (Pacak et al. 2007). Although rare in children, they are the commonest pediatric endocrine tumor with an instance of 1–2 per million (Stringel et al. 1980). The majority of paragangliomas arise in the adrenal medulla (Lenders et al. 2005), but when they arise in extra-adrenal sites, they occur in decreasing order of frequency in the abdomen – in the organ of Zuckerkandl, pelvis, mediastinum, and the head and neck (Pacak et al. 2001). In the head and neck, they are mainly parasympathetic and nonsecreting with a specific entity arising in the carotid body – carotid body tumor – which is extremely rare in childhood (Deal et al. 1990). In childhood, they are often multiple or bilateral with 40% probably associated with an underlying genetic condition and very rarely are malignant (Krijger et al. 2006).

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1 Intra-adrenal (Pheochromocytoma) and Extra-adrenal Paraganglioma

• Bernadette Brennan 

1. Department of Pediatric Oncology and Haematology, Royal Manchester Children’s Hospital, Oxford Road, M13 9WL, Manchester, UK

   Bernadette Brennan

1.1 Introduction and UK Registry Childhood Cancer Registry Data

The WHO in 2004 reclassified endocrine tumors and redefined pheochromocytoma as intra-adrenal paraganglioma and those tumors of extra-adrenal sympathetic or parasympathetic paraganglia as extra-adrenal paragangliomas (Pacak et al. 2007). Although rare in children, they are the commonest pediatric endocrine tumor with an instance of 1–2 per million (Stringel et al. 1980). The majority of paragangliomas arise in the adrenal medulla (Lenders et al. 2005), but when they arise in extra-adrenal sites, they occur in decreasing order of frequency in the abdomen – in the organ of Zuckerkandl, pelvis, mediastinum, and the head and neck (Pacak et al. 2001). In the head and neck, they are mainly parasympathetic and nonsecreting with a specific entity arising in the carotid body – carotid body tumor – which is extremely rare in childhood (Deal et al. 1990). In childhood, they are often multiple or bilateral with 40% probably associated with an underlying genetic condition and very rarely are malignant (Krijger et al. 2006).

1.1.1 Pheochromocytomas in the United Kingdom National Registry of Childhood Tumors, 1971–2002

The registration of nonmalignant tumors has clearly been incomplete, especially before 1981. Detailed data therefore only covers the period 1981–2000 (Spoudeas and Harrison 2005) (Tables 42.1.1 and 42.1.2).

Table 42.1.1 Numbers of registrations by calendar period and tumor behavior

Table 42.1.2 Numbers of registrations by age and sex, 1981–2002

Pheochromocytoma was more common in older children, with boys more frequently affected (1.5:1).

Incidence of malignant pheochromocytoma was 0.02 per million children.

For benign and unspecified, a minimum estimate of incidence is 0.11 per million.

Among 31 children with benign or unspecified tumors, three were diagnosed at postmortem; no other deaths have been recorded.

Of five children registered with malignant ­pheochromocytoma, two died at intervals of 2 days and 14 months after diagnosis; the other three are alive with survival times between 3 and 22 years.

1.2 Clinical Presentation

In children the presentation can be very variable, but symptoms are mainly due to the excess catecholamine secretion (Caty et al. 1990; Criftci et al. 2001; Ein et al. 1997). Twice as many cases occur in boys than girls with a mean age of about 11 years at presentation, the majority presenting with hypertension which may be intermittent and not present in all cases (Barontini et al. 2006; Beltsevich et al. 2004; Ludwig et al. 2007). Other symptoms of catecholamine excess include headache, palpitations, excess sweatiness, weight loss, vomiting, anxiety, and behavioral problems (Haws et al. 2007).

Probably in nearly half of paragangliomas in childhood there will be a hereditary basis (Barontini et al. 2006; Krijger et al. 2006; Ludwig et al. 2007), so where there is a clinical suspicion of pheochromocytoma, a detailed family history and clinical examination for the physical characteristics of the following familial/genetic syndromes should be undertaken.

• Neurofibromatosis type 1 (NF-1) – Café au lait patches, axillary freckling, neurofibromas, macrocephaly, and Lisch nodules of iris

• Multiple endocrine neoplasia type 2B (MEN2B) – Marfanoid habitus, ganglioneuromatosis of bowel, neuromas of tongue and lips, hyperplasia of nerves of conjunctiva

• Multiple endocrine neoplasia type 2A (MEN 2A) – Thyroid mass, Hirschsprung’s disease, cutaneous lichen amyloidosis

• Von Hippel–Lindau (VHL) – Retinal hemangiomas, CNS hemangioblastoma (mainly cerebellar), renal carcinoma (usually in adult life)

• Paraganglioma syndrome (SDH) – Head and neck paragangliomas, intra-adrenal paragangliomas, extra-adrenal paragangliomas

1.3 Diagnostic Investigations

1.3.1 Biochemical

The diagnosis of pheochromocytoma should be confirmed by the measurement of at least two 24-h urine samples for metanephrines (normetanephrine or metanephrine) and catecholamines, and the degradation product urinary vanillylmandelic acid (VMA) (Lenders et al. 2002; Pacak et al. 2007). If the diagnosis of pheochromocytoma is in doubt, for superior diagnostic accuracy, measurement of plasma-free metanephrine and normetanephrine are considered more accurate biochemical tests both in adults and probably in children (Sawka et al. 2003; Weise et al. 2002).

1.3.2 Imaging/Localizing Investigations

Tumor localizing investigations should not be performed until a biochemical diagnosis has been made. However, where there is a hereditary or genetic predisposition, imaging investigations may be used for screening. Magnetic resonance imaging (MRI) of the abdomen and pelvis should be performed avoiding the radiation exposure of computed tomography (CT) scan. The MRI scan clearly helps to localize site of the tumor, assess its size, and look at its relationships to major vessels (Pacak et al. 2001). Functional imaging is required, however, using I¹²³ metaiodobenzylguanidine (MIBG) scintigraphy to confirm the diagnosis and detect multiple synchronous primaries and possible malignant disease (Ilias and Pacak 2004; Velchik et al. 1989). This may necessitate further cross-sectional imaging. It should be noted that malignant paragangliomas lose the ability to accumulate MIBG and hence may not detect all sites of metastatic disease. Further imaging that may be useful in this situation include [¹⁸F]-fluorodeoxyglucose positron emission tomography (FDG-PET) (Timmers et al. 2007a).

1.3.3 Other Investigations

Echocardiography and ECG for long-standing evidence of hypertension.

1.4 Preoperative Medical Management

Definitive treatment for pheochromocytoma is surgical resection but only after there has been effective blockade of catecholamines for at least 10–14 days prior to surgery. If there is adequate preoperative α-adrenergic blockade with phenoxybenzamine, as the usual agent, the risk of intraoperative complications is significantly reduced (Goldstein et al. 1999). Doxazosin could be considered if phenoxybenzamine is poorly tolerated. β blockers for tachycardia should only be used after adequate α-adrenergic blockade has been achieved. Adequate hydration is necessary to support the relatively reduced circulating blood volume resulting from the α-blockade (Hack 2000).

1.5 Operative Management

The preferred approach to resection is laparoscopic, but open resection is acceptable, particularly with invasive or metastatic disease (Brunt et al. 2002). If there are multiple tumors, there should be an attempt to remove all tumors at the same time, and in children with bilateral adrenal involvement, cortical-sparing adrenalectomies should be considered to avoid the difficulties of cortical steroid replacement during adolescence (Table 42.1.3).

1.6 Malignant Paragangliomas

The incidence of malignancy is probably low at less than 6% in childhood paragangliomas (Barontini et al. 2006; Chrisoulidou et al. 2007; Criftci et al. 2001). Malignancy cannot be diagnosed by histology alone but by the presence of local invasion and/or metastatic disease usually in bone, lung, or liver. Although generally incurable, some patients can survive for many years (Havekes et al. 2007). There is little or no literature on children with malignant paragangliomas, but individual cases are included in adult series (Gonias et al. 2009; Havekes et al. 2007). Unresectable tumors can be managed symptomatically in order to improve the quality of life of the child with either phenoxybenzamine or doxazosin. Following debulking surgery, MIBG therapy maybe effective either alone or in association with chemotherapy (Sisson et al. 1999) (Loh et al 1997) usually a combination of vincristine, cyclophosphamide, and dacarbazine (Auerbach et al. 1988). In a recent study, including small numbers of children, high-dose MIBG therapy was used with stem cell support producing an improved 5 year survival rate of 64% but with significant toxicities (Gonias et al. 2009).

Temozolamide may have a role presurgery in reducing metastatic disease, although this is based only on a single case report (Bravo et al. 2009).

1.7 Carotid Body Tumors

Carotid body tumors (CBT) are a distinct clinical group of extra-adrenal paragangliomas which arise in the chemoreceptive tissue located in the carotid bifurcation or glomus body and hence also described as glomus body tumors. Certainly, in adults, CBT is the most frequent paranganglioma in the head and neck (Dardik et al. 2002; Pellitteri et al. 2004); however, data in children is lacking with only individual cases reported (Gounot et al. 1990; Ophir 1991) either in adults series, (Dickinson et al. 1986; Shamblin et al. 1971) or in pediatric paraganglioma series (Takautz et al. 2003). Carotid body tumors are often bilateral (Dardik et al. 2002; Dickinson et al. 1986), can be multicentric, the most common association between an intravagal paraganglioma and CBTs (Borba and Al-Mefty 1996). Carotid body tumors are usually sporadic but rarely can have a familial inheritance associated with paraganglioma syndromes due to mutations in the succinate dehydrogenase (SDH) genes (Benn et al. 2006). Presentation is usually as a slowly enlarging pulsatile mass in the upper neck, often misdiagnosed as cervical lymphadenopathy, neurofibromas, or brachial cysts. Later, cranial nerve or adjacent pharynx may be involved (Gujrathi and Donald 2005; Takautz et al. 2003).

Malignancy is rare in CBTs (Shamblin et al. 1971), and as with paragangliomas arising at other sites, it is defined by metastatic spread, usually to cervical lymph nodes but infrequently to distant organs. The risk of malignancy is probably greatest in younger patients with heritable tumors associated with SDH mutations (Timmers et al. 2007b). There is only one report, however, of a child with distant metastatic disease from a CBT (Hajnzic et al. 1999).

Once CBTs are suspected, ultrasound studies can help exclude other causes of neck masses such as lymph nodes, thyroid, or brachial cysts with Doppler studies evaluating the hypervascularity of the tumor. MRI scanning, however, usually reveals a well-defined carotid space lesion (Mey et al. 2001). ¹¹¹In octreotide scintigraphy can detect metastases in patients with malignant tumors with a role for possible PET scanning (Gujrathi and Donald 2005). Complete surgical resection is usually curative for the majority of patients with prior tumor embolization only being reported in one child (Zaupa and Höllwarth 2007), although there is still a risk of stroke or cranial nerve palsies. Larger and more invasive CBTs in children may require carotid shunting and vascular reconstruction (Thompson and Cohen 1989). The treatment of malignant CBTs remains, as for other paragangliomas, surgical, though as nonsecreting tumors, they do not respond to α-adrenergic blockade with phenoxybenzamine.

1.8 Genetic Management

Following the diagnosis of paranganglioma in childhood, referral for genetic testing should be done in all cases as approximately nearly half of parangangliomas in children will have an underlying genetic or hereditary basis (Krijger et al. 2006). The absence of a family history does not preclude the patient having a mutation; indeed childhood paragangliomas can be considered a probable genetic disease requiring lifelong follow-up (Ein et al. 1990). It is important when taking a history and examining patients with paragangliomas to consider a diagnosis of the following hereditary syndromes.

1.8.1 Multiple Endocrine Neoplasia Type 2 (MEN 2)

This autosomal dominant tumor syndrome is a result of a mutation in the RET (rearranged during transfection) proto-oncogene in an autosomal dominant pattern. There is a high percentage of bilateral parangangliomas in more than 50% of cases, but malignant paragangliomas are rare (Eisenhofer et al. 2001).

1.8.2 Von Hippel–Lindau (VHL) Disease

This autosomal dominant disease is due to a mutation in the VHL gene on chromosome 3p25-26 with paragangliomas developing in 10–20% of patients (Ong et al. 2007). Though the paragangliomas mainly develop in adulthood, they have been reported in ­children with VHL and are often bilateral, but malignant disease is rare (Criftci et al. 2001; Krijger et al. 2006; Ludwig et al. 2007).

1.8.3 Neurofibromatosis Type 1 (NF 1)

This distinctive clinical syndrome occurs from a mutation in the NF1 gene on chromosome 17q11.2. Parangangliomas only occur in a small percentage of patients.

1.8.4 Paraganglioma Syndrome (SDH)

Mutations in subunits of the succinic dehydrogenase enzyme complex gene in the mitochondrial respiratory chain are associated with familial paragangliomas. Two particular subunits, SDH and SDHB, are most likely to be associated with childhood with paragangliomas (Pham et al. 2006). Patients with SDHD ­mutation are more likely to have head and neck parangangliomas, multifocal disease, and a small chance of developing malignant tumors (Benn et al. 2006; Havekes et al. 2007). Patients with SDHB mutations are more likely to present at a younger age with paragangliomas in extra-adrenal sites with a higher chance of metastatic disease (Benn et al. 2006; Ludwig et al. 2007; Timmers et al. 2007b).

1.9 Conclusions

The management and diagnosis of paragangliomas in childhood has improved over time with better preparation prior to surgery, increasing use of laparoscopic techniques, and potentially newer imaging studies to detect metastatic disease. The outcome is generally excellent for children, but genetic testing is paramount to determine the lifelong risk for further disease and malignancy.

2 Adrenocortical Tumors in Children

• Carlos Rodriguez-Galindo 

1. Department of Pediatric Oncology, Dana-Farber/Children’s Hospital Cancer Center, Harvard Medical School, 450 Brookline avenue, 02115, Boston, MA, USA

   Carlos Rodriguez-Galindo

2.1 Introduction

Adrenocortical tumors (ACT) encompass a spectrum of diseases with often seamless transition from benign (adenoma) to malignant (carcinoma) behavior. Their incidence in children is extremely low (only 0.2% of pediatric cancers) (Bernstein and Gurney 1999), and most pediatric oncologists see few cases or none. Little is known about these tumors, and most available information has been learned from their more frequent adult counterpart. In recent years, an international registry has provided insight into the clinical characteristics and relevant management issues regarding pediatric ACT and tumor tissue for biological studies. These studies have resulted in the discovery of a novel mechanism of tumorigenesis (Ribeiro et al. 2001).

2.2 Epidemiology of Adrenocortical Cancer

ACT appear to follow a bimodal distribution, with peaks during the first and fourth decades (Wooten and King 1993). In children, 25 new cases are expected to occur annually in the United States, for an estimated annual incidence of 0.2–0.3 cases/million. Internationally, however, the incidence of ACT appears to vary substantially. The incidence of ACT is particularly high in southern Brazil, where it is approximately 10–15 times of that observed in the United States. Most cases occur in the contiguous states of Sao Paulo, Paraná, and Santa Catarina (Figueiredo et al. 2006; Pianovski et al. 2006; Ribeiro and Figueiredo 2004; Rodriguez-Galindo et al. 2005).

Predisposing genetic factors have been implicated in >50% of the cases in North America and Europe and in 95% of the Brazilian cases. Germline TP53 mutations are almost always the predisposing factors. In the non-Brazilian cases, relatives of children with ACT often, though not invariably, have a high incidence of other nonadrenal cancers (Li–Fraumeni syndrome), and germline mutations usually occur within the region coding for the TP53 DNA-binding domain (exons 5–8, primarily at highly conserved amino acid residues). In the Brazilian cases, in contrast, the patients’ families do not exhibit a high incidence of cancer, and a single, unique mutation at codon 337 in exon 10 of the TP53 gene is consistently observed (see below).

Patients with Beckwith–Wiedemann and hemihypertrophy syndromes have a predisposition to cancer, and as many as 16% of their neoplasms are ACT (Hoyme et al. 1998). However, less than 1% of children with ACT have these syndromes (Steenman et al. 2000). ACT have also been reported in association with other genetic diseases such as congenital adrenal hyperplasia (Varan et al. 2000).

The differential diagnosis of ACT includes other diseases characterized by adrenal hormone hyperproduction. ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a benign proliferative disorder of the adrenal cortex that presents with ACTH-independent Cushing’s syndrome. The majority of patients with AIMAH present in the fifth decade of life with sporadic isolated disease; however, in children, AIMAH can be associated with McCune–Albright syndrome (Sutter and Grimberg 2006). A similar macronodular adrenocortical hyperplasia is seen in up to one third of patients with multiple endocrine neoplasia syndrome type 1 (MEN1) and although rare, adrenocortical carcinomas have been described in this population, usually in adult age (Langer et al. 2002). Primary pigmented nodular adrenocortical disease (PPNAD) is a benign bilateral proliferative disorder characterized by small hyperpigmented nodules, usually associated with the Carney complex. This is an autosomal dominant syndrome that includes lentiginosis (perioral, ocular, or genital), cardiac and peripheral myxomas, melanotic schwannomas, and endocrine overactivity. Clinically evident PPNAD is seen in up to 30% of patients with Carney complex and usually presents in childhood, late adolescence, or early adulthood (Sutter and Grimberg 2006).

2.3 Biology of ACT

The molecular mechanisms of tumorigenesis of the adrenal cortex are not well understood (Kirschner 2002; Barlaskar and Hammer 2007). Carcinogenesis is a multistep process, and the pathogenesis of ACT may combine dedifferentiation and unchecked proliferation induced through the activation of hormonal or growth factor signaling receptors. The insulin-like growth factor (IGF) system is well characterized for its contribution to normal and pathological adrenocortical growth. Clues to the role of this pathway in the development of ACT also came through the recognition of the increased incidence of ACT in children with Beckwith–Wiedemann syndrome (BWS) (Steenman et al. 2000). Genetic alterations associated with BWS are mapped to regions of chromosome band 11p15 designated BWS chromosomal regions (BWSCR) 1, 2, and 3 (Steenman et al. 2000). IGF2 is mapped to BWSCR1. The strong association of BWS, IGF2, and ACC suggests that IGF2 participates in tumorigenesis, and studies have shown increased IGF2 protein and mRNA in ACC (Ilvesmaki et al. 1993; Boulle et al. 1998). Sporadic adrenocortical carcinomas (ACC) also show striking overexpression of IGF2, and studies in adults have documented >100-fold higher expression levels in carcinomas in comparison to adenomas and normal adrenal tissue (Gicquel et al. 2001). This differential IGF2 expression between adenomas and carcinomas doesn’t seem to be observed in pediatric tumors (see below) (Almeida et al. 2008; West et al. 2007). Interestingly, the antiproliferative effect of ACTH is blunted in ACT cell lines overexpressing IGF1R (Weber et al. 2000). Further, transgenic mice expressing IGF2 postnatally develop adrenal hyperplasia (although not frank malignancy) (Weber et al. 1999). Taken together, the evidence strongly suggests that the IGF system is involved in adrenal growth and tumorigenesis. High local IGF2 levels combined with elevated IGF1R expression would provide a significant growth advantage, but additional steps are required for neoplastic transformation (Kirschner 2002; Barlaskar and Hammer 2007; Weber et al. 2000). Studies in several model organisms indicate the presence of undifferentiated multipotent adrenocortical cells, and a few molecular studies have implicated Wnt signaling pathway activation in ACC (Tissier et al. 2005). Further investigations are necessary to elucidate the contributions of developmental signaling pathways like Wnt in adrenal tumorigenesis.

The hypothetical multistep transformation process also requires intracellular signaling abnormalities other than dedifferentiation- and proliferation-inducing signals. TP53 mutations appear to underlie such abnormalities in most cases, and ACT are strongly associated with germline TP53 mutations. ACT are among the tumors most increased in frequency in ­families with Li–Fraumeni syndrome (Birch et al. 2001; Kleihues et al. 1997; Gonzalez et al. 2009), suggesting that germline TP53 mutations exert tissue-specific effects. The diagnosis of ACT in a young patient should be considered a strong indicator of a germline TP53 mutation, regardless of the family history (Gonzalez et al. 2009). A wide spectrum of germline TP53 alterations have been described in ACT, and these mutations may contribute to the etiology of more than 80% of cases in children (Varley et al. 1999; Wagner et al. 1994). Consistent with the presence of a germline TP53 mutation, relatives of children with ACT often have a high incidence of cancer; however, the lack of family history should not preclude investigation of TP53 germline status (Varley et al. 1999; Wagner et al. 1994; Ariffin et al. 2008; Khayat and Johnston 2004; Rossbach et al. 2008). In North American children, the spectrum of germline TP53 mutations in ACT is quite diverse, although germline mutations occur primarily in the TP53 DNA-binding domains (exons 4–8) (Wagner et al. 1994; Reincke et al. 1994; Varley et al. 1999). In the Brazilian cases, by contrast, the patients’ families do not have a high incidence of cancer, and a single mutation in exon 10 of the TP53 gene is consistently observed. This mutation encodes an arginine in place of histidine at codon 337 (TP53-R337H) within the tetramerization domain. The families of these children do not share common ancestry. Recent studies have indicated that the R337H mutation is a relatively common polymorphism among southern Brazilians. Further, the penetrance of this mutation is low (only 10–15% of carriers develop ACT), and it appears not to predispose carriers to other malignancies later in life (Figueiredo et al. 2006). The wild-type allele is deleted in these tumors, and the mutant p53 protein accumulates in the nucleus. Functional analyses have shown that the mutant TP53 retains transactivation function and can induce apoptosis (Ribeiro et al. 2001). However, the mutant tetramerization domain is less stable than the wild-type domain and is sensitive to slightly increased pH, suggesting that a unique physiological condition within adrenocortical cells may contribute to the observed tissue-restricted pathogenesis (DiGiammarino et al. 2001). Thus, this inherited unique TP53 mutation represents a low-penetrant, hypomorphic allele that contributes to the development of ACT in a tissue-specific manner (Ribeiro et al. 2001). Other TP53 mutations, such as the TP53R157L, with sufficient activity to suppress Li–Fraumeni syndrome but not ACC, have been described (West et al. 2006), thus the importance of in-depth evaluation and genetic counseling of children with ACT and their families.

Additional genetic alterations may be necessary for malignant transformation. ACT are characterized by a high frequency of chromosomal gains and amplifications, and several chromosomal subregions containing candidate proto-oncogenes are affected (Dohna et al. 2000; Figueiredo et al. 1999; Loncarevic et al. 2008). Interestingly, the pattern of genomic imbalances in pediatric ACT appears to be different from their adult counterparts. In a series of nine cases in Southern Brazil, the most consistent findings were a gain of all or part of chromosome arm 9q (eight cases) and amplification of band 9q34 (five cases) (Figueiredo et al. 1999). Loncarevic et al. analyzed 14 pediatric ACT by comparative genomic hybridization. Recurring genomic changes included gains of 1q, 12p, 12q, 1p, 7q, 9q, and 15q; and losses of 4q, 11q, 4p, and 16q (Loncarevic et al. 2008). Of particular interest is the consistent finding of gain of 9q in both series. The steroidogenic factor 1 gene (SF1, NR5A1) is located within this region and has been shown to be overexpressed in nearly all childhood ACT (Doghman et al. 2007). Enforced expression of SF1 increases human adrenocortical cell proliferation and promotes adrenocortical tumorigenesis in transgenic mouse models. Collectively, these findings strongly implicate SF1 as a driver in the initiation and/or progression of ACT. Additional studies are required to determine whether deregulation of SF1 cooperates with TP53 loss in ACT.

Microarray studies in childhood ACT show distinct patterns of gene expression that distinguish normal adrenal tissue, adenomas, and carcinomas (West et al. 2007). A significantly increased expression of FGFR4 and IGF2 was found in childhood ACC, although the degree of IGF2 expression seems to be lower than adult tumors, and in contrast to adult ACT, this expression does not distinguish childhood adrenocortical adenoma from carcinoma. Also, there was a remarkable correlation in gene expression profiles between normal fetal adrenal tissue and pediatric ACT. There were very significant differences in gene expression between pediatric adenomas and carcinomas; remarkably, expression of major histocompatibility class II genes was lower in carcinomas than in adenomas, suggesting that malignant tumors may have evolved mechanisms to evade recognition by the immune ­system (West et al. 2007).

The distinctive clinical features suggest that ACT arises from the fetal zone of the fetal adrenal cortex. The fetal zone represents 85% of the adrenal cortex during fetal development, and it is oriented toward dehydroepiandrosterone production. It is thus possible that the presence of a constitutional TP53 mutation increases the penetrance of ACT in the fetal adrenal cortex with lower risk for the remaining layers. Disruption of the TP53 pathway under certain conditions may result in abnormalities of other cellular pathways leading to tumor formation.

2.4 Clinical Characteristics of Pediatric ACT

The clinical characteristics, treatment, and outcome of ACT have been described mainly in adults; because there are few reports about pediatric ACT, it is difficult to discriminate features unique to either age group. The degree and type of endocrine disturbance appear to be related to patient age (Wooten and King 1993; Wajchenberg et al. 2000). Older patients tend to have a much higher incidence of nonfunctional tumors, whereas more than 90% of childhood ACT are functional (Wajchenberg et al. 2000; Ribeiro et al. 1990; Ciftci et al. 2001; Driver et al. 1998). Adults usually have mixed virilization-hypercortisolism syndromes, whereas virilization syndrome is the most common presentation in children (Wajchenberg et al. 2000; Ribeiro et al. 1990; Ciftci et al. 2001; Driver et al. 1998).

Despite the rarity of childhood ACT, its clinical and pathologic characteristics have been well characterized in recent years (Ribeiro et al. 1990; Ciftci et al. 2001; Driver et al. 1998; Wieneke et al. 2003; Sandrini et al. 1997; Bugg et al. 1994; Ribeiro and Figueiredo 2004; Rodriguez-Galindo et al. 2005; Teinturier et al. 1999). Significant information has been obtained from the International Pediatric Adrenocortical Tumor Registry (IPACTR) (www.stjude.org/ipactr), established in 1990 by the St. Jude Children’s Research Hospital International Outreach Program, and institutions in Brazil. The registry has served as an information-exchange Web site, and more than 300 patients have been registered to date (Michalkiewicz et al. 2004). The registry now also includes a tumor bank component to collect from international sites both ­normal and adrenal tumor tissue for detailed biological studies.

Childhood ACT typically present during the first 5 years of life (median age, 3–4 years), although there is a second, smaller peak during adolescence (Ribeiro et al. 1990; Ciftci et al. 2001; Wieneke et al. 2003; Sandrini et al. 1997; Teinturier et al. 1999; Michalkiewicz et al. 2004; Narasimhan et al. 2003). Female sex is consistently predominant in most studies, with a female to male ratio of 1.6:1 (Wieneke et al. 2003; Sandrini et al. 1997; Michalkiewicz et al. 2004; Ciftci et al. 2001; Narasimhan et al. 2003; Hanna et al. 2008). According to the IPACTR data, the female predominance is more significant for patients younger than 3 years of age (1.7:1) and for patients older than 13 years (6.2:1), but not for patients between 3 and 12 years (Michalkiewicz et al. 2004). Because pediatric ACT are almost universally functional, they cause endocrine disturbances, and a diagnosis is usually made 5–8 months after the first signs and symptoms emerge (Ciftci et al. 2001; Wieneke et al. 2003; Michalkiewicz et al. 2004). Virilization (pubic hair, accelerated growth, enlarged penis, clitoromegaly, hirsutism, and acne) due to excess of androgen secretion is seen, alone or in combination with hypercortisolism, in more than 80% of patients (Fig. 42.2.1). Isolated Cushing’s syndrome is very rare (5% of patients), and it appears to occur more frequently in older children (median age 12.6 years in the IPACTR) (Ciftci et al. 2001; Wieneke et al. 2003; Teinturier et al. 1999; Michalkiewicz et al. 2004; Hanna et al. 2008). Likewise, nonfunctional tumors are rare (less than 10%) and tend to occur in older children (Michalkiewicz et al. 2004). Half of the patients have severe hypertension at presentation, and hypertensive crisis resulting in seizures is the presenting feature in 10% of cases (Ribeiro et al. 1990; Wieneke et al. 2003; Sandrini et al. 1997; Michalkiewicz et al. 2004; Wang et al. 2007). However, isolated Conn’s syndrome with hypertension, hypokalemia, and pseudoparalysis resulting from hyperproduction of aldosterone or deoxycorticosterone is extremely rare (less than 1% in the IPACTR data) but has been described (Michalkiewicz et al. 2004; Narasimhan et al. 2003). An abdominal mass can be palpated in approximately half the patients (Ciftci et al. 2001; Teinturier et al. 1999).

Fig. 42.2.1

Two-year-old boy presenting with virilization (a, b). CT scan demonstrated a right adrenal mass (c)

At the time of diagnosis, two thirds of pediatric patients have limited disease (tumors are completely resected), and the remaining patients have either unresectable or metastatic disease (Michalkiewicz et al. 2004). In up to 20% of the cases, intracaval extension of the tumor is present (Michalkiewicz et al. 2004; Tucci et al. 2005). Unlike adult ACT, histologic differentiation of adenomas and carcinomas is difficult. However, approximately 10–20% of pediatric cases are adenomas (Wieneke et al. 2003; Michalkiewicz et al. 2004).

2.5 Diagnosis

Children with ACT usually present with striking endocrine syndromes, most commonly virilization, and thus are usually diagnosed earlier than adults. Because of the hormone hypersecretion, it is possible to establish an endocrine profile for each particular tumor, which may facilitate the evaluation of response to treatment and monitor for tumor recurrence. Laboratory evaluation can also help distinguish physiological adrenarche or congenital adrenal hyperplasia from ACC. Patients with adrenarche have elevated basal concentration of DHEAS and androstenedione, while those with congenital adrenal hyperplasia may show increased basal or ACTH-stimulated peak concentration of 17-OH-progesterone (Ribeiro and Figueiredo 2004). While the diagnosis of ACC is usually clinical, imaging studies are important to complete staging and for surgical planning. Magnetic resonance imaging (MRI) and computed tomography (CT) are needed for evaluation of the size and location of the primary tumor, the degree of invasion to surrounding structures, the presence of metastases, and involvement of venous structures. Although bone metastases at diagnosis are extremely rare, scintigraphic studies are recommended. On CT, large tumors usually have a central area of stellate appearance caused by hemorrhage, necrosis, and fibrosis; this central area is usually hyperintense on T2-weighted MRI and STIR images. Calcifications are also common (Ribeiro et al. 2000). In order to evaluate tumor extension into the vena cava, ultrasound or MRI are always recommended, and a careful evaluation of the presence of a tumor thrombus must always be performed prior to surgery (Ribeiro and Figueiredo 2004; Tucci et al. 2005). Because ACT are metabolically active, whole-body fluorodeoxyglucose (FDG) positron emission tomography (PET) is being increasingly used. Although the experience in pediatrics is limited, available information suggests that this may be a very useful technique in the imaging of the regional and metastatic extension, and in the diagnosis of recurrences in areas not typically imaged (Mackie et al. 2006; Murphy et al. 2008).

The distinction between benign (adenomas) and malignant (carcinomas) tumors can be problematic. In fact, adenoma and carcinoma appear to share multiple genetic aberrations and may represent points on a continuum of cellular transformation (Dohna et al. 2000; Figueiredo et al. 1999). Macroscopically, adenomas tend to be well defined and spherical, and they never invade surrounding structures. They are typically small (usually <200 cm³), and some studies have included size as a criterion for adenoma. Microscopically, they may resemble normal adrenal cortex. By contrast, carcinomas have macroscopic features suggestive of malignancy; they are larger, and they show marked lobulation with extensive areas of hemorrhage and necrosis. Microscopically, carcinomas comprise larger cells with eosinophilic cytoplasm, arranged in alveolar clusters. Several authors have proposed histologic criteria that may help to distinguish the two types of neoplasm (Weiss 1984; Slooten et al. 1985). However, morphologic criteria may not allow reliable distinction of benign and malignant ACC. Mitotic rate is consistently reported as the most important determinant of aggressive behavior (Weiss et al. 1989; Kendrick et al. 2001; Stojadinovic et al. 2002; Harrison et al. 1999). IGF2 expression also appears to discriminate between carcinomas and adenomas in adults but not in children (Almeida et al. 2008; West et al. 2007; Rosati et al. 2008; Erickson et al. 2001). Other histopathologic variables are also important, and risk groups may be identified on the basis of a score derived from characteristics, such as venous, capsular, or adjacent organ invasion; tumor necrosis; mitotic rate; and the presence of atypical mitoses (Stojadinovic et al. 2002). Two retrospective studies have investigated histological criteria of malignancy in pediatric ACT. Bugg et al. analyzed histology, ploidy, proliferative index, and tumor size in 54 cases (Bugg et al. 1994). The histologic criteria for malignant tumors were the mitotic index, the presence of confluent necrosis and atypical mitoses, and the nuclear grade, as previously defined by Weiss (Weiss 1984; Weiss et al. 1989). The most statistically significant predictors of outcome were tumor histology and tumor weight (<100 g vs. >100 g). Ploidy and proliferative index were not predictive of outcome (Bugg et al. 1994). More recently, Wienecke et al. analyzed features associated with increased probability of a malignant behavior in a series of 83 pediatric ACC (Wieneke et al. 2003). Tumor weight >400 g, tumor size >10.5 cm in the largest diameter, vena cava, capsular or vascular invasion, extension into periadrenal soft tissues, confluent necrosis, presence of severe nuclear atypia, atypical mitoses, and presence of >15 mitotic figures/20 high-power field were all associated with adverse outcome. However, on multivariate analysis, only vena cava invasion, presence of necrosis, and high mitotic rate retained prognostic significance. The incorporation of gene expression techniques to the diagnostic evaluation of ACT may provide additional means to anticipate the clinical and biological behavior, both in adult (Reynies et al. 2009) and pediatric (West et al. 2007) tumors. However, still unknown biological events rather than histopathologic tumor characteristics are likely to dictate clinical behavior.

2.6 Prognostic Factors

In an analysis of 40 cases in Southern Brazil, Ribeiro et al. (1990) found tumor volume >200 mL or weight >80 g, and age >3.5 years to be associated with worse outcome, although only tumor size was independently predictive. In the IPACTR data, several clinical features, including age, sex, clinical syndrome, interval between first symptoms and diagnosis, blood pressure, disease stage, tumor spillage, tumor thrombus, and tumor weight were examined for their association with outcome. In patients with localized disease, age between 0 and 3 years, virilization alone, normal blood pressure, disease stage I, absence of spillage during surgery, and tumor weight ≤200 g were associated with a greater probability of survival. In a Cox regression model analysis, only stage I, virilization alone, and age 0–3 years were independently associated with a better outcome (Michalkiewicz et al. 2004) (Figs. 42.2.2 and 42.2.3).

Fig. 42.2.2

Probability of 5-year event-free survival according to age at the time of diagnosis in 254 children with ACT (From Michalkiewicz et al. (2004) With permission)

Fig. 42.2.3

Probability of 5-year event-free survival according to disease stage at the time of diagnosis in 254 children with ACT (From Michalkiewicz et al. (2004) With permission)

Thus, available data suggest that tumor size is especially important in children; patients with small tumors have an excellent outcome with surgery alone, regardless of histologic features (Ribeiro et al. 1990; Wieneke et al. 2003; Bugg et al. 1994; Michalkiewicz et al. 2004; Michalkiewicz et al. 1997). A staging system based on disease extent and tumor size has been proposed on the basis of these findings (Table 42.2.1) (Rodriguez-Galindo et al. 2005; Sandrini et al. 1997). The overall probability of 5-year survival for children with ACT is reported to be 54–74% (Ciftci et al. 2001; Wieneke et al. 2003; Sandrini et al. 1997; Teinturier et al. 1999; Michalkiewicz et al. 2004; Hanna et al. 2008; Tucci et al. 2005). Data from the IPACTR and other series show the staging system to be highly predictive of outcome in children with stage I or stage IV disease: more than 90% of patients with stage I disease, but only 10% of those with stage IV disease, are long-term survivors (Fig. 42.2.3). Determining the prognosis of patients with intermediate-stage disease is much more difficult. Despite presumed complete tumor resection, local recurrence is the most common adverse event in patients with stage II disease (30–50% of cases) (Michalkiewicz et al. 2004; Tucci et al. 2005).

Table 42.2.1 Proposed staging of adrenocortical tumors in children

2.7 Treatment of Pediatric ACT

Treatment of childhood ACT has evolved from the data derived from the adult studies, and same guidelines are used; surgery is the most important mode of therapy, and mitotane- and cisplatin-based regimens are ­recommended for patients with advanced disease (Ribeiro and Figueiredo 2004; Rodriguez-Galindo et al. 2005; Zancanella et al. 2006; Hovi et al. 2003). An aggressive surgical approach of the primary tumor and all metastatic sites is recommended when feasible (Tucci et al. 2005; Stewart et al. 2004). Because of tumor friability, rupture of the capsule with resultant tumor spillage is frequent (approximately 20% of initial resections and 43% of resections after recurrence) (Sandrini et al. 1997; Michalkiewicz et al. 2004). In fact, spontaneous tumor rupture resulting in acute abdomen as presentation of a pediatric ACT has been described (Leung et al. 2002). When the diagnosis of ACT is suspected, laparotomy and a curative procedure are recommended rather than fine-needle aspiration, to avoid the risk of tumor rupture (Kardar 2001). Laparoscopic resection is associated with a high risk of rupture and peritoneal carcinomatosis; thus, open adrenalectomy remains the standard of care (Gonzalez et al. 2005). The lymph node drainage of the adrenal gland is complex. There is an extensive subserosal network of lymphatic channels around the gland, crossing several levels in different directions inside the fascia and connective tissue involving the adrenal gland. The incidence of lymph node involvement is not known, although some studies report it to be close to 40% in adults (Crucitti et al. 1996; Lee et al. 1995). In children, available data suggests that nodal involvement is present in approximately 30% of the cases (Stewart et al. 2004). Whether ipsilateral retroperitoneal lymph node dissection may improve local control is a matter of debate and a question currently being investigated in the Children’s Oncology Group ARAR0332 study (see below).

Chemotherapeutic regimens used for patients with advanced disease have derived from the standard treatments used in adults. A cisplatin-based combination, usually incorporating doxorubicin and etoposide, is most commonly used (Ribeiro and Figueiredo 2004; Rodriguez-Galindo et al. 2005; Ciftci et al. 2001; Teinturier et al. 1999; Michalkiewicz et al. 2004; Zancanella et al. 2006). Because of cisplatin’s renal dose-limiting toxicity, Ayass and coworkers substituted carboplatin for cisplatin given in combination with etoposide to a 17-month-old boy with ACT that had metastasized to the brain and chest. After complete resection of the primary tumor and eight cycles of etoposide and carboplatin, the metastatic disease responded completely and the patient survived long-term (Ayass et al. 1991).

Little information is available about the use of ­mitotane in children, although response rates appear to be similar to those seen in adults (Ribeiro and Figueiredo 2004; Zancanella et al. 2006). There have been several reports of complete responses in children with advanced or metastatic ACT, but these appear to be rare events (Coelho Netto et al. 1963; Ostuni and Roginsky 1975). In a review of 11 children with advanced ACT treated with mitotane and a cisplatin-based chemotherapeutic regimen, measurable responses were seen in seven patients. The mitotane daily dose required for therapeutic levels was around 4 g/m², and therapeutic levels were achieved after 4–6 months of therapy (Zancanella et al. 2006). Compliance with daily mitotane administration is a major limitation to therapy in young children; nausea, vomiting, diarrhea, and neurologic alterations are common (Zancanella et al. 2006). Monitoring for neurotoxicity is particularly important in young patients as the use of mitotane has been associated with motor and speech developmental delays (De Leon et al. 2002).

The use of radiotherapy in pediatric ACT has not been consistently investigated. ACT are generally considered to be radioresistant (Wajchenberg et al. 2000). Furthermore, because many children with ACT carry germline TP53 mutations that predispose to cancer, radiation may increase the incidence of secondary tumors. Driver et al. reported that three of five long-term survivors of pediatric ACT died of secondary sarcoma that arose within the radiation field (Driver et al. 1998). For most patients with metastatic or recurrent disease that is unresponsive to mitotane and chemotherapy, repeated surgical resection is the only alternative. However, given the infiltrative nature of the disease, complete resection is difficult to achieve. Image-guided tumor ablation with radiofrequency currently offers a valid alternative for these patients. Radiofrequency ablation is a minimally invasive and safe treatment for patients in whom surgery may not be possible. Using this technique, Wood et al. reported responses in 53% of the adult patients treated; these results suggest that radiofrequency ablation has a role in the management of this aggressive malignancy (Wood et al. 2003). Data regarding the use of this treatment modality in children is limited; however, it appears to offer a valid alternative for children with unresectable ACT (Hoffer et al. 2009).

Finally, advances in our understanding of ACT biology may lead to the identification of new molecular targets (Kirschner 2006). In particular, new developments in IGF pathway inhibition, such as monoclonal antibodies against the IGF1R, may provide effective alternatives and are currently being investigated (Table 42.4.1) (Almeida et al. 2008; Barlaskar et al. 2009).

2.8 A Collaborative Research Initiative for Childhood ACT

Cooperative multi-institutional efforts have been pivotal in the advancement of pediatric oncology during the past several decades. Rare pediatric tumors, however, have remained research orphans, and children with these rare malignancies have yet to benefit from group-wide initiatives. In recent years, the Children’s Oncology Group (COG) has made a commitment to develop research programs in rare childhood malignancies. Part of this effort is a collaboration between COG and Brazilian institutions to develop a study ­protocol for childhood ACC (ARAR0332) (Table 42.2.2). This protocol investigates three main clinical questions: (1) the efficacy of surgery alone for stage I tumors; (2) the role of retroperitoneal lymph node resection in reducing local recurrence of stage II tumors; and (3) the impact of mitotane- and cisplatin-based chemotherapy for unresectable and metastatic disease.

Table 42.2.2 Treatment on the COG ARAR 0332 protocol

Table 42.4.1 Guidelines for diagnosis and management of pediatric adrenocortical tumors

Table 42.1.3 Guidelines for diagnosis and management of pheocromocytoma and paraganglioma

The ARAR0332 protocol also attempts to provide further insight into the biology of ACC and the ­different patterns of TP53 mutations. In addition to the near-requisite germline TP53 mutations, a number of consistent chromosomal gains and losses have been observed in childhood ACT. These genetic alterations presumably favor the expression of tumor-promoting oncogenes while eliminating potential tumor suppressors. Genomic DNA analyses used with microarray gene expression profiling should allow the identification of the genes that cooperate with p53 inactivation to promote development of ACT.

3 Medulloepithelioma

• Gianni Bisogno 

1. Division of Hematology/Oncology, Department of Pediatrics, University-Hospital of Padova, Via Giustiniani 3, 35100, Padova, Italy

   Gianni Bisogno

Medulloepithelioma (MEP) is a rare tumor derived from the primitive neuroepithelium located in the ciliary body of the eye; however, tumors arising from the optic nerve or from the central nervous system have also been described (Vajaranant et al. 2005; Molloy et al. 1996).

Ocular medulloepitheliomas occur in early childhood with a mean age at diagnosis of 4 years. Rarely, these tumors can affect adults possibly as a late malignant transformation of a benign asymptomatic MEP arisen in childhood (Carrillo and Streeten 1979). It is a locally aggressive tumor that may extend anteriorly into the iris or posteriorly into the vitreous cavity involving the retina, with the entire globe filled with tumor similar to retinoblastoma. In advanced cases, it may present with extraocular extension and involve the regional lymph nodes. Distant metastasis to lungs and parotid gland have been rarely described (Broughton and Zimmerman 1978; Viswanathan et al. 2008). There is no racial or sexual predilection, and both eyes are equally affected (Vajaranant et al. 2005).

MEP can be associated with central nervous system malignancies (i.e., pinealoblastoma) or malformations (i.e., corpus callosum agenesia, schizencephaly) (Vajaranant et al. 2005). In addition, it has recently been suggested that MEP is a manifestation of a familiar tumor predisposition associated with pleuropulmonary blastoma (Priest et al. 2011).

3.1 Clinical Characteristics

The most common presenting symptoms are pain and poor vision, related to secondary lens subluxation, glaucoma, or cataract formation. Leukocoria and the evidence of a mass in the iris or ciliary body are also part of the initial signs (Chung et al. 2007).

On fundoscopic examination, the tumor presents an irregular surface with characteristic cystic lesions (Fig. 42.3.1a). In up to 60% of patients, cysts break off the surface and float freely in aqueous or vitreous humor. Retinal detachment is seen in many cases. MEP may also contain calcifications in some cases (Chung et al. 2007).

On ultrasound, MEP appears as an echogenic ­irregular mass with a cystic structure and calcification in some cases. CT scan shows a dense irregular mass in the region of the ciliary body with marked to moderate enhancement after contrast. On MRI, the mass is moderately hyperintense compared to vitreous on T1-weighted images, hypointense on T2-weighted images with marked enhancement after gadolinium administration (Fig. 42.3.1b) (Vajaranant et al.

Fig. 42.3.1

(a) Medulloepithelioma-Variably pigmented ­cilliary body mass. (b) MRI highlights characteristic intralesional cysts.

2005).

3.2 Diagnosis

The diagnosis requires a histopathologic examination. MEP is characterized by proliferating sheets and cords of poorly differentiated neuroepithelium with cystic spaces in between and rosette-like structures visible in some cases. It has been classified as teratoid and nonteratoid types. The nonteratoid MEP medulloepithelioma is a pure proliferation of cells of the medullary epithelium. The teratoid subtype includes also heteroplastic elements, such as cartilage, skeletal muscle, and brain-like tissue, and account for 30–50% of cases. Benign MEPs medulloepitheliomas exist, but more than two third of cases are malignant. The histopathological criteria for malignancy are the presence of poor cellular differentiation, cellular pleomorphism, sarcomatous changes, and invasion of surrounding ocular tissues (Broughton and Zimmerman 1978).

When MEP is very extensive and includes calcification, it may be difficult to distinguish it from an anteriorly located retinoblastoma. Differential diagnosis should also include benign conditions such xanthogranuloma, a cyst of the ciliary body, or the persistence and hyperplasia of the primary vitreous (PHPV) (Vajaranant et al. 2005; Chung et al. 2007).

3.3 Treatment

MEP treatment is usually based on the surgical removal of the tumor. Limited procedures can be adopted with small tumors, but enucleation may be necessary in larger lesions and exenteration when there is evidence of extraocular extension. Unfortunately, there is a substantial risk of relapse even after a complete tumor resection. The prognosis is less favorable for tumors with extraocular extension. In these cases, ­chemotherapy and/or radiotherapy have been adopted. Recent reports have showed tumor response after the administration of a regimen including vincristine, carboplatin and etoposide underlining the possible use of preoperative chemotherapy to limit the aggressiveness of surgery (Meel et al. 2010). The successful use of brachytherapy after conservative surgery has also been reported (Cassoux et al. 2010).

MEP may also arise from the optic nerve from where it may extend anteriorly into the ocular globe or posteriorly, intracranially. Enucleation with resection of the optic nerve is the usual therapeutic approach. When radiotherapy and chemotherapy have been implemented, there is conflicting results (Chavez et al. 2004).

A small series of MEP arising in the central nervous system has been published, and the most common location is the periventricular region; however, the prognosis is poor (Molloy et al. 1996).

4 Chordoma

• Gianni Bisogno 

1. Division of Hematology/Oncology, Department of Pediatrics, University-Hospital of Padova, Via Giustiniani 3, 35100, Padova, Italy

   Gianni Bisogno

Chordoma is a rare but aggressive tumor that occurs in the spine. It is believed to arise from notochord remnants located along the craniovertebral axis. The notochord develops during the third week of gestation and is located in the central portion of the future vertebral bodies. When vertebrae develop, the notochord cells form the nucleus pulposis of the intervertebral discs. It has never been shown that intravertebral discs are the site of origin of chordoma, but the fact that this tumor most frequently arises in the sacrococcygeal and sphenooccipital regions, where ectopic notochord remnants are most often found in fetuses, and with the morphological similarities between notochord and chordoma cells supports this view.

It has been estimated that about 300 new cases of chordoma/year occur in the United States, and this correspond to an incidence of approximately one case per million people/year (McMaster et al. 2001).The median age at presentation is 60 years. It is extremely rare in children and young adults where it represents less than 5% of all chordomas. No sex predisposition has been described.

Chordoma etiology is unknown. Rarely, families with multiple affected members have been reported, suggesting an inherited condition. Although extremely rare, chordoma in children and young adults present distinctive clinical and pathological characteristics but share with adults the same unsatisfactory prognosis.

4.1 Clinical Characteristics

In younger patients, chordoma more frequently arises at the base of the skull, including the clivus, rather than in the mobile spine and sacrum which are the typical site in adults (Hoch et al. 2006). Very rarely, chordoma can occur outside the spine.

The tumor tends to remain localized, but the risk of distant dissemination seems higher in children under 5 years, with metastasis most frequently in the lungs, but also in lymph nodes, bone, liver kidney, adrenal gland, and heart (Borba et al. 1996).

Chordoma is generally a slow-growing neoplasm and causes symptoms from invading the nearby structures. Pain and neurological signs are more often reported: skull base tumors cause headache, cranial nerves palsy, and torticollis, while chordoma of the spine cause alteration of bowel and/or bladder function, pain, tingling, and numbness or weakness of the arms and legs.

4.2 Diagnosis

Chordoma usually presents as a soft tissue mass associated with bone destruction and may extend into the intracranial compartment and sphenoid bone and sphenoid sinus. Both MRI and CT scan are employed to have a clear picture of tumor extension and bone involvement. CT shows an enhancing soft tissue mass with internal densities thought to represent fragments of bone and invasion of surrounding structures. On MRI, the lesion presents variable intensity and enhancement on T1-weighted images and high signal intensity on T2-weighted images (Lui et al. 2011).

A total body CT scan is also indicated to exclude distant metastasis. Conventional (or classic) chordoma is histologically characterized by a lobular ­pattern of growth with epithelioid cells arranged in nests, sheets, and syncytial cords in an abundant mucoid matrix.

The cells show some degree of nuclear atypia, the number of mitosis is usually low, and some necrosis may be present. Immunohistochemistry is usually ­positive for cytokeratin, epithelial membrane antigen, vimentin, S-100 protein, and variably for carcinoembryonic antigen and NSE. According to Louis et al. (2007), two more subtypes are recognized: the chondroid chordoma that contains elements that resembles neoplastic hyaline cartilage and behaves less aggressively than the conventional type, and the dedifferentiated chordoma, rarely encountered in children. Two more subtypes have been described in the pediatric age: (a) the cellular chordoma, possibly a conventional chordoma that lacks stroma, and (b) the poorly differentiated chordoma composed of sheets of epithelioid cells tightly packed with high nuclear/cytoplasmic ratio and distinct nucleoli. This latter variant affects very young children, behaving aggressively, tending to grow rapidly, and is often associated with metastasis (Hoch et al. 2006).

The differential diagnosis with chondrosarcomas may be difficult as they can occur in the same locations and share some morphological similarities (Rosenberg et al. 1999).

4.3 Treatment

Due to the small number of cases described in the literature, the management of pediatric cases of chordoma mainly derives from the experience gathered with adults.

Surgery has an established role, and complete tumor resection at diagnosis provides the best chances for local control and long-term survival (Park et al. 2006; Tzortzidis Elahi et al. 2006). Unfortunately, aggressive surgery is often required with a high risk of postoperative death (Borba et al. 1996) and significant morbidity (Sekhar et al. 2001). In most cases, only partial tumor resection is feasible and high-dose radiotherapy is administered. Doses in excess of 60 Gy are required, and this represents a major limitation in children. Techniques to maximize the dose of radiation to the tumor, while sparing adjacent critical structures, have been used, including proton therapy and ­intensity-modulated radiation therapy (IMRT). A limited number of patients have been treated so far, and the results seem promising: an overall survival of 81% has been reported in a series of 73 children and adolescents treated with proton bean radiotherapy after surgery. This compares favorably with a 55% 5-year survival described in adults with chordoma treated at the same institution (Hoch et al. 2006).

Chordomas are generally resistant to chemotherapy with only few reports describing a response to chemotherapy, including ifosfamide and doxorubicin (Scimeca et al. 1996), ifosfamide and etoposide (Dhall et al. 2011), or cisplatinum, vinblastine, and bleomycin (Azzarelli et al. 1988). The administration of 9-nitro-camptothecin in a phase 2 study including 15 patients with chordoma reported only one patient with an objective response (Chugh et al. 2005).

Recently, imatinib has been shown to have antitumor effects in some patients with advanced chordomas (Casali et al. 2004). The use of other targeted therapies such as cetixumab and gefinitinib has been reported (Hof et al. 2006).

4.4 Prognosis and Survival

Currently, the overall survival rate for chordoma in adults in the United States is 68% at 5 years and 40% at 10 years, with a median survival of about 7 years (McMaster et al. 2001).

Reports describing pediatric cases have shown conflicting results with some series describing worse results than in adults (Coffin et al. 1993). Recent reports of patients treated at single institutions have shown better outcome with four out of six patients alive at a median follow-up of 9 years described by Dhall et al. (2011) and an overall survival rate of 81% (median follow-up 7.2 years) in a cohort of patients with skull base chordoma referred to the Boston Massachusetts General Hospital for proton beam radiotherapy (Hoch et al. 2006). Complete tumor resection (Hug 2001) and histological subtype (Hoch et al. 2006) seem to be the major prognostic determinants. Patients with conventional chordoma have the best prognosis, while the chance of survival in the poorly differentiated subtype remains very low.