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Endocrine Reviews 27(4):371397 Copyright 2006 by The Endocrine Society doi: 10.1210/er.2006-0002

Craniopharyngiomas
Niki Karavitaki, Simon Cudlip, Christopher B. T. Adams, and John A. H. Wass
Department of Endocrinology (N.K., J.A.H.W.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, United Kingdom; and Department of Neurosurgery (S.C., C.B.T.A.), Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom
Craniopharyngiomas are rare, mainly sellar/parasellar, epithelial tumors diagnosed during childhood or adult life. Histologically, two primary subtypes have been recognized (adamantinomatous and papillary) with an as yet, unclarified pathogenesis. They may present with a variety of manifestations (neurological, visual, and hypothalamo-pituitary). Despite their benign histological appearance, they often show an unpredictable growth pattern, which, combined with the lack of randomized studies, poses significant difficulties in the establishment of an optimal therapeutic protocol. This should focus on the prevention of recurrence(s), improvement of survival, reduction of the significant disease and treatmentrelated morbidity (endocrine, visual, hypothalamic, neurobehavioral, and cognitive), and preservation of the quality of life. Currently, surgical excision followed by external beam irradiation, in cases of residual tumor, is the main treatment option. Intracystic irradiation or bleomycin, stereotactic radiosurgery, or radiotherapy and systemic chemotherapy are alternative approaches; their place in the management plan remains to be assessed in adequately powered long-term trials. Apart from the type of treatment, the identification of clinical and imaging parameters that will predict patients with a better prognosis is difficult. The central registration of patients with these challenging tumors may provide correlates between treatments and outcomes and establish prognostic factors at the pathological or molecular level that may further guide us in the future. (Endocrine Reviews 27: 371397, 2006)

I. II. III. IV. V. VI. VII. VIII. IX.

X. XI.

XII. XIII.

Introduction History Epidemiology Pathogenesis Pathology Location Presenting Manifestations Imaging Features Treatment Options A. Surgical excision with or without adjuvant conventional external beam irradiation B. Intracystic irradiation C. Intracystic bleomycin D. Stereotactic radiosurgery E. Stereotactic radiotherapy F. Systemic chemotherapy/interferon Risk Factors for Recurrence Long-Term Outcome after Surgery with or without Conventional External Beam Irradiation A. Morbidity B. Mortality Treatment Algorithm Conclusions I. Introduction

They may be diagnosed during childhood or adult life and are often associated with an enigmatic and unpredictable growth pattern. Despite their benign histological appearance, their often infiltrative tendency into critical parasellar structures and their aggressive behavior, even after apparently successful therapy, may result in significant morbidity and mortality posing a considerable medical and social problem. Their optimal management remains a subject of debate, as comprehensively summarized in a statement by J. Rutka: There is perhaps no other primary brain tumor that evokes more passion, emotion, and as a result, controversy than does the craniopharyngioma (1). This manuscript highlights the clinical and laboratory features of craniopharyngiomas at presentation and analyzes the pros and cons of the available therapeutic options. We end with a treatment algorithm based on the currently available data and point the way to further studies in this controversial treatment area.
II. History

RANIOPHARYGIOMAS ARE RARE epithelial tumors arising along the path of the craniopharyngeal duct.

First Published Online March 16, 2006 Abbreviations: BMI, Body mass index; CSF, cerebrospinal fluid; CT, computed tomography; DI, diabetes insipidus; GTR, gross total removal; MRI, magnetic resonance imaging; PR, partial removal; RT, radiotherapy; SDS, sd score; SR, subtotal removal. Endocrine Reviews is published by The Endocrine Society (http:// www.endo-society.org), the foremost professional society serving the endocrine community.

Zenker in 1857 was the first to identify masses of cells resembling squamous epithelium along the pars distalis and pars tuberalis of the pituitary (2). Extensive study by Luschka (3) of the squamous epithelial cells in the adenohypophysis followed in 1860. The significance of these findings was not initially recognized, and for many decades they remained overlooked (4). In 1902 Saxer (5) reported a tumor consisting of these cells. Two years later, Erdheim, after a systematic study of the squamous epithelial cells in the adenohypophysis, described them only in the glands of adult patients, usually on the anterior surface of the infundibulum and in groups or islets of variable size, shape, and number (6). Because a few of these groups of cells contained small cysts similar to some pituitary tumors unnamed at that time, he
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was convinced that both lesions had the same origin and called them hypophyseal duct neoplasms (6). Interestingly, he did not find any cell rests along the route of the regressed craniopharyngeal duct, a discrepancy explained by von Mihalkovitcs theory that the developing adenohypophysis underwent a forward and upward rotation carrying with it the cranial insertion of the gland (6). Similar observations on clumps of cell rests were later published by Duffy, Kiyono, and Carmichael (reported in Ref. 4), but it wasnt until 1932 that squamous epithelial cells were also detected in the pituitary glands of childhood populations by Susman (7). The first attempt for surgical removal of such a tumor (from a patient presenting the symptoms associated with hypophyseal growths but without acromegaly) by Dr. A. E. Halstead in St. Lukes Hospital (Chicago, IL) was reported in 1910 by Lewis (8). During the following years, different terminologies were used for them (including hypophyseal duct or craniopharyngeal duct or Rathkes pouch tumors, interpeduncular or dysontogenetic or suprasellar or craniobuccal cysts, suprasellar epitheliomas and adamantinomas), until 1932, when the name craniopharyngioma was introduced by Cushing (9). Commenting on the new terminology, Cushing wrote: This admittedly somewhat cumbersome term has been employed for want of something more brief to include the kaleidoscopic tumors, solid and cystic, which take their origin from epithelial rests ascribable to an imperfect closure of the hypophyseal or craniopharyngeal duct (9).
III. Epidemiology

strated (2527). Beta-catenin gene mutations have been identified only in the adamantinomatous subtype (28, 29) affecting exon 3, which encodes the degradation targeting box of betacatenin; this is compatible with an accumulation of nuclear beta-catenin protein (a transcriptional activator of the Wnt signaling pathway) (29). Furthermore, strong beta-catenin expression has been demonstrated in immunohistochemical studies of the adamantinomatous subtype (29, 30), indicating reactivation of the Wnt signaling pathway, which is implicated in the development of several neoplasms (31). In contrast, mutations in the p53 tumor suppressor gene (32) and the gsp or gip oncogenes have not been found (24). Vascular endothelial growth factor has been detected in the epithelial cells of both types of these tumors (33), and the degree of its expression is probably related to the development of macroscopic cysts (34). Cases of coexistence of craniopharyngioma with prolactinoma (35) or pineocytoma (36) have been previously reported, but this combination is probably merely coincidental.
V. Pathology

Craniopharyngiomas are rare tumors with an overall incidence of 0.13 cases per 100,000 person-years (10). They account for 25% of all the primary intracranial neoplasms (11) and 5.6 15% of the intracranial tumors in children (12 15). Although they are the commonest lesions to involve the hypothalamopituitary region in childhood populations, almost half of the total cases are diagnosed in adults (10, 15). They may be detected at any age, even in the prenatal and neonatal periods (16, 17), and a bimodal age distribution has been shown, with peak incidence rates in children of ages 514 yr and adults of ages 50 74 yr (10). In population-based studies from the United States and Finland, no gender differences have been found (10, 18). Craniopharyngioma cases have been reported within two families (19, 20), but it is not as yet clear whether there is any underlying genetic susceptibility. This seems unlikely with the numbers involved.
IV. Pathogenesis

Craniopharygiomas are epithelial tumors arising along the path of the craniopharyngeal duct, the canal connecting the stomodeal ectoderm with the evaginated Rathkes pouch. Their pathogenesis is uncertain; according to one hypothesis they arise from neoplastic transformation of embryonic squamous cell rests of the involuted craniopharyngeal duct (21), whereas a second theory suggests that they result from metaplasia of adenohypophyseal cells in the pituitary stalk or gland (22, 23). A subset of these tumors are monoclonal in origin (24), and a number of chromosomal abnormalities including translocation, deletion, and an increase in DNA copies have been demon-

Craniopharyngiomas are grade I tumors, according to the World Health Organization classification (37). Although considered histologically benign, rare cases of malignant transformation (possibly triggered by previous irradiation) (38, 39) have been reported. At the time of initial surgery, their average size in macroscopic specimens is 3.5 cm (40), with a preponderance of cystic or mixed lesions (84 99%) over the solid ones (116%) (6, 40, 41). Histologically, two primary subtypes have been recognized, the adamantinomatous and the papillary, but transitional or mixed forms have also been described (40, 42 44). The adamantinomatous type (Fig. 1) is the most common and may occur at all ages, but predominantly affects young subjects during their first two decades of life (44 46). It bears similarity with the adamantinoma of the jaw (47) and the calcifying odontogenic cyst (48), raising the possibility that this variant may arise from embryonic rests with enamel organ potential. Macroscopically, they show cystic and/or solid components, necrotic debris, fibrous tissue, and calcification, which is particularly common in children (reported in up to 94% in this age group) (6, 40 42, 45). Interestingly, bone formation (6, 40) or development of teeth within the tumor has been reported (40, 49, 50). The cysts may be multiloculated and contain liquid ranging from machinery oil to shimmering cholesterol-laden fluid, which consists mainly of desquamated squamous epithelial cells, rich in membrane lipids and cytoskeleton keratin (11). The color of the fluid is the result of the suspended blood products, protein, and cholesterol crystals. Their margins are sharp and irregular, often merging into a peripheral zone of dense reactive gliosis, with abundant Rosenthal fiber formation (consisting of irregular masses of granular deposits within astrocytic processes) in the surrounding brain tissue and the vascular structures, that may be easily mistaken for a glioma (this is particularly the case when a portion of the gliosis is biopsied and sent for frozen section) (11, 5153). Importantly, this reaction results in an anomalous, indistinct, and adherent interface between the craniopharyngioma and the normal brain tissue and makes the identification and manipulation of surgical planes often very difficult; in such cases, forcible

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tion identical to those seen in the epidermis (51). The flat squames are desquamated singly or in distinctive stacked clusters forming nodules of wet keratin, often heavily calcified and apparent grossly as white flecks (42, 44, 52, 53). The keratinous debris often elicits an inflammatory and foreign body giant cell reaction (40). The demonstration of adamantinomatous epithelium or of wet keratin alone is diagnostic, whereas features only suggestive of the diagnosis in small or nonrepresentative specimens include fibrohistiocytic reaction, necrotic debris, calcification, and cholesterol clefts (52). The papillary variety (Fig. 2), with the exception of rare

FIG. 1. Adamantinomatous craniopharyngioma. A, The epithelium consists of palisaded basal layer of cells (arrowhead), the intermediate stellate reticulum, and a layer of flattened, keratinized squamous cells. Nodules of wet keratin (arrow) are a distinctive feature (HE. 10). B, Gliotic reaction rich in Rosenthal fibers (arrow) in the surrounding parenchyma (HE. 40). [Courtesy of Dr O. Ansorge, Neuropathology Department, Radcliffe Infirmary, Oxford, UK.].

removal may be accompanied by severe damage to critical structures (6). The histological patterns of the adamantinomatous craniopharyngioma include sheets, nodular whorls, intricate anastomosing trabeculae, and clover leaves, as well as cysts lined by an attenuated epithelium (52). The epithelium is composed of a distinct palisaded basal layer of small cells with darkly staining nuclei and little cytoplasm (somewhat resembling the basal cells of the epidermis of the skin); above this is an intermediate layer of variable thickness composed of loose aggregates of stellate cells (termed stellate reticulum), whose processes traverse empty intercellular spaces, and a top layer facing into the cyst lumen with abruptly enlarged, flattened, and keratinized to flat platelike squamous cells (53). The cells show positive immunoreactivity for cytokeratins (54) and the epithelial membrane antigen (52). They do not contain secretory granules and exhibit tonofilaments, desmosomes, keratohyalin granules, and keratiniza-

FIG. 2. Papillary craniopharyngioma. The characteristic epithelium in this histological type consists of mature squamous epithelium forming pseudopapillae downward into the underlying tissues. The absence of adamantinomatous epithelium and keratinizing nodules is characteristic (A, HE. 5; B, HE. 20). [Courtesy of Dr. O. Ansorge, Neuropathology Department, Radcliffe Infirmary, Oxford, UK.].

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pediatric cases (accounting for up to 2% in this age group) (41, 42, 46), has been almost exclusively described in adult populations (accounting for 14 50% in this age group) (44, 45). Its cellular structure resembles the oropharyngeal mucosa, and although its origin remains unclear, it may represent the one extreme of a spectrum of differentiation within a single group of tumors (40). Macroscopically, it tends to be solid or mixed with cystic and solid components (42, 45, 55, 56). Calcification is rare (42, 44, 45, 53, 55), and the cyst content, in contrast to the adamantinomatous subtype, is usually viscous and yellow (42). It is generally well circumscribed, and infiltration of adjacent brain tissue by neoplastic epithelium is less frequent than in the adamantinomatous type (44) or absent (42). Microscopically, it is composed of mature squamous epithelium forming pseudopapillae and of an anastomosing fibrovascular stroma without the presence of peripheral palisading of cells or stellate reticulin (42, 44, 45, 55). The epithelial cells are also positive for cytokeratin and epithelial membrane antigen stains, and their ultrastructural examination shows abundant cytoplasm with bundles of tonofilaments, prominent microvilli, and well-formed desmosomes (42). The stroma underlying the squamous epithelium contains a small number of chronic inflammatory cells including lymphocytes, plasma cells, and, in some cases, small aggregates of foamy histiocytes (42). Discrete nodules of wet keratin are not present, but small aggregates of keratinized cells may be seen in some tumors (42, 55). The distinction between a papillary craniopharyngioma and a Rathkes cleft cyst may be difficult, particularly in small biopsy specimens, due to the capacity of the epithelial lining of the Rathkes cysts to undergo squamous differentiation (42). In such cases, the lack of a solid component and the presence of extensive ciliation and/or mucin production are suggestive of Rathkes (52). It has also been proposed that Rathkes cysts, in contrast to craniopharyngiomas, do not express cytokeratins 8 and 20 (57). The comparative pathological features of craniopharyngiomas and related lesions, Rathkes and epidermoid cysts, are shown in Table 1. A great many overlapping characteristics may be encountered among them, giving ground to the hypothesis that they represent a continuum of ectodermally derived epithelial masses (58). It has been proposed that craniopharyngiomas express

pituitary hormones (59), chromogranin A (60), human chorionic gonadotropin (61), enamel proteins, and lymphoid enhancer factor 1 (only the adamantinomatous type suggesting odontogenic epithelial differentiation) (62), as well as estrogen (63) and progesterone receptor mRNA (64) and protein (65). Interestingly, treatment of craniopharyngioma cell cultures by progesterone causes reduced [3H]thymidine uptake and increased oxidative 17 -estradiol oxidoreductase activity (resulting in significantly increased estrone formation from the added 17 -estradiol substrate) (64); the therapeutic implications of these biological actions remain to be investigated. In their cystic fluid, human chorionic gonadotropin (61, 66), IGF-I, IGF-II, and IGF-binding proteins (67), as well as IL-1 , IL-6, and TNF- have been detected (68). The significance of these findings also remains to be established. Strong IGF-I receptor expression has been demonstrated in cell lines and paraffin-embedded material in a subset of craniopharyngiomas; in this group of tumors, treatment with an IGF-I receptor inhibitor caused growth arrest (69). Further studies on a larger collection of cases are required to elucidate the clinical value of these results. Notably, recurrent craniopharyngiomas, when compared with nonrecurrent ones, show higher microvessel density values (33), lower levels of galectin-3 and macrophage migration inhibiting factor (which play a significant role in the intracellular signaling pathways that control the apoptosismediated elimination of embryological remnants of epithelial tissue) (71), lower levels of retinoic acid receptor , and higher levels of retinoic acid receptor (a family of biological regulators driving maturation in different types of epithelia) (72).

VI. Location

Craniopharyngiomas may arise anywhere along the craniopharyngeal canal, but most of them are located in the sellar/parasellar region. The majority (94 95%) has a suprasellar component (purely suprasellar, 20 41%; both supraand intrasellar, 5375%) (40, 73, 74), whereas the purely intrasellar ones represent the least common variety (5 6%) (73, 74). Occasionally, a suprasellar tumor may extend into the anterior (9%), middle (8%), or posterior (12%) fossa (40).

TABLE 1. Comparative pathological features of craniopharyngiomas and related lesions

Feature Adamantinomatous craniopharyngioma Papillary craniopharyngioma Rathkes cleft cyst Epidermoid cyst

Gross pattern of epithelium Keratin Keratohyaline granules Mucinous cells Ciliated cells Hyalinized stroma Calcification Necrosis Cholesterol
a

Complex adamantinomatous Billowy wet keratin forming discrete nodules Absent Rare Absent Absent Frequent Frequent Frequent

Papillary squamous Individual cells, nodules of keratinized cells Absent Frequent Rare Frequent Rare Absent Rare

Simple columnar or cuboidal; focally squamousa Absent Absent Frequent Frequent Absent Absent Absent Absent

Stratified squamous Flaky, laminated Frequent Absent Absent Absent Absent Absent Absent

Reprinted with permission from Crotty et al., 1995 (42). American Association of Neurological Surgeons. Resulting from metaplasia of the lining epithelium.

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Other rare locations include the nasopharynx (75), the paranasal area (76), the sphenoid bone (77), the ethmoid sinus (78), the intrachiasmatic area (79), the temporal lobe (80), the pineal gland (81), the posterior cranial fossa (82), the cerebellopontine angle (83), the midportion of the midbrain (84), or completely within the third ventricle (85).
VII. Presenting Manifestations

The potential proximity to and the subsequent pressure effects of craniopharyngiomas on vital structures of the brain (visual pathways, brain parenchyma, ventricular system, major blood vessels, and hypothalamo-pituitary system) predispose the patients to multiple clinical manifestations, the severity of which depends on the location, the size, and the growth potential of the tumor (40, 44, 74, 86 90). The duration of the symptoms until diagnosis ranges between 1 wk and 372 months (74, 89 94). The commonest presenting clinical manifestations (neurological, visual, hypothalamopituitary) are summarized in Tables 2A and 2B. Headaches, nau-

sea/vomiting, visual disturbances, growth failure (in children), and hypogonadism (in adults) are the most frequently reported. Visual field defects usually present as bitemporal hemianopia (in up to 49% of the cases) (86, 89, 91). Notably, temporal alterations of their pattern due to intermittent emptying of the cyst fluid into the ventricular system may occur (95). Other less common or rare features include motor disorders, as hemi- or monoparesis (15, 40, 74, 90, 96), seizures (15, 40), psychiatric symptoms, as emotional lability, hallucinations, paranoic delusions (40, 74, 89, 90, 96 98), autonomic disturbances (40), precocious puberty (91, 96), the syndrome of inappropriate secretion of antidiuretic hormone (99), chemical meningitis due to spontaneous cyst rupture (100), hearing loss (88), anosmia (40), nasal obstruction (101), epistaxis (102), photophobia (103), emaciation (98, 104), Webers syndrome (ipsilateral III cranial nerve palsy with contralateral hemiplegia due to midbrain infarction) (105), and Wallenbergs syndrome (signs due to occlusion of the posterior inferior cerebellar artery) (106). The hypothalamo-pituitary function at presentation may

TABLE 2A. Most common presenting clinical manifestations of craniopharyngiomas in children and adults
Ref. 12 96 40 86 145 44 89 90 15 74 Range
a b

No. of patients 57 67 241 74 61 56 121 122 75 119

Age (yr) All All 38 All 26 32 29 All 41 16 16 18 21 19 16 16 16.4 16

Headache (%) 81 66 78 50 77 7 adults, 15 children 74 53 65 56 adults, 78 children 7 81

Nausea/ vomiting (%) 68 37 34 43

Papilloedema (%) 53 31 25 29

Cranial nerves palsy (%) 6

Ataxia/ unsteadiness (%)

Cognitive dysfunction (%)a 3b 36

Decreased consciousness/ coma (%) 7

Optic atrophy (%) 20

Visual field defects (%) 58 35 71c 72 59d 60 adults, 54 children 62 79 44 60 adults, 46 children 3579

20 8 children 2 3 15 9 adults, 27 children 227

18 20 adults, 8 children 10 13 17 3 adults, 7 children 318 17 adults, 10 children 336

21 49 26 adults, 54 children 21 68

10 16 32 6 adults, 29 children 6 53

29 8 16 4 adults, 10 children 329

15 40 40 14 adults, 5 children 5 40

Memory loss, confusion, disorientation. Reported as slow mentality . c Reported as visual difficulties . d Patients with decreased visual acuity are also included. TABLE 2B. Most common presenting clinical manifestations of craniopharyngiomas in children and adults
Decreased visual acuity or visual deterioration (%) 58 Failure of sexual developmenta (%) Hypogonadism (adults) (%) Anorexia/poor weight gain or weight loss (%) Obesity or weight gain (%) Polyuria/ polydipsia (%) 9 12

Ref.

No. of patients

Age (yr)

Growth failurea (%)

Poor energy (%)

Somnolence (%)

12 96

57 67

All All

16 16

39 7 (42% with retarded bone age) 93 25 8 17 45 33 32 793

20 (of pubertal children) 85 4 14 40 5 24 4 24 28 10 85 32 adults, 22 children 2232 10 23

40 86 145 44 89 90 15 74 Range
a

241 74 61 56 121 122 75 119

20 38 All 26 32 29 All 41 18 21 19 16 16 16.4 16

47 adults, 50 children 62 80 47 40 adults, 39 children 39 80

6 23 13 3 adults 4 children 8 12 18 28 15 adults, 15 children 328

20 10 adults, 5 children 520

31 8 adults, 20 children 8 31

15 13 adults, 5 children 4 15

Children.

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TABLE 3. Pituitary hormone deficits and hyperprolactinemia at presentation in children and adults with craniopharyngioma
Ref. 205 86 145 87 204 88 190 No. of patients 42 74 61 35 75 143 18 Age (yr) All 38 All 13 All 30 17.2 18 21 19 16.3 16 GH deficiency 13/18 (72) 12/34 (35) 27/35 (77) 13/15 (87) 59/82 (72), 17/23 in children (74) 7/18 (39) FSH/LH deficiencya 3/8 (38) ACTH deficiency 4/17 (24) 18/74 (24) 7/34 (21) 12/35 (34) 16/50 (32) 45/143 (32), 8/30 in children (27) 9/18 (50) TSH deficiency 7/29 (24) 31/74 (42) 7/34 (21) 13/35 (37) 20/62 (32) 35/143 (25), 6/30 in children (20) 7/18 (39) Hyperprolactinemia DI 4/24 (17) 8/74 (12) 8/34 (23) 13/35 (38) 22/75 (29) 23/143 (16), 3/30 in children (10) 1/18 (6)

74 Range

121

No age range reported 42 16

27/33 (82) 3/6 (50) 96/143 (77), 10/11 in children (91) 10/18 (56)

7/29 (24) 12/37 (32) 59/143 (41), 5/30 in children (17) 6/18 (33)

21/22 (95), 15/15 in children (100) 35100

40/54 (74)b 38 91

40/65 (62), 15/22 in children (68) 21 68

29/81 (36), 7/28 in children (25) 20 42

24/44 (55)b 1755

19/104 (18), 7/32 in children (22) 6 38

The use of different tests and diagnostic criteria for establishing the compromised pituitary function in the various series should be taken into account. Data are presented as the number of patients with the defect/total number of patients tested (relevant percentages). a Prepubertal children were excluded from the evaluations. b Only adults were included in the evaluations.

be severely compromised; interestingly, in a series of 122 patients, 85% had one to three hormone deficits (90). A summary of the results of various studies, in which, however, different diagnostic tests and criteria have been adopted, shows that GH deficiency is present in 3595% of the evaluated patients, FSH/LH deficiency in 38 82%, ACTH deficiency in 21 62%, TSH deficiency in 21 42%, and diabetes insipidus (DI) in 6 38% (Table 3). It should also be noted that the rates of GH deficiency reported in some studies may overestimate the true incidence of this disorder, due to selection bias of the patients (particularly adults) tested, because the symptomatic ones are more likely to have been assessed. It has been proposed that the presenting clinical manifestations may be distinct in the various age groups, with most commonly reported the symptoms of raised intracranial pressure in young children (15, 96, 107), the sexual immaturity in adolescents (96), the visual field defects and features of hypopituitarism in young and middle-aged adults (96, 107, 108), and the mental changes in elderly subjects (109). In a large series of patients, comparing the presenting manifestations between childhood and adult populations, apart from headaches, nausea/vomiting, papilloedema, and cranial nerve palsies, which were more frequent in children [probably associated with the high rates of hydrocephalus in this age group (44, 74, 90)], no further differences in the clinical picture, the symptoms duration, and the rates of endocrine deficits were found (74). It should be noted that the data on the clinical manifestations should be cautiously interpreted because they are extracted from retrospective studies and are not based on specific systematic questionnaires, but instead represent what has been documented in the medical notes of the patients.
VIII. Imaging Features

angiography provided the best means for determining the direction and the degree of tumor extension, particularly in large lesions, in which neither changes in the size of the sella nor calcification would indicate their true size (6, 110). The relevant pneumoencephalographic changes included enlargement or displacement of the ventricular system and/or deformity of the neighboring subarachnoid cisterns (98). Although plain skull x-ray films have been superseded by newer imaging techniques, they may still be useful in cases of tumor calcification (Fig. 3). They may also show an abnormal sella (widening of its outlet, uniform expansion, and shortening or erosion of the dorsum sellae), reported in 46 87% of the cases (12, 93, 96, 98, 111). CT is the ideal modality for the evaluation of the bony anatomy and the detection of calcifications (112). It is also helpful in distinguishing the solid and cystic components of

Currently useful tools for the neuroradiological characterization of the craniopharyngiomas include plain skull xrays, computed tomography (CT), magnetic resonance imaging (MRI), and occasionally, cerebral angiography. Before the introduction of CT scans, air studies and carotid

FIG. 3. Skull x-ray film: craniopharyngioma causing enlarged sella with sellar destruction and suprasellar flocculonodular calcification. [Reprinted from A. S. Kashyap: Postgrad Med J 76:513514, 2000 (70) with permission from the BMJ Publishing Group.].

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the tumor. Pre- and postcontrast enhanced images in the axial plane followed by postcontrast coronal images have been advocated (15). The CT appearance of craniopharyngiomas depends on the proportion of the solid and the cystic components; they are usually of mixed attenuation, the cyst fluid has low density, and the contrast medium enhances any solid portion, as well as the cyst capsule (15, 113) (Figs. 4 and 5). MRI, particularly after contrast enhancement, is valuable for the topographic and structural analysis of these tumors (112, 114). A typical protocol includes axial T2W with sagittal and coronal T1W sequences, before and after iv gadolinium enhancement (113). The appearance of the craniopharyngioma depends on the proportion of the solid and cystic components, the content of the cyst(s) (cholesterol, keratin, hemorrhage), and the amount of calcification present. The signal of a solid tumor is iso- or hypointense relative to the brain on precontrast T1W sequences showing enhancement after gadolinium, whereas it is usually of mixed hypo- or hyperintensity on T2W sequences (56, 113). Calcification is difficult to detect on MRI studies, but if a large area is present, it may be seen as a low signal on T1W and T2W sequences (113). Rarely, calcium may produce high signal on T1W images (115). The cystic component is usually hypointense on T1W and hyperintense on T2W sequences (113). Protein, cholesterol, and methemoglobin may cause high signal on T1W images (112, 115), whereas very concentrated protein, calcification, and various blood products may be associated with low T2W signal (115). Postcontrast T1-weighted images demonstrate the thin peripheral contrast-enhancing rim of the cyst (56). Interestingly, edema in the adjacent brain parenchyma [representing a reaction to the craniopharyngioma itself or a focal disturbance in the cerebrospinal fluid (CSF) flow] spreading along the visual pathways may be present, providing a useful MRI finding for distinguishing craniopharyngiomas from other common parasellar tumors (73, 116) (Figs. 69). The size of craniopharyngiomas, as evaluated by CT or MRI, has been reported to be larger than 4 cm in 14 20% of the cases, 2 4 cm in 58 76%, and smaller than 2 cm in 4 28% (44, 111). Rare cases of giant tumors with diameter up to 12 cm have been also described (117). Notably, in a series of 45 patients, no significant difference in the tumor volume

FIG. 5. Axial CT brain demonstrating a suprasellar lesion with coarse calcification and dilatation of the temporal horns of the lateral ventricles. [Reprinted from D. R. Warakaulle and P. Anslow: Clin Radiol 58:922933, 2003 (250), with permission from the Royal College of Radiologists.]

was found among subjects older than 20 yr or younger than 20 yr (43). Their consistency is purely or predominantly cystic in 46 64% of the cases (74, 111, 118), purely or predominantly solid in 18 39% (74, 91, 111, 118), and mixed in 8 36% (74, 118). Notably, apart from rare cases with a significant cystic component, most of the intraventricular craniopharyngiomas have been reported as solid (85). It has also been proposed that the composition of a recurrent tumor is similar to the primary lesion (111). Interestingly, in a study of 91 images, there was no significant difference in the tumor consistency between children and adults (74).

FIG. 4. Axial unenhanced (A) and contrast-enhanced (B) CT demonstrating an inhomogeneously enhancing soft-tissue mass (straight arrows) in the suprasellar cistern extending into the third ventricle. Specks of calcium (curved arrows) and small cysts are also shown. [Reprinted with permission from O. P. Eldevik et al.: Am J Neuroradiol 17:14271439, 1996 (43). American Society of Neuroradiology.]

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FIG. 6. Sagittal T1-weighted MRI noncontrast (A) and contrast-enhanced (B) showing an intra-/suprasellar craniopharyngioma with a hyperintense cystic peripherally enhancing mass and a small solid inhomogeneously enhancing portion. [Reprinted with permission from S. Sartoretti-Schefer et al.: Am J Neuroradiol 18:77 87, 1997 (56). American Society of Neuroradiology.]

The calcification patterns vary from solid lumps to popcorn-like foci, or less commonly to an eggshell pattern lining the cyst wall (113). The presence of calcification confirmed by skull x-ray films or CT has been shown in 4557% of the subjects (89, 90, 93, 98, 111) and is probably more common in children, ranging between 78 and 100% (12, 40, 41, 46, 90, 91, 96, 108, 111). Hydrocephalus has been reported in 20 38% of the cases (44, 74, 86, 89, 90); it is probably more frequent in childhood populations [4154% in children (44, 74, 90, 118) and 1230% in adults (44, 74, 90)] for reasons not yet clarified. Apart from the reported cases of intraventricular craniopharyngiomas, which probably most frequently belong to the papillary type (119), the location of the two histological subtypes does not differ (56). In terms of consistency, in a series of 42 patients, the adamantinomatous type appeared predominantly cystic in 59% of the cases, mixed in 30%, and predominantly solid in 11% (56). The relevant rates for the papillary range between 12 and 27%, 27 and 53%, and 35 and 47%, respectively (42, 56). Attempts to identify radiological appearances clearly discriminating the two histological variants have not provided consistent data. Thus, analysis of the MRI features of 42 histologically proven craniopharyngiomas (56) suggested that characteristics on T1W sequences significantly useful for differentiating the two histological

types are the encasement of vessels, the lobulated shape, and the presence of hyperintense cysts for the adamantinomatous; and the round shape, the presence of hypointense cysts, and the predominantly solid appearance for the papillary. Crotty et al. (42) found no calcification in images of 17 papillary tumors, and Sartoretti-Schefer et al. (56) proposed that calcification was commoner in the adamantinomatous variant, but still not discriminatory (56). Finally, Eldevik et al. (43), in a review of 45 cases, did not find any correlation between the histological pattern and the imaging characteristics. In this series though, adamantinomatous and mixed or transitional forms but not typical squamous craniopharyngiomas were included. The differential diagnosis includes other sellar or parasellar tumors (Table 4). It may be particularly difficult to differentiate a craniopharyngioma from a Rathkes cleft cyst [typically small, round, purely cystic lesion lacking calcification (58)], and also in the rare case of a homogenously enhancing solid craniopharyngioma, from a pituitary adenoma. Finally, cerebral angiography may be useful for clarifying the anatomical relationship of the tumor with the blood vessels. Interestingly, in 65 cases of craniopharyngioma in which angiography was performed, displacement/encasement of the carotid or basilar artery was detected in 54 and 22%, respectively (89).

FIG. 7. Sagittal noncontrast (A) and contrast-enhanced (B) T1-weighted MRIs demonstrating a hypointense suprasellar tumor with peripherally enhancing cystic areas and an inhomogeneously enhancing solid tumor part. [Reprinted with permission from S. Sartoretti-Schefer et al.: Am J Neuroradiol 18:77 87, 1997 (56). American Society of Neuroradiology.]

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FIG. 8. Unenhanced (A) and contrastenhanced (B) sagittal T1-weighted MRIs showing an intra-/suprasellar multilobular cystic craniopharyngioma (straight arrows) with areas of calcification (curved arrows). [Reprinted with permission from O. P. Eldevik et al.: Am J Neuroradiol 17:14271439, 1996 (43). American Society of Neuroradiology.]

IX. Treatment Options A. Surgical excision with or without adjuvant conventional external beam irradiation

1. Primary therapy. Craniopharyngiomas pose a significant surgical challenge, even with the advent of modern neurosurgical techniques; their often large size, their sharp and irregular margins, and their adherence to vital neurovascular structures do not allow a clear line of cleavage, and thus, make complete resection difficult and potentially hazardous to critical brain areas. The surgical approach should provide wide exposure of all parts of the tumor and minimize the damage to vital structures. Its choice depends on the location, the consistency, the degree of calcification, the shape and size of the tumor, as well as on the surgeons preference and experience. Resection is usually attempted by craniotomy through a large number of approaches used alone or in combination for difficult tumors (e.g., subfrontal, pterional, lamina terminalis, transcallosal, transcortical, and bifrontal) (86, 111, 120, 121). The less traumatic transsphenoidal route is best reserved for smaller intrasellar-infradiaphragmatic tumors (86, 122). For massive lesions, a two-stage removal may be necessary: transsphenoidal debulking followed by craniotomy several weeks later. This policy may allow the tumor to descend caudally, facilitating its further resection during the second surgery (89, 123). In cases of hydrocephalus, resection can be

achieved more easily after decompression of the ventricles and stabilization of the clinical status of the patient. Similarly, when large cystic components are present, fluid aspiration provides relief of the obstructive manifestations and facilitates the consecutive removal of the solid tumor portion; the latter should not be delayed for more than a few weeks, due to the significant risk of cyst refilling (reported in up to 81% of the cases at a median period of 10 months) (74, 111). It has been proposed that radical surgery may be successful in selected tumors; in reports published during the microsurgical era with radiological confirmation of the operative result, complete removal has been accomplished in 18 84% of the cases (44, 74, 90, 111, 118, 123). The extent of resection depends on the size (44, 111, 118, 123) [achieved in 0% of lesions 4 cm (111)] and location [particularly difficult for retrochiasmatic (90) or within the third ventricle (111)] of the tumor (90, 111, 123); the presence of hydrocephalus (111, 118), of more than 10% calcification (111), and of brain invasion (90); as well as on the experience, the individual judgment during the operation, and the general treatment policy (aggressive or not) adopted by each neurosurgeon. Reasons for incomplete removal, as reported in 56 patients who underwent primary surgery, include firm adherence to hypothalamus (26.8%), obstructed view (21.4%), major calcifications (14.3%), adherence to perforating vessels (10.7%), adherence to major vessels (7.1%), severe bradycardia during dissection (5.4%), advanced age of the patient (3.6%), high

FIG. 9. Nonenhanced (A) and contrastenhanced (B) coronal T1-weighted MRIs demonstrating an intra-/suprasellar craniopharyngioma extending into the third ventricle (two-toned arrows) with multiple calcifications (curved arrows) and small cysts (white arrows). [Reprinted with permission from O. P. Eldevik et al.: Am J Neuroradiol 17:14271439, 1996 (43). American Society of Neuroradiology.]

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TABLE 4. Differential diagnosis of craniopharyngioma in CT or MRI (121)

Diagnosis Characteristics on CT and/or MRI

Rathkes cleft cyst

Dermoid cyst Epidermoid cyst Pituitary adenoma

Germinoma

Hamartoma Suprasellar aneurysm

Arachnoid cyst Suprasellar abscess

Langerhans cell histocytosis Sarcoidosis Tuberculosis

Hypothalamic or optic pathway glioma Meningioma

Small, round, purely cystic lesion lacking calcification (58). On CT, typically a homogeneous, hypodense mass, which usually does not enhance. The MRI signal returned by the cyst is variable depending on its content that of CSF or of a protein-rich fluid or of altered hemorrhage (113, 115) . Some contain a nonenhancing intracystic proteinaceous nodule thought to be indicative of the diagnosis (249). On CT, round or lobulated, often with negative density values and foci of calcification; no contrast enhancement or surrounding edema. On T1-weighted MRI, high signal, due to the lipid content (250). On CT, a lobulated mass with attenuation values similar to CSF. Calcification may be present. The MRI signal characteristics are usually similar to CSF. It does not enhance (250). On CT, macroadenomas are isodense or hypodense relative to brain tissue with variable patterns of enhancement after contrast administration. Calcification may be seen occasionally. On MRI, they have homogeneous low intensity on T1-weighted images and homogeneous enhancement after contrast administration that is less intense than the enhancement in the adjacent pituitary. Cysts or areas of necrosis cause foci of moderate hypointensity on T1- and hyperintensity on T2-weighted sequences, and heterogeneous enhancement with gadolinium. Hemorrhage in the subacute or chronic phase shows high signal on T1-weighted images. On CT, microadenomas show little inherent contrast to the normal pituitary tissue, and iv contrast demonstrates nonenhancement against a background of normal gland enhancement. On MRI, they are hypointense on T1-weighted sequences, and this contrast may or may not be amplified after gadolinium (113, 249). On CT, well-delineated masses, usually hyperdense on noncontrast scans. Calcification is common. Most cases show strong homogeneous enhancement. On MRI, isointense on T1weighted images and iso-to-hyperintense on T2-weighted images. Enhancement is intense and often heterogeneous (251). Typically, a pedunculated mass, isodense on CT and isointense on MRI, relative to gray matter. It does not calcify or enhance after administration of contrast media (113). On unenhanced CT, slightly denser than the cerebral tissue, or if a large clot is present, substantially denser; it shows enhancement after contrast administration. On MRI, flowing blood within the aneurysm usually has a characteristic signal void, often associated with regions of high signal intensity on T1-weighted images, suggesting blood. The presence of a clot or turbulent flow within the aneurysm may create a variety of different patterns. Angiography will confirm the diagnosis (249, 252). Cystic lesion with a clearly defined border. The density on CT and the signal intensity on MRI are similar to that of the CSF. It does not show calcification and does not enhance after contrast administration (113). On CT, a central area of hypodensity surrounded by a ring of increased density, which shows marked enhancement after iv contrast material. On MRI, the T1-weighted images show a marked hyperintense lesion with significant enhancement of the abscess wall after contrast administration. The T2-weighted scans show hyperintensity of the abscess contents surrounded by an area of increased signal intensity indicating edema (253). Hypothalamus and pituitary are frequent sites of involvement, showing enhancing mass lesions on CT or bright, gadolinium-enhancing areas on MRI. An enhancing, thickened infundibulum may also be seen (252, 254). On CT, isodense lesion with contrast enhancement and generally without surrounding edema or calcification. On MRI, more variable appearance, but usually hyperintense on T2-weighted images (113, 254). On contrast-enhanced CT, an enhancing mass with hypodense central necrosis and hypodense surrounding edema. A T1 gadolinium-enhanced MRI scan shows a strong rim enhancement, whereas a T2 gadolinium-enhanced scan shows hyperintense vasogenic edema, hypointense granuloma ring, and a hyperintense central necrosis (253). On MRI, sharply marginated homogeneous suprasellar mass, clearly separate from the pituitary gland. Usually hypointense or isointense with gray matter and may or may not enhance. It is rarely calcified and usually lacks a cystic component (249, 255). On CT, isodense to slightly hyperdense dural-based lesion, with homogeneous enhancement after contrast administration. Minimal to extensive peritumoral edema and calcification may be present (256). On MRI, usually an isointense with gray matter lesion in both T1- and T2weighted images. It shows dense uniform enhancement after contrast administration. Typical are the presence of a thickened dura in the region of the meningioma ( dural tail sign ), bony hyperostosis adjacent to the lesion, and normal sellar dimensions (249).

blood loss because of coexistent aneurysm (1.8%), very thin capsule (1.8%), and impression of complete removal (7.1%) (111). The recently developed intraoperative MRI seems to be a promising tool in the complex surgical management of the craniopharyngiomas (124, 125). The advances in neuroimaging, microsurgical techniques, perioperative care, and hormone replacement therapy have

significantly improved the perioperative mortality. Thus, in contrast to earlier rates of up to 41% (18, 93, 98, 108, 126), in recent reports this ranges between 1.7 and 5.4% for the primary operations (44, 74, 89, 90, 91, 111). It has been proposed that procedures resulting in radical excision may carry substantial perioperative morbidity and mortality (89, 91, 94, 118, 120, 127). This has not been confirmed in two large recent

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series (74, 111), but whether this is attributed to the differences in the tumors amenable or not to total resection cannot be excluded. It is anticipated that modern microsurgery in the hands of experienced neurosurgeons will contribute to the safety of radical procedures. Notably, in a series of 93 patients, deterioration of vision was observed in 6 and 7% of the subjects after gross total removal (GTR) or partial removal (PR), respectively (74). The data on the impact of the radicality of surgery on the pituitary function are not consistent; some suggest that the degree of postoperative endocrine deficits depends on the extent of removal (118), whereas others have not found differences after aggressive or conservative procedures (44, 74, 88). Surgery combined or not with adjuvant external beam irradiation is currently one of the most widely used first therapeutic approaches for these tumors. Notably, until 1937 when Carpenter et al. (128) first described the beneficial effects of radiotherapy (RT) after aspiration of cyst contents in four cases, craniopharyngiomas were considered radioresistant. Historically, the role of irradiation started being established almost two decades later, following the report of the favorable outcome of the combination of minimal surgery and high-dose supervoltage irradiation in a series of 10 patients by Kramer et al. (129). The irradiation of cystic craniopharyngiomas carries the risk of enlargement, which does not represent tumor recurrence and may later regress (130) or necessitate further intervention (74, 131). Notably, Rajan et al. (131) in a series of 188 irradiated patients, reported that 14% of them developed acute complications (visual deterioration, hydrocephalus and/or global deficit leading to loss of consciousness) around the time of RT, due to cystic enlargement or hydrocephalus alone (probably attributed to the inflammation of the epithelial lining of the ventricles). These complications could not be predicted by patient or disease characteristics, and they did not seem to be influenced by the dose, fractionation, and technique of irradiation. Surgical intervention was of importance for the survival; in fact, the mortality was 0% for the patients who had intervention and 86% for those who did not. Recurrent tumors may arise even from small islets of craniopharyngioma cells in the gliotic brain adjacent to the tumor, which can remain even after GTR (44). The mean interval for their diagnosis after various primary treatment modalities ranges between 1 and 4.3 yr (44, 74, 90, 91, 132, 133). Notably, recurrences as late as 26 (134) or 30 yr (46) after initial therapy have been detected. Their size, with the exception of a few cases showing significant extensions (135, 136), ranges between 0.8 and 4 cm (89). Remote recurrences after apparent successful removal have also been reported; possible mechanisms include transplantation during the surgical procedures and dissemination by meningeal seeding or CSF spreading (137140). The recurrence rates in large series of patients treated by various degrees of surgical removal (performed mainly during the microsurgical era) and combined or not with adjuvant RT are shown in Table 5. It should be noted that the reliability of the data of some of the presented studies may be affected by the absence of histological confirmation in a number of cases, and particularly in those treated with irradiation alone,

as well as by the occasional arbitrary inclusion in the surgery only treated groups of subjects who received RT postoperatively. In most studies, the GTR was confirmed by postoperative imaging, because the neurosurgeons assessment during the operative procedure, hindered by blind spots, may not always be accurate. In fact, tumor remnants were radiographically detected in 18 26% of the cases in which it was thought that complete resection had been achieved (118, 141, 142). Series with radiological confirmation of the radicality of resection show that GTR is associated with recurrence rates of 0 62% at 10-yr follow-up (44, 74, 89, 90, 111, 118, 123, 133, 143, 144). These are significantly lower than the ones following partial or subtotal removal (SR) (25100% at 10-yr follow-up) (74, 89, 111). When adjuvant RT is offered after limited surgery, the local control rates are significantly improved (recurrence rates 10 63% at 10-yr) (44, 74, 89, 90, 107, 111, 118, 123, 132, 133, 143145). Interestingly, Rajan et al. (132) found that the surgical result (biopsy or aspiration, subtotal or partial and total removal) in patients who subsequently received irradiation was not an independent predictor of recurrence, suggesting that RT may be effective in controlling the progression of both microscopic and macroscopic disease. Notably, studies with statistical comparisons of the local control rates achieved by GTR or a combination of surgery and RT have not provided consistent results (44, 74, 144). Finally, RT alone provides 10-yr recurrence rates between 0 and 23% (132, 145). Although not widely accepted (146, 147), it has been proposed that the tumor control correlates with the irradiation dose (107, 148, 149). Sung et al. (107), in a series of 49 patients treated by surgery and RT, reported relapse rates of 46.7% with a tumor dose less than 5000 rads, 16% with a dose of 5500 5700 rads, and 22.2% with a dose of 6000 7000 rads (the recurrences at the highest dose level were outside the irradiated volume). Regine and Kramer (148), in a series of 15 children irradiated postoperatively, found that recurrence developed in 50% of those receiving doses no greater than 5400 cGy and 15% of those with doses above 5400 cGy. Varlotto et al. (149), in a series of 24 subjects, noted no local failures with a total dose of at least 6000 cGy. Still, the optimum total dose or fractionation protocols have not been established (150), due to the lack of comparative randomized controlled trials. The interpretation of the data on the effectiveness of each therapeutic modality has to be done with caution, because the published studies are retrospective, nonrandomized and often specialty-biased [i.e., the results of large RT or neurosurgical centers may be different, because patients who die from postoperative complications have not been referred for subsequent irradiation (132)]. Thus, the favorable outcome of the totally resected tumors or of those offered only RT could be attributed to the fact that they represent selected, less aggressive cases on the basis of size, location, and clinical status of the patient at presentation, allowing the radical removal or the adoption of a treatment modality with delayed efficacy (irradiation alone). Furthermore, the possibility that the most aggressively growing tumors not amenable to complete resection have been offered postoperative irradiation cannot be excluded. Finally, in series covering extensive periods, the advances in the diagnostic (particularly

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TABLE 5. Recurrence rates in patients with craniopharyngioma treated by various modalities

No. of patients 109 Recurrence rates at 10-yr follow-up (%) Age (yr) 43 16 GTR Adults 84, children 53 Limited surgery (PR/SR) Adults 90, children 93 (SR) Surgery RT RT Details of RT Mean dose adults: 5700 rads (4000 6900) in 4 8 wk; children: 5500 rads (5000 6000) in 57 wk Median dose: 56 Gy (6 70) in 24 34 daily fractions (32% of patients) in 57 wk; 50 Gy (50 56) in 30 33 daily fractions (68% of patients) in 6 7 wk Median dose: 5464 cGy (5040 6598) in 180 200 cGy/d fractions over a median of 43 d (3155) 5000 5500 cGy, no further details reported Follow-up period, follow-up duration (range) 1950 1977, no data on follow-up duration

Ref. 107a

Adults 51, children 22 (SR, PR, biopsy aspiration)

132b

173

77

16

23 (biopsy or aspiration), 12 (PR or SR), 0 (GTR)

23

1950 1986, median 12 yr (0.08 35)

145c

61

All

21

69 (SR

GTR)

14 (biopsy-aspiration-VP shunt-combination of the above-SR-GTR) 63 (SR)

1970 1990, median 10 yr (220.5)

44d 123
e

56 57

26 7

21 18

17 0

50 (SR) 33 (SR), 25 (PR)

118f 111g

73 115

All

16.4

22 19

72 51 (SR), 84 (PR)

Median dose: 50 Gy (40 60)

29 Children

89h

121

31

16

19

59 (SR)

10 (SR)

Mean dose: 5381 rads (4400 6480)

133 90i 143 144j 74k

36 122 25 71 103

All 29 All

16 16 16

62 26 34 53 0 49 (SR), 77 (PR) 100 78 at 2.5 yr (SR) 62 (PR) 16 (SR) 0 (GTR), 23 (PR) Median dose: 54 Gy (44 55.8) Median dose: 5000 cGy (4000 5400, apart 1 patient with 3500), 2530 fractions (apart 2 patients with 13 fractions) No details of RT reported

All 1.524.8 37 16

19811991, mean 49 months (7187) No data on follow-up period, mean 6.5 yr (2.515.5) 19731994, mean 6.5 yr 19831997, median 55.5 months (0.07 175) 1974 1991, no data on follow-up duration 1986 1998, 52 months (1149) 19752000, 7 yr (0.4 month21 yr) 19831996, median 10 yr (316) 1974 2001, median 7.6 yr 1964 2003, mean 94 months (0.3 468)

VP, Ventriculo-peritoneal. a Confirmation of total removal with postoperative CT only after 1975 ( 25% of the patients) probably explaining the high recurrence rates after GTR. PR defined as minimal removal. b Histological confirmation not available in 68 patients. No definition of PR and SR. Extent of resection determined from operation notes. No difference in the recurrence rates among treatment subgroups (GTR and RT not included in these comparisons). c Histological confirmation not available in patients treated with RT alone (15%). Radiological confirmation of the GTR available in 33% of the patients, in the remaining cases based on the surgeons report. P 0.001 in the recurrence rates among the three groups. d Nine patients of the study had undergone previous surgery, and one had received RT alone. Recurrence rates provided for whole follow-up period. P 0.01 in the recurrence rates among the GTR, SR, and RT groups. e SR, when small fragments of the capsule were left attached to important structures. PR, fragments or parts of tumor remained in situ with the capsule. Recurrence rates are provided for the whole follow-up period. f Three percent and 29% of patients in the GTR and PR groups, respectively, had RT postoperatively. PR defined as incomplete resection. Complete resection and elective RT were factors less likely to be associated with recurrent disease (P 0.05). g Histological confirmation not available in seven cases. SR, when a small portion of firmly attached to critical structures residual tumor remained or when postoperative imaging showed a small contrast enhancing or calcified area. PR, presence of a larger portion of residual tumor. Postoperative RT was offered in 1, 9, and 38% of patients of the three groups, respectively. P 0.001 in the recurrence rates among the three groups. h P 0.0001 in the recurrence rates among the GTR and SR groups. i No definition of PR and SR. Fifty-four percent of the patients treated with PR received RT postoperatively, but no separate data are provided. j Surgical outcome confirmed by postoperative imaging in all but seven cases, in which it was based on the surgeons report. SR, presence of residual tissue postoperatively (also includes cases with biopsy and cyst aspiration only). P 0.001 in the recurrence rates among GTR and SR, as well as SR and SR RT. RT but not extent of surgery was predictor of local control (P 0.01). k P 0.0001 in the recurrence rates among the three groups (the difference remained even after assessing the outcome of patients treated later than 1980).

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the imaging modalities) and therapeutic (microsurgery, radiation planning/delivery techniques) tools taking place during the follow-up interval may have influenced the relevance of the results. 2. Treatment of recurrent disease. The management of recurrent tumors remains difficult, because scarring/adhesions from previous operations or radiation decrease the possibility of successful excision. Indeed, in such cases, the success rate of total removal drops dramatically (0 25%), when compared with primary surgery (74, 90, 111), and there is increased perioperative morbidity (111, 120, 151) and mortality (10.5 24%) (74, 111), suggesting that for many recurrent lesions palliative surgery is the most realistic target. The beneficial effect of RT (preceded or not by second surgery) in recurrent lesions has been clearly shown; in a series of 25 irradiated patients (19 of whom underwent a second surgical procedure before RT), the 10-yr progressionfree survival from the time of the first recurrence was 72% (152). Notably, the outcome was not affected by the performance or not of a second surgery (10-yr progression-free survival rates in patients subjected or not to salvage surgery were 80 and 69%, respectively) (152). There was also no significant difference in the tumor control among patients offered adjuvant RT after primary surgery and those receiving irradiation for recurrence (152); although the two treatment groups may not be comparable in terms of tumor aggressiveness, the authors proposed that RT may be equally effective at the time of recurrence, as at the time of primary presentation. Stripp et al. (144), in a series of 22 children or young adults irradiated for recurrence, found an actuarial 10-yr local control rate of 83%. Kalapurakal et al. (153), in 14 children with recurrent tumors, found a 5-yr second relapsefree survival of 100% in those offered RT and 0% in those treated by surgery alone. Finally, in a group of 19 subjects with recurrence, Karavitaki et al. (74) showed a significant difference in the 2.5-yr local control rates after PR (50%), RT alone (83%), or PR followed by RT (100%). Recurrent lesions with significant cystic component not amenable to total extirpation may be treated by repetitive aspirations through an indwelling Ommaya reservoir apparatus (154). Alternatively, ventriculo-cisternal cystostomy (allowing spontaneous dilution of the cyst contents in the CSF) or establishment of a permanent communication between the cyst and the sphenoid sinus for continuous drainage may be palliative (155). These are less invasive procedures, but they carry the risks of aseptic meningitis, CSF fistulae, and ascending infections (155).
B. Intracystic irradiation

Intracavitary irradiation (brachytherapy) is a minimally invasive management strategy, first reported by Leksell and Liden in 1952 (156). It involves stereotactically guided instillation of -emitting isotopes into cystic craniopharyngiomas delivering higher radiation doses to the cyst lining than the ones offered by conventional external beam RT. The beneficial effect is achieved through destruction of the secretory epithelial lining causing elimination of the fluid production and cyst shrinkage (157). Subsequent studies as-

sessed the efficacy of various - and -emitting isotopes (mainly 32phosphate, 90yttrium, 186rhenium, and 198gold) (158 163); because none of them has the ideal physical and biological profile [i.e., pure -emitter with short half-life and with tissue penetrance limited to cover only the cyst wall (164)], there is no consensus on which therapeutic agent is the most suitable. 90Yttrium has the shortest physical half-life (2.67 d) but the greatest maximum energy (2.27 MeV) and half-value tissue penetrance (1.1 mm), thereby exposing critical structures to higher doses of irradiation (162). 32Phosphate is a pure -emitting radionuclide but with a long half-life (14.3 d) (164). Both 186rhenium and 198gold emit a considerable amount of -radiation (162). The data to follow include the largest series of patients with relatively long follow-up periods. Van den Berge et al. (162) treated a total of 35 cysts in 31 patients (ages, 4 64 yr; in 26 as primary therapy, and in five after surgery and/or cyst aspirations or intracavitary brachytherapy) with 90yttrium. The radiation dose to the inner surface of the cyst was 200 Gy. During a mean follow-up of 41 months, complete or partial cyst resolution was observed in 22 (70.9%) patients [however, new cyst formation took place in three of them and was successfully treated with new 90yttrium injection(s)], stabilization in six (19.3%), and increase in three (9.6%). In two subjects (6.5%), the solid part of the tumor increased in size. Deterioration of the visual acuity or fields was observed in 58 and 52% of the eyes tested, respectively. It occurred more frequently in the secondary treatment group and was attributed to failure of cyst collapse, formation of new cysts, increase in the solid tumor, or possibly radiation damage. The endocrine function was normalized in one patient, whereas the number of those diagnosed with three or more pituitary hormone deficits increased from 10 before brachytherapy to 17 after treatment. Finally, during the observation period, five subjects (16.1%) died of tumor-related causes. Pollock et al. (159) treated 32 cysts in 30 patients with 32P [median age, 26 yr (range, 370); in 13 as primary therapy (average dose to the cyst wall 267 Gy), and in 17 as adjuvant following surgery combined or not with RT (average dose to the cyst wall 240 Gy)]. During a median follow-up of 37 months, 87.5% of the cysts disappeared or decreased more than 50% in size, 3.1% remained stable, and 9.4% increased. The favorable effect was usually noted within 3 months and often continued in the following 2 yr. During the observation period, 20% of the subjects developed new cysts, and 6.6% had growth of the solid portion of the tumor. Overall, 33% of the patients required further intervention for tumor growth (10% because of increase in the size of the treated cyst, 16.6% because of new cyst formation, and 6.6% due to increase in the solid portion). No intra- or perioperative complications were noted. The visual function improved or remained stable in 63% of the subjects, whereas 37% of them experienced delayed worsening (6.6% due to increase in the solid portion of the tumor, 16.6% due to new cyst formation, 6.6% due to increase in the size of the treated cyst, and 6.6% because of optic neuropathy, probably related to the irradiation or to the traction of the optic apparatus during the cyst regression). Thirty-seven percent of the patients with normal pretreatment anterior pituitary function developed hormonal deficits, and 18% were diagnosed with new onset DI.

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During the follow-up period, 10% of the patients died (6.7% because of tumor progression and 3.3% because of unrelated causes). There was no difference between the primary and the adjuvant treatment groups in terms of cyst control, visual deterioration, and endocrine preservation. Voges et al. (160) treated 78 cysts in 62 patients [median age, 17 yr (range, 4 71); with predominantly cystic or mixed tumors, in 27 after surgery with or without fractionated RT] by stereotactically applied -emitting isotopes (90yttrium, n 66; 32phosphorous, n 8; and 186rhenium, n 4). The inner surface of the cyst was irradiated with a cumulative dose of 200 Gy. Cyst leakage requiring second stereotactic intervention occurred in 10.2% of the cases, but this was not associated with any adverse sequelae; no further perioperative morbidity or mortality was reported. A total of 54.8% of the subjects underwent additional treatments including surgery, CSF shunt, fractionated RT, stereotactic radiosurgery, and repeated intracavitary irradiation. During a median observation period of 11.9 yr, 44.9% of the cysts disappeared (90Y, 48.5%; 32P, 37.5%; 186Re, 0%), 34.6% decreased in volume by more than 25% (90Y, 34.8%; 32P, 50%; 186Re, 0%), 15.4% showed an increase or decrease by no more than 25% (90Y, 13.6%; 32P, 12.5%; 186Re, 50%), and 5.1% increased by more than 25% (90Y, 3%; 32P, 0%; 186Re, 50%). In cases of remission, this result remained stable. Interestingly, in nonresponsive cysts, the application of a different isotope had no significant effect. During the first 6 months after the isotope instillation, 60.5% of the patients with visual deficits showed improvement, and 39.5% remained stable. Side effects within 6 12 months after the application of the radioactive sources occurred only in the yttrium group and included deterioration of vision in four patients, pituitary hormone deficits in three, and III cranial nerve palsy in one. The 5-yr actuarial survival rate, influenced though by the additional therapies, was 55%. Tumor progression was the cause of death in 20 of 31 nonsurviving patients (64.5%) (new cyst formation responsible in 13 and growth of solid tumor parts in seven). Among the subjects treated exclusively by intracavitary irradiation, those with solitary cysts had the longest survival times. Hasegawa et al. (163) treated a total of 54 cysts in 49 patients (34 adults, 15 children, in 25 as primary treatment and in 24 for residual or recurrent cysts previously treated by surgical removal combined or not with RT, cyst aspiration, or intracavitary bleomycin) with 32P. The mean radiation dose to the cyst wall was 224 Gy, and the mean follow-up period was 4 yr after 32P treatment and 7 yr after the tumor diagnosis. The total control rate (i.e., disappearance, decrease, or no change) was 87% for the mono- or multicystic tumors and 88% for the mixed solid and cystic ones. During the follow-up, six patients (13%) developed new cysts. The actuarial cystic tumor control rate at 10 yr after the intracavitary irradiation was 70% and was not associated with patient age, tumor consistency, prior treatment, cyst volume, radiation dose, or preoperative visual acuity or fields. Notably, of 41 patients who underwent follow-up, 12 (29%) required secondary cyst aspiration, because of persistent symptoms attributed to a larger cyst (1 wk to 18 months after the intracavitary irradiation), and 10 (24%) eventually required craniotomy (three because of cyst progression, five because of tumor progression, and two because of both solid

and cystic component progression). Forty-eight percent of the subjects showed improved visual function, and 23% of those with pre- and postoperative visual testing had delayed worsening (15% as a result of tumor progression, and 8% attributed to irradiation). Twenty-nine percent of the patients with normal preoperative pituitary function showed worsening. No further complications were developed during the follow-up period. The 10-yr actuarial survival rate, estimated from the time of diagnosis but also affected by various subsequent salvage treatments in cases of 32P failure, was 80%. The risk of isotope leakage into the surrounding structures may be eliminated by adopting appropriate technical measures, such as accurate volume determination of the cyst and cyst puncture with a very small needle (165). Although -emitters have short-range tissue penetrance, lesions in close proximity to the optic apparatus should be approached with caution (164). In summary, within the limitations of studies including heterogeneous (with regard to previous treatments) groups of patients, intracavitary irradiation seems to offer a good prospect for the reduction or stabilization of cystic craniopharyngiomas. This effect, combined with its reported low surgical morbidity and mortality, renders this management option attractive for predominantly cystic tumors and particularly the monocystic ones. Still, the most beneficial isotope and the long-term impact on the quality of survival (vision, neuroendocrine, and cognitive function) remain to be assessed.
C. Intracystic bleomycin

The intracystic instillation of the antineoplasmatic agent bleomycin was initially described by Takahashi et al. in 1985 (166). The drug is administered through an Ommaya reservoir connected to a catheter [placed in the cyst stereotactically or through craniotomy (by direct vision or transcortically under ultrasound guidance or transventricularly under ultrasound and ventriculoscopic guidance)] (166 168). It has been proposed that its efficacy is associated with the spatial distribution of the S-phase proliferative cells in the squamous epithelial layer of the cyst wall (169). The small number of published series (based on a limited number of patients and with variable total doses and time intervals between repeated instillations) suggest that intracystic bleomycin may be an effective therapy for some cystic tumors (166, 167). Thus, Takahashi et al. (166), during a median follow-up of 5.5 yr, found a recurrence rate of 0% in four children with predominantly cystic tumors treated initially by PR or aspiration/biopsy and followed by injection of bleomycin into the cyst. Hader et al. (167) reported more than a 50% decrease in tumor size in six of seven (85.7%) children with newly diagnosed cystic craniopharyngiomas offered intracystic bleomycin and observed for a mean period of 3 yr. During the follow-up, four of these children remained stable, and two underwent microsurgical removal (in one case due to persistent headaches not attributed to cyst enlargement, and in the second due to enlargement of a second cyst). Less optimal results have been described by Frank et al. (170) in a series of six patients; all the cysts regrew within 1 yr, with five of them requiring reoperation.

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The administration of bleomycin may be associated with transient fever, headaches, and occasionally nausea and vomiting within the first 24 h (167, 171). Direct leakage, particularly from the orifices of the catheter to surrounding tissues, diffusion though the cyst wall, or high drug dose have been reported to cause various toxic (hypothalamic damage, blindness, hearing loss, ischemic attacks, peritumoral edema) (167, 168, 170, 172) or even fatal effects (173). Usage of special catheters with a limited number of holes, avoidance of passing the catheter through the subarachnoid space or the ventricular system, confirmation of sealed cysts, documented intracystic catheter placement, and protocols based on the volume of the tumor cyst contents may be helpful in preventing serious complications (167). The lactate dehydrogenase activity and particularly the slowest moving fraction of the lactate dehydrogenase isoenzymes, L5 (an intimate indicator of anaerobic glycolysis), have been found elevated in the cystic fluid of craniopharyngiomas (174). Takahashi et al. (166) have shown that local injection of bleomycin is associated with a decrease in these enzymes, which may be used as a marker of therapeutic response, suggesting the possibility for repeated bleomycin injections (166). However, this finding has not been confirmed by other groups (167, 171, 175). The combination of the intracystic instillation of bleomycin and 32P may be associated with improved outcome. Jiang et al. (171) injected both agents in nine patients with cystic lesions; during a follow-up period of up to 24 months, six cysts almost disappeared, and the remaining three showed 5778% regression compared with the original volume. However, a few months later, two patients suffered bilateral thalamic infarction, which in one case was fatal. The possibility of a cumulative damage by the two agents cannot be excluded. In summary, the value of the intracystic injection of bleomycin in the tumor control or even in the delaying of potentially harmful resection and/or RT, especially in young children, as well as the optimal therapeutic protocol and the clear-cut criteria predicting the long-term outcome, remains to be established in large series of patients with appropriate follow-up.
D. Stereotactic radiosurgery

Stereotactic radiosurgery delivers a single fraction of highdose ionizing radiation on precisely mapped targets, keeping the exposure of adjacent structures to a minimum and possibly reducing the late radiation-induced adverse sequelae. Tumor volume and close attachment to critical structures are limiting factors for its application, with 10 and 15 Gy being the maximum tolerated doses to the optic apparatus and the other cranial nerves, respectively (176). Its role in the treatment of craniopharyngiomas has been assessed in a small number of reports, which cover relatively short follow-up periods. During the period 19921998, Mokry (177) treated 23 patients (15 adults and 8 children; all had previously undergone some type of operative procedure and one had also received fractionated RT) with a mean prescription dose of 10.8 Gy (range, 8 15) and a mean dose to the visual pathways of 8.3

Gy (range, 1.117). In 10 subjects with cystic tumors, intracystic bleomycin preceded radiosurgery. Fourteen of the 23 patients (61%) showed a decrease in their mean treated tumor volume from 3.8 to 1.9 cm3 during a mean follow-up of 22.6 months (one of these patients developed a cystic recurrence 3 months after radiosurgery, which was successfully treated by a second instillation of bleomycin). Three of the 23 patients (13%) required a second radiosurgical intervention resulting in reduction of the mean treated tumor volume from 2.8 to 0.9 cm3 at a mean interval of 18 months after the second therapy (one of them was also re-operated before the second radiosurgical intervention). The remaining 26% (6 of 23) had further tumor growth during a mean follow-up of 26.7 months. The initial tumor volume was a significant prognostic factor for the response. All the tumors with poor response were multicystic. In the group of the good responders, monocystic lesions amenable to bleomycin instillation predominated, pointing out the importance of a multimodality approach. Between 1993 and 1999, Chung et al. (178) treated 31 patients (22 adults and 9 children; in six as primary therapy and in 25 for recurrent disease) with a mean margin dose of 12.2 Gy (range, 9.516) and a mean dose to the visual pathways of 8 Gy (range, 7.2 to 12.5). Treatment before gamma knife included surgical excision combined or not with conventional RT, intracavitary irradiation, aspiration and Ommaya reservoir implantation, and ventriculo-peritoneal shunt. During a mean follow-up of 33 months, the overall response rate was complete (residual tumor volume, 20% of the original) in 32.3% of the cases and partial (residual tumor volume, 20 50% of the original) in 32.3%. No change was observed in 22.6%, and uncontrolled tumor progression was observed in 12.8%. Enlargement of the cystic component was experienced by 10.3% of the subjects 517 months after radiosurgery, possibly attributed to hemorrhage, change in the permeability of the adjacent vasculature, or reactive postirradiation fluid hypersecretion; after minor procedures (stereotactic aspiration and/or Ommaya reservoir implantation or intracystic bleomycin), the tumors remained well controlled. Smaller volume ( 4.2 cm3 or diameter 2 cm) or single component tumors (solid or cystic) had a better control rate. Notably, previous aspiration of the cystic contents in three subjects assisted the successful performance of radiosurgery. No additional endocrinological or neurological impairment was noted as attributable to radiosurgery. The overall clinical outcome was excellent (improved quality of life, totally independent, not requiring hormonal replacement) in 29% of the patients, good (improved quality of life, independent, needing hormonal replacement) in 38.7%, fair (some deterioration in the quality of life, partially dependent, needing hormonal replacement) in 16.1%, and poor (severe deterioration or unchanged quality of life, totally dependent, with a major medical problem) in 6.5%. Tumors with a volume less than 14 cm3 or with a single component were associated with a better clinical outcome. Between 1988 and 1998, Chiou et al. (179) offered 12 stereotactic radiosurgical procedures in 10 consecutive patients (aged 9 64 yr) with small (<2.5 cm) residual or recurrent tumors previously treated by surgery with or without RT. The mean marginal dose was 16.4 Gy (range, 12.520), and

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the dose to the optic apparatus was less than 8 Gy. During a median follow-up of 63 months, 58.3% (7 of 12) of the lesions showed shrinkage or complete regression (within a median interval of 8.5 months). Prior visual field defects improved in six subjects, whereas two patients had delayed visual deterioration (both, however, had prior 32P intracavitary irradiation for a cystic craniopharyngioma). Between 1968 and 1995, Ulfarsson et al. (180) treated 21 consecutive patients [11 children and 10 adults; in 13 after treatment failure (surgery combined or not with RT or after isotope instillation), and in eight as primary therapy after stereotactic biopsy and/or cyst aspiration procedure]. The adopted policy was to treat the solid part of the tumor by gamma knife and the cystic by instillation of 90Y. Gamma knife radiosurgery was offered to 22 tumors (one had been surgically separated into two parts and had different treatment doses) with a median dose to the tumor periphery (estimated by also including the cystic parts) of 5 Gy (range, 325). After a median observation period of 3.5 yr, 22.7% (5 of 22) of the lesions reduced in size ( 25% of the original), 13.6% (3 of 22) remained unchanged, and 63.6% (14 of 22) increased. The reduction was mainly observed between 10 wk and 23 months after gamma knife, and 83% of these patients had no recurrence during a mean follow-up period of 12 yr. Tumor progression was correlated with a low dose to the tumor margin ( 6 Gy). Deterioration of vision was observed in 38% (8 of 21) of the subjects; in all but one, there was a volume increase after gamma knife treated mainly with intracystic isotope and therefore, the contribution of other factors cannot be excluded. By the end of follow-up, four patients developed additional pituitary deficits; three of them had an increase in their tumor volume, which may have contributed to the endocrine morbidity. The results of this study should be cautiously interpreted, because the less sophisticated imaging technology used in the pre-MRI era may have been responsible for actual radiation doses lower than the calculated ones, as well as for difficulties in the evaluation of small volume changes. Furthermore, most patients in this series were treated before the availability of advanced computer programs with treatment plans based on one target point only, which did not allow excellent conformity between the prescribed radiation and the target volume. Yu et al. (181) offered combined treatment with stereotactic instillation of 32P (for cystic parts) and gamma knife surgery (for solid parts) in 46 patients [mean age, 39 yr (range, 3 60); 28 had previously undergone total or SR with or without external beam RT, and 14 had previously received stereotactic intracavitary irradiation]. The marginal dose of gamma knife therapy was between 8 and 18 Gy, and the inner surface of the cyst wall received a cumulative dose of 250 Gy. Three subjects received another radioisotope injection due to cyst recurrence. The assessment of the imaging outcome of 38 patients after a mean follow-up of 16 months showed that the tumor control rate (disappearance, decrease, or no change) was 90% in solid and 85.7% in mixed tumors (92.1% for their solid segment). Between 1994 and 2000, Amendola et al. (182) treated 14 patients [two adults and 12 children; in two as primary therapy and in 12 for recurrent disease (previously treated by surgery with or without conventional RT or by 32P instilla-

tion)]. The mean minimum dose was 14 Gy (range, 1120), the maximum 29 Gy (range, 24 40), and the dose to the optic chiasm less than 8 Gy. All cystic components were previously surgically decompressed to reduce the target volume. During a mean follow-up of 39.2 months, the local control rate was 86% (12 of 14). Two subjects with extensive tumors required retreatment with gamma knife for persisted disease and one of them relapsed later. There were no complications directly related to the gamma knife. Interestingly, a robotically controlled frameless radiosurgical system consisting of a linear accelerator mounted on a robotic arm has been developed recently. It uses a large number of beams and allows the position of the robot to be updated with real-time radiographs obtained during treatment, thereby achieving precision and accuracy that rivals that of the frame-based systems. It may also offer advantages particularly important for pediatric patients (treatment of young children with thin skulls unsuitable for frame-based methods, no need for rigid head fixation and possible avoidance of general anesthesia) (183). In conclusion, stereotactic radiosurgery achieves tumor control in a substantial number of patients with small volume lesions. It may be particularly useful for well-defined residual tissue after surgery or for the treatment of small solid recurrent tumors, especially after failure of conventional RT. The optimal marginal dose remains to be defined. In cases of large cystic portions, multimodality approaches with instillation of radioisotopes or bleomycin may provide further benefits. Studies with long-term clinical follow-up evaluating its role in the prevention of tumor growth and its effects on the neurocognitive and neuroendocrine functions are required.
E. Stereotactic radiotherapy

Stereotactic RT is a modality combining the accurate focal dose delivery of stereotactic radiosurgery with the radiobiological advantages of fractionation (184). It requires sophisticated treatment planning systems, a dedicated high-energy linear accelerator, and stereotactic mobilization devices. Compared with the conventional RT, it adopts reduced safety margins and offers optimal sparing of the normal tissue surrounding the tumor, thereby possibly minimizing the acute and long-term toxicities of irradiation (184). The data on the usefulness of stereotactic RT for the management of craniopharyngiomas are limited, but the largest series published so far provides promising results (185). Thus, Schulz-Ertner et al. (185) treated 26 patients (21 adults and five children; in nine as adjuvant therapy after surgery, and in 17 for recurrent tumor or progressive growth of the cysts after initial surgery). The median target dose was 52.2 Gy with conventional fractionation and the safety margin 2 mm. The 10-yr actuarial local control and overall survival rates were 100 and 83%, respectively. The acute toxicity was mild. Two patients developed initial enlargement of the cystic component, necessitating stereotactic aspiration in one of them. During a median follow-up of 43 months (range, 7143), impaired pituitary function occurred in 16.6% of the subjects at risk; no deterioration of vision, radionecrosis, or second malignancies were observed.

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Long-term prospective studies are required to establish the potential of stereotactic RT in sustaining local control and in minimizing treatment-related adverse sequelae, particularly those affecting the neurocognitive function.
F. Systemic chemotherapy/interferon

The value of systemic chemotherapy in craniopharyngiomas has been investigated in a very limited number of patients. Thus, Bremer et al. (186) reported a case of successful management of a recurrent cystic tumor with the combination of vincristine, carmustine, and procarbazine. Lippens et al. (187), after the administration of five courses of doxorubicin and lomustin in four children with multiple or very rapid recurrences followed up for 312 yr, achieved local control in 75% of cases. Finally, Jakacki et al. (188), in a series of 12 patients younger than 21 yr with progressive or recurrent craniopharyngiomas, showed that after 12 months of treatment with interferon , tumor reduction of at least 25% was observed in three subjects. However, during the first weeks of therapy, six patients experienced an increase in the size of the cystic component, which was finally considered as progressive disease in half of them. Interestingly, 67% of the patients completing 1 yr of therapy without progressive disease had an increase in the size of their tumor at a median period of 11 months after discontinuation of the drug. The cytotoxicity (predominantly hepatic, neurological, and cutaneous) requiring temporary discontinuation and/or dose reduction within the first 8 wk of therapy was significant (in up to 60% of the cases). The pros and cons of this treatment modality, particularly for aggressive tumors, remain to be assessed by trials with large numbers of patients and adequate follow-up.
X. Risk Factors for Recurrence

be associated with increased recurrence rates. However, because these features may affect the resectability of the tumor, their impact on the recurrence may simply reflect the surgical result achieved (111, 118). On the other hand, Eldevik et al. (43) did not find any imaging characteristics predictive of recurrence, and Duff et al. (89) as well as Weiner et al. (44) did not confirm the effect of tumor size on the prognosis. Lastly, other studies propose that the location (intrasellar, extrasellar, or both) (74), the consistency of the tumor (74, 146), the presence of calcification (146), hydrocephalus (74) or third ventricular wall/floor invasion (74) are not associated with an unfavorable outcome. The prognostic significance of the two pathological subtypes remains controversial. A few series suggest that the papillary type may have a better outcome (45, 46, 192), whereas others do not support this view (42, 44, 89). The small number of papillary tumors in most series, the difficulties in the classification of lesions with intermediate characteristics (193), and in many cases, the absence of correction for the type of treatment make the interpretation of these data difficult. Finally, studies on the prognostic value of the immunoreactivity of the tumor proliferation marker MIB-1 have provided contradictory data. Nishi et al. (194) suggest differences between recurrent and nonrecurrent lesions, whereas others have not reached similar conclusions (195197). Furthermore, Weiner et al. (44) found that the presence of one or more mitotic figures within the tumor did not correlate with subsequent recurrence.

XI. Long-Term Outcome after Surgery with or without Conventional External Beam Irradiation A. Morbidity

The growth rate of craniopharyngiomas varies considerably, and reliable clinical, radiological, and pathological criteria predicting their behavior are lacking. Thus, apart from the previously discussed significant impact of the treatment modality, attempts to identify other prognostic factors have not provided consistent data. Age group at tumor diagnosis (childhood or adult life) probably does not affect the risk of recurrence; studies with appropriate statistical evaluations on patients who were offered various types of treatment have not confirmed differences in the local control rates between tumors diagnosed during childhood or adult life (43, 44, 74, 89, 108, 132, 189). Still, the age at presentation may affect the risk of recurrence when comparisons are performed within childhood populations only. De Vile et al. (118), in a series of 75 children, found that age less than 5 yr was a significant predictive factor for recurrence. No differences have been detected among males and females (74, 132) The role of the imaging features has been investigated in a number of reports, which have not provided consistent results. Some series suggest that large (118, 145, 146, 190), calcified (191) lesions involving many intracranial compartments (118) or causing severe hydrocephalus (118, 146) may

The long-term morbidity of patients with craniopharyngiomas is substantial, and it mainly involves endocrine, visual, hypothalamic, neurobehavioral, and cognitive sequelae, compromising the normal psychosocial integration and the quality of living. These complications are attributed to the damage of critical neuronal structures by the primary or recurrent tumor and/or to the adverse effects of the therapeutic interventions. Notably, the severity of the radiationinduced late toxicity (endocrine, visual, hypothalamic, neurocognitive) is associated with the total and per fraction doses, the volume of the exposed normal tissue, and the young age in childhood populations (148, 149, 198 202). It has been proposed that the use of modern high-energy machines and irradiation doses of 55 Gy or less at 1.8 Gy per fraction should minimize toxicity (118). 1. Endocrine. Partial or complete hypopituitarism is encountered in a substantial number of patients. In series including subjects with various treatment modalities and follow-up periods, the frequency of individual hormone deficits ranges from 88 100% for GH (74, 203), 80 95% for FSH/LH (74, 88, 203, 204), 55 88% for ACTH (74, 88, 91, 132, 203, 204), 39 95% for TSH (74, 88, 91, 132, 203, 204), and 25 86% for antidiuretic hormone (74, 88, 91, 120, 132, 203, 204). Moreover, at least three pituitary hormone deficiencies have been reported in

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54 100% (87, 92, 141, 143145, 204, 205). Apart from symptomatic DI, which is probably more common in surgically treated patients (145), the long-term endocrine morbidity is not affected by the type of tumor therapy (44, 74, 92, 143, 145, 204). Interestingly, restoration of preexisting hormone deficits after surgical removal, in contrast to anterior pituitary tumors (206), is absent (74, 87, 142, 205) or uncommon (88). It has also been suggested that there is no significant difference in the long-term endocrine morbidity between childhood- and adult-onset disease (44, 74). Notably, rare cases of precocious puberty after surgery have been described (207, 208). The phenomenon of growth without GH has been reported in some children with craniopharyngioma who show normal or even accelerated linear growth, despite their untreated GH deficiency (204, 209). The pathophysiological mechanism has not been clarified; the obesity-associated hyperinsulinemia (209 211) or the presence of hyperprolactinemia (209) has been proposed as a factor stimulating growth by affecting serum concentrations of IGF-I or by binding directly to the IGF-I receptor (212). Data on the auxology of 488 children from the Pharmacia and Upjohn International Growth Database (KIGS) recruited between 1988 and 1996 showed that 79% of them achieved height over 2 sd of their target height and had evidence of further growth potential (213). The growth response was not affected by tumor recurrence within the treatment period or by prior tumor management (213). A 3-yr longitudinal analysis of the changes in height, weight, and body mass index (BMI) sd score (SDS) in 199 GH-treated prepubertal children with postsurgical and/or postirradiated craniopharyngioma from the KIGS database (Pfizer International Database) showed that GH therapy induced excellent linear growth compared with children with other forms of organic GH deficiency. Still, the ones with craniopharyngioma had a higher BMI; GH had no salutary effect on weight SDS and caused only a mild improvement in BMI SDS (214). Finally, large observational studies support the view that GH replacement in children and adults does not increase the risk of tumor recurrence (213, 215). Studies with appropriate control groups are required to confirm this finding. 2. Visual. The visual outcome is compromised in a significant number of patients. Duff et al. (89) found that 62.5% of 121 patients treated by surgery alone or combined with RT exhibited at least quadrantanopia during a mean observation period of 10 yr. Karavitaki et al. (74) in a series of 97 patients treated with similar modalities, estimated that the cumulative probability for major visual field defects at 10-yr follow-up was 48%. Pereira et al. (216) reported deterioration of visual fields/acuity in 36% of 54 patients treated by surgery with or without adjuvant RT and followed up for a median period of 10 yr. Rajan et al. (132), in a series of 173 subjects offered external beam RT either alone or after surgery and observed for a median period of 12 yr, found deterioration of pretreatment visual deficits in almost one third of the cases. In this study, by using an accurate RT technique and doses below the tolerance limit of the central nervous system, vision remained unaffected in those with normal sight before RT (132).

The visual outcome is adversely affected by the presence of visual symptoms at diagnosis (191, 217, 218) and by daily irradiation doses above 2 Gy (199); it is not significantly associated with age at diagnosis or tumor histopathological findings (44). Furthermore, Karavitaki et al. (74) suggested that among patients treated by complete resection or PR followed or not by irradiation, the deterioration of vision is more common in the PR-only group, probably as a consequence of their significantly increased recurrence rates. 3. Hypothalamic. Hypothalamic damage may result in hyperphagia and uncontrollable obesity (74, 89, 91, 145, 219), disorders of thirst and water/electrolyte balance (204, 220), behavioral and cognitive impairment (89, 118), loss of temperature control (221, 222), and disorders in the sleep pattern, with excessive daytime sleepiness (223225) and reduced nocturnal melatonin levels (224). Obesity is the most frequent manifestation of hypothalamic damage reported in 26 61% of the patients treated by surgery combined or not with RT (74, 89, 91, 144, 145, 219, 225). It results from the disruption of the mechanisms controlling satiety, hunger, and energy balance (226). In a study of 63 survivors of childhood craniopharyngioma, all subjects with marked obesity after surgery had evidence of significant alterations of the normal hypothalamic anatomy, with their MRI showing either complete deficiency or extensive destruction of the floor of the third ventricle (227). Possible contributing mechanisms include lack of sensitivity to endogenous leptin (228), vagally mediated hyperinsulinemia, and autonomic imbalance (229), as well as reduced physical activity, which is exaggerated by the neurological defects, the visual failure, and the somnolence (230). Interestingly, high levels of the orexigenic gastric hormone ghrelin have not been found in these patients (231). Hypothalamic obesity often results in devastating metabolic (232) and psychosocial complications, necessitating provision of dietary and behavioral modifications, encouragement of regular physical activity, psychological counseling, and antiobesity drugs. DI with an absent or impaired sense of thirst confers a significant risk of serious electrolyte imbalance and is one of the most difficult complications to manage (204, 220). De Vile et al. (204) found this abnormality in 14% of children treated primarily by complete or subtotal tumor excision with or without irradiation; notably, all the identified subjects had other evidence of significant hypothalamic dysfunction (204). Smith et al. (220) reported absence of thirst in 19% of adults with DI previously offered surgery combined or not with RT. In this group of patients, the maintenance of the osmotic balance has been shown to be precarious, with recurrent episodes of hyper- or hyponatremia contributing to morbidity and mortality (204, 220). Careful fluid balance in and out and regular weighing are important. Factors associated with significant hypothalamic morbidity are young age at presentation in children (225), manifestations of hypothalamic disturbance at diagnosis (118), hypothalamic invasion (225, 233), tumor height greater than 3.5 cm from the midline (118), attempts to remove adherent tumor from the region of hypothalamus (118), multiple operations for recurrence (225), and hypothalamic radiation doses greater than 51 Gy (234).

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4. Neuropsychological and cognitive/functional outcome. The deterioration of the neuropsychological and cognitive function in patients with craniopharyngioma contributes significantly to poor academic and work performance, compromised family and social relationships, and impaired quality of life (90, 91, 145, 216, 235238). Duff et al. (89), in a series of 121 patients treated by surgery with or without adjuvant RT and followed up for a mean period of 10 yr, found poor outcome in 40% of subjects [the outcome was based on motor deficits, vision, dependence for activities of daily living, Karnofsky Performance Scale (assessing the ability to perform normal activity and to do active work and the need for assistance), school and work status, and debilitating psychological or emotional problems]. Van Effenterre and Boch (90) in a cohort of 122 patients treated mainly by surgery, found that during a mean observation period of 7 yr, 16% of the adults and 26% of the children did not achieve independent living with social integration and normal professional occupation or school status. Pereira et al. (216), in a study of 54 consecutive patients offered surgery with or without additional RT and followed up for a median interval of 10 yr, showed that 47% had psychosocial impairment (evaluated by independent living, social integration, professional occupation, and school performance) and 49% had neurological morbidity (defined as the presence of any of the following: concentration problems, personality changes, short-term memory loss, anosmia, or epilepsy). De Vile et al. (118), in a series of 75 children who had surgical removal followed or not by irradiation and followed up for a mean period of 6.4 yr, demonstrated that 40% of them had IQ below 80 and 23% had severe motor disorders combined or not with epilepsy. Finally, Karavitaki et al. (74), in a series of 121 patients treated by surgery with or without RT, found cumulative probabilities for permanent motor deficits, epilepsy, psychological disorders necessitating treatment, and complete dependency for basal daily activities at 10-yr follow-up of 11, 12, 15, and 9%, respectively. At the same time period, almost one fourth of the adults or children were unable to work in their previous occupation or were behind their expected school status (74). The data on the therapeutic option with the least unfavorable impact on the neurobehavioral outcome are rather inconsistent. Anderson et al. (236), in a study of 20 children who had subfrontal craniotomy and were followed up for 38 months, found no difference in the outcome among those treated by PR or GTR. Honegger et al. (239) assessed 13 adults preoperatively and 3 months postoperatively (10 had transcranial surgery, all treated during the microsurgical era, with complete tumor removal achieved in eight) and found no impairment of the overall neuropsychological performance. Cavazzuti et al. (235), in a series of 35 children, suggested that radical tumor resection (performed during the premicrosurgical era) was associated with less favorable outcome (frontal lobe and visual perceptual dysfunction) compared with irradiation alone or minimal surgery. In this series, memory defects and decreased manual dexterity were present in all groups. Graham et al. (92), in a study of 40 children treated by surgery combined or not with RT, showed that the conservative surgery with adjuvant irradiation group was the one with the most consistent return to school and achievement of employment or tertiary education. Prospective stud-

ies with formal neuropsychological testing and specific behavioral assessments before and after any intervention are needed to elucidate this issue; these data will be particularly important for the young children in whom the questions of whether delaying irradiation is a reasonable policy, and whether the neurotoxicity of the recurrent disease and the subsequent surgery is higher than the one associated with irradiation offered to prevent relapse, need to be answered. The assessment of the treatment option providing the most favorable functional outcome is difficult, because the experience of the neurosurgeon (240), the recurrences, and the subsequent therapeutic interventions contribute to the final result. The comparative evaluation of published studies is further complicated by the variable, often subjective, and not validated parameters defining the good outcome. Moreover, most of them assess patients treated before the advances in neurosurgery, imaging, and RT techniques, and often they do not take into account the status of the patients at diagnosis. Thus, Yasargil et al. (120) report that 5.7% of 51 children and 5.4% of 61 adults who underwent primary microsurgical complete excision had poor outcome (severe deterioration or unchanged poor condition, totally dependent, and with major medical problems). In this study, the outcome (evaluated by deterioration of the general condition, dependence, endocrine replacement, and psychoorganic syndrome) was significantly compromised in patients with large tumors or hydrocephalus or in those who underwent second or subsequent craniotomy for recurrence or uncontrolled growth of the original tumor (120). Rajan et al. (132) propose that 46% of the patients treated by RT alone or after surgery lived normal independent lives and 6% had total disability even for self-care activities. De Vile et al. (118) found that the mean morbidity scores (based on endocrine deficiencies, vision, motor disorders and epilepsy, learning difficulties, behavioral problems, IQ, hypothalamic dysfunction) were not different between children who received RT after SR and those who had complete removal. However, the scores of children with additional surgery for recurrence were higher than the ones after their initial surgery and higher than those of children without recurrence. They also suggest that severe hydrocephalus, occurrence of intraoperative complications (vascular or frontal lobe trauma), and young age at presentation were predictors of poor long-term outcome. Interestingly, Duff et al. (89) suggest that GTR is associated with better clinical outcome, whereas there is no difference between patients who received or did not receive RT, children or adults, and patients diagnosed with the adamantinomatous or the papillary type. In this series, factors associated with poor outcome were lethargy, visual deterioration or papilloedema at presentation, tumor calcification and adhesiveness to surrounding neurovascular structures, as well as hydrocephalus. Weiner et al. (44) found that the Karnofsky Performance Status was significantly lower in patients who underwent two or more operative procedures, whereas age or tumor histopathological findings could not predict this status. Finally, Karavitaki et al. (74) found no difference in the cumulative probability of morbidities not present at diagnosis (hyperphagia/obesity, severe motor disorders, epilepsy, complete dependency for basal daily ac-

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Karavitaki et al. Craniopharyngiomas

tivities, and deterioration of work or school status) among patients treated by GTR, PR, or PR combined with RT. 5. Other. Other rare long-term irradiation-attributed morbidities include vasculopathy (149, 184) and brain tumors, with reported cases of astrocytoma (241), meningioma (84), glioblastoma (242), and glioma (144, 145).
B. Mortality

Importantly, craniopharyngiomas are associated with decreased survival; overall mortality rates of three to six times higher than that of the general population have been reported (216, 243). Interestingly, among 1014 patients with hypopituitarism of various causes included in the West Midlands Hypopituitary Database, those with craniopharyngioma had a significantly higher standard mortality ratio (9.28 vs. 1.61) (244). The overall survival rates (reflecting the impact of different treatment modalities) in earlier series were as low as 67 69% at 5-yr follow-up (18, 107) and 4377% at 10-yr follow-up (132, 146, 184, 245). The advances in neuroendocrinology, neuroradiology, microsurgery, supportive care, and radiation oncology techniques (132) have contributed to improvements, so that in studies published during the last decade, the rates range between 80 and 91% at 5 yr (10, 74, 90) and between 83 and 92.7% at 10 yr (74, 90, 111, 144, 216). Apart from those deaths directly attributed to the tumor (pressure effects to critical structures) and those related to the surgical interventions (74, 111, 145, 243), the risk of cardio-/cerebrovascular (243, 244) and respiratory (244) mortality is enhanced. It has also been suggested that in childhood populations, the hypoadrenalism and the associated hypoglycemia, as well as the metabolic consequences of antidiuretic hormone deficiency and absent thirst, may contribute to the excessive mortality (144, 203, 204). The data on the treatment option with the most favorable impact on survival are not consistent, and often the relevant studies lack statistical evaluations. Furthermore, the reported mortality rates are probably affected by the different therapeutic interventions for the recurrence(s) resulting in significant heterogeneity among the compared groups. Thus, the 10-yr survival rates range from 81.3100% after radiologically confirmed total removal (74, 90, 111), 25 86% after SR or PR (74, 90, 92, 107, 246), 77100% after PR and subsequent RT (74, 92, 107, 132, 145, 246, 247), and 81100% after RT alone (132, 145). The lower limits of these rates represent data of earlier series. Selection bias in the choice of treatment, with less aggressive tumors being offered RT only, should also be taken into account. Karavitaki et al. (74) found no significant difference in the 10-yr survival rates between patients treated by GTR (100%), PR alone (86%), and PR followed by RT (87%). Similarly, Stripp et al. (144) found comparable 10-yr survival rates in patients treated by surgery alone (GTR or SR) (86%) or surgery combined with RT (83%), with the extent of resection not predicting survival. Finally, Rajan et al. (132), in a series of 173 patients treated with external beam RT either alone or after surgery, found that the survival was not influenced by the degree of surgery. The unfavorable effect of tumor recurrence on mortality is widely accepted (74, 107, 184, 190, 243), with 10-yr survival

rates ranging between 29 and 70% (depending on the subsequent treatment modalities) (74, 107). Interestingly, Jose et al. (152) suggest that the survival is not different among patients offered irradiation for recurrence or as adjuvant therapy after primary surgery and among those with recurrence subjected or not to salvage surgery before RT. The impact of age at diagnosis as a prognostic factor of survival is controversial; some studies suggest better outcome in younger patients (107, 111, 243), others in older age groups (10, 132), while others have found no difference between children and adults (40, 74, 189, 246). Notably, neonates with craniopharyngioma have poor prognosis independently of tumor therapy, with death being the usual outcome (248). With the exception of Bulow et al. (243) and Pereira et al. (216), who found that females had higher mortality, no gender differences have been confirmed (74, 132, 144, 146, 246). The histological type (42) and the consistency or location of the lesion (intrasellar, extrasellar, or both) have no prognostic significance (40, 74, 146). Finally, no consistent results exist for the tumor size (40, 146) or the presence of hydrocephalus (74, 120, 144).

XII. Treatment Algorithm

A clear consensus on the best therapeutic approach of primary or recurrent craniopharyngiomas has not been established as yet. Based on the data in this review, which covers all the significant literature available, we propose a treatment algorithm, shown in Fig. 10. Due to the lack of current data on the outcome of clinical/ imaging observation alone in tumors not causing significant pressure effects, therapeutic intervention is suggested for all the patients with imaging consistent with a craniopharyngioma. Clinical and radiological factors at presentation may guide the initial approach. When compressive signs or symptoms are evident, surgical excision is considered necessary, which in cases of predominantly cystic lesions may be facilitated by previous fluid aspiration. GTR is a reasonable target, provided it is performed by skilled neurosurgical hands and hazardous manipulations to critical brain areas are avoided. In view of the poor local control rates associated with radiographically confirmed residual tumors and the high morbidity and mortality after reoperation(s), in cases of no total removal and conservative surgery, postoperative irradiation is recommended. Although this policy is debated for young children, the radiation toxicity (probably minimized with the new treatment planning and delivery techniques) to the developing brain needs to be balanced with the risks of a recurrent mass and subsequent possible multiple surgical procedures. In small tumors not causing pressure effects (visual, neurological, hypothalamic), RT (preceded by biopsy for confirmation of the diagnosis) offers an attractive option for avoiding the risks of surgery. In predominantly cystic craniopharyngiomas, previous aspiration of the fluid may decrease the adverse sequelae of possible cyst enlargement during irradiation. The therapeutic decisions for recurrent disease depend on the nature of the previous interventions and the severity of

Karavitaki et al. Craniopharyngiomas

Endocrine Reviews, June 2006, 27(4):371397 391

FIG. 10. Treatment algorithm for craniopharyngiomas.

the clinical picture. In recurrent lesions not previously irradiated, RT seems beneficial. Given the high morbidity and mortality accompanying repeated surgery, this option is suggested only in cases of acute pressure effects. The plans for control of further local failure are individualized and include the alternatives of gamma knife radiosurgery, cyst controlling procedures, surgical debulking (for significant solid life-threatening component), and systemic chemotherapy.

XIII. Conclusions

The craniopharyngiomas remain challenging and often enigmatic tumors; despite their benign histological appearance, they are often associated with unfavorable and occasionally disastrous sequelae. The lack of prospective randomized studies (which practically may not be feasible and seem unlikely to be undertaken) makes their optimal therapy

controversial. The goals for primary or recurrent disease should focus not only on the long-term tumor control and survival, but also on the reduction of the disease and treatment-related morbidity and the preservation of quality of living. Overall, the management is undoubtedly complex: lifelong surveillance by a multidisciplinary support team (experienced neurosurgeons, endocrinologists, neurooncologists, ophthalmologists, neurologists, neuropsychologists, and rehabilitation doctors) is required for better long-term results. Covering of educational needs, parent education, and appropriate adult transition services is particularly important for childhood populations. The severity and rarity of craniopharyngiomas mandates central registration, which may provide correlates between treatments and outcomes, guiding us in the future. Apart from the type of treatment, the identification of clinical and imaging parameters designating patients with a better prognosis appears difficult. The clarification of their pathogenesis, the establishment of prognostic factors at the pathological or molecular level, and the

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Karavitaki et al. Craniopharyngiomas immunoelectron microscopic analysis. Virchows Arch [A] 399:49 59 Sarubi JC, Bei H, Adams FF, Boson WL, Friedman E, Brandao K, Kalapothakis E, Mirana D, Valle FL, Sarquis MS, De Marco L 2001 Clonal composition of human adamantinomatous craniopharyngiomas and somatic mutation analyses of the patched (PTCH), Gs and Gi2 genes. Neurosci Lett 310:5 8 Gorski GK, Morro LE, Donaldson MH, Freed M 1992 Multiple chromosomal abnormalities in a case of craniopharyngioma. Cancer Genet Cytogenet 60:212213 Karnes PS, Tran TN, Cui MY, Raffel C, Gilles FH, Barranger JA, Ying KL 1992 Cytogenetic analysis of 39 pediatric central nervous system tumors. Cancer Genet Cytogenet 59:1219 Rienstein S, Adams EF, Pilzer D, Goldring AA, Goldman B, Friedman E 2003 Comparative genomic hybridization analysis of craniopharyngiomas. J Neurosurg 98:162164 Sekine S, Shibata T, Kokubu A, Morishita Y, Noguchi M, Nakanishi Y, Sakamoto M, Hirohashi S 2002 Craniopharyngioma of adamantinomatous type harbor beta-catenin gene mutations. Am J Pathol 161:19972001 Buslei R, Nolde M, Hofman B, Meissner S, Eyupoglu IY, Siebzehnrubl F, Hahnen E, Kreutzer J, Fahlbusch R 2005 Common mutations of beta-catenin in adamantinomatous but not in other tumours originating from the sellar region. Acta Neuropathol (Berl) 109:589 597 Hassanein AM, Glanz SM, Kessler HP, Eskin TA, Liu C 2003 Beta-catenin is expressed aberrantly in tumors expressing shadow cells. Pilomatricoma, craniopharyngioma, and calcifying odontogenic cyst. Am J Clin Pathol 120:732736 Kato K, Nakataki Y, Kanno H, Inayama Y, Ijiri R, Nagahara N, Miyake T, Tanaka M, Ido Y, Aida N, Tachibana K, Sekido K, Tanaka Y 2004 Possible linkage between specific histological structures and aberrant reactivation of the Wnt pathway in adamantinomatous craniopharyngioma. J Pathol 203:814 821 Nozaki M, Tada M, Matsuko R 1998 Rare occurrence of inactivating p53 gene mutations in primary non-astrocytic tumours of the central nervous system: reappraisal by yeast functional assay. Acta Neuropathol 95:291296 Vidal S, Kovacs K, Lloyd RV, Meyer FB, Scheithauer BW 2002 Angiogenesis in patients with craniopharyngiomas. Correlation with treatment and outcomes. Cancer 94:738 745 Vaquero J, Zurita M, de Oya S, Coca S, Morales C, Salas C 1999 Expression of vascular permeability factor in craniopharyngioma. J Neurosurg 91:831 834 Wheatley T, Clark JD, Stewart S 1986 Craniopharyngioma with hyperprolactinaemia due to a prolactinoma. J Neurol Neurosurg Psychiatry 49:13051307 Hazen S, Freiberg SR, Thomas C, Wallman J, Clerkin EP, Lo TC 1989 Multiple distinct intracranial tumours: association of pinealoma and craniopharyngioma: case report. Surg Neurol 31:381 386 Kleihnes P, Burger P, Scheithauer B 1993 Histological typing of tumours of the central nervous system. World Health Organization International Histological Classification of Tumours. Heidelberg: Springer-Verlang Nelson GA, Bastian FO, Schlitt M, White RL 1988 Malignant transformation of craniopharyngioma. Neurosurgery 22:427 429 Kristopaitis T, Thomas C, Petruzzelli GJ, Lee JM 2000 Malignant craniopharyngioma. Arch Pathol Lab Med 124:1356 1360 Petito CK, De Girolami U, Earle K 1976 Craniopharyngiomas. A clinical and pathological review. Cancer 37:1944 1952 Zhang YQ, Wang CC, Ma ZY 2002 Pediatric craniopharyngiomas: clinicomorphological study of 189 cases. Pediatr Neurosurg 36: 80 84 Crotty TB, Scheithauer BW, Young WF, Davis DH, Shaw EG, Miller GM, Burger PC 1995 Papillary craniopharyngioma: a clinico-pathological study of 48 cases. J Neurosurg 83:206 214 Eldevik OP, Blaivas M, Gabrielsen TO, Hald JK, Chandler WF 1996 Craniopharyngioma: radiologic and histologic findings and recurrence. Am J Neuroradiol 17:14271439 Weiner HL, Wisoff JH, Rosenberg ME, Kupersmith MJ, Cohen H, Zagzag D, Shiminski-Maher T, Flamm ES, Epsten FJ, Miller D 1994 Craniopharyngiomas: a clinicopathological analysis of factors

full assessment of the impact of novel or improved therapeutic modalities are eagerly awaited.
Acknowledgments
Address all correspondence and requests for reprints to: Prof. J. A. H. Wass, Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, United Kingdom. E-mail: john.wass@ noc.anglox.nhs.uk

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