First published online on March 16, 2006
Endocrine Reviews, doi:10.1210/er.2006-0002
Endocrine Reviews 27 (4): 371-397
Copyright © 2006 by The Endocrine Society
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
Correspondence: 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{at}noc.anglox.nhs.uk
 |
Abstract
|
|---|
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 treatment-related 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.
- I. Introduction
- II. History
- III. Epidemiology
- IV. Pathogenesis
- V. Pathology
- VI. Location
- VII. Presenting Manifestations
- VIII. Imaging Features
- IX. 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
- X. Risk Factors for Recurrence
- XI. Long-Term Outcome after Surgery with or without Conventional External Beam Irradiation
- A. Morbidity
- B. Mortality
- XII. Treatment Algorithm
- XIII. Conclusions
|
I. Introduction
|
|---|
CRANIOPHARYGIOMAS ARE RARE epithelial tumors arising along the path of the craniopharyngeal duct. 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
|
|---|
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 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 wasn’t 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. Luke’s 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 Rathke’s 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
|
|---|
Craniopharyngiomas are rare tumors with an overall incidence of 0.13 cases per 100,000 person-years (10). They account for 2–5% of all the primary intracranial neoplasms (11) and 5.6–15% of the intracranial tumors in children (12, 13, 14, 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 5–14 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 Rathke’s 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 demonstrated (25, 26, 27). Beta-catenin gene mutations have been identified only in the adamantinomatous subtype (28, 29) affecting exon 3, which encodes the degradation targeting box of beta-catenin; 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 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 (1–16%) (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, 43, 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, 45, 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, 41, 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, 51, 52, 53). 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 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 keratinization 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).
View larger version (125K):
[in this window]
[in a new window]
|
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. x 10). B, Gliotic reaction rich in Rosenthal fibers (arrow) in the surrounding parenchyma (HE. x 40). [Courtesy of Dr O. Ansorge, Neuropathology Department, Radcliffe Infirmary, Oxford, UK.].
|
|
The papillary variety (Fig. 2), with the exception of rare 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 Rathke’s cleft cyst may be difficult, particularly in small biopsy specimens, due to the capacity of the epithelial lining of the Rathke’s 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 Rathke’s (52). It has also been proposed that Rathke’s cysts, in contrast to craniopharyngiomas, do not express cytokeratins 8 and 20 (57).
View larger version (83K):
[in this window]
[in a new window]
|
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. x 5; B, HE. x 20). [Courtesy of Dr. O. Ansorge, Neuropathology Department, Radcliffe Infirmary, Oxford, UK.].
|
|
The comparative pathological features of craniopharyngiomas and related lesions, Rathke’s 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 17ß-estradiol oxidoreductase activity (resulting in significantly increased estrone formation from the added 17ß-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 apoptosis-mediated elimination of embryological remnants of epithelial tissue) (71), lower levels of retinoic acid receptor ß, 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 supra- and intrasellar, 53–75%) (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). 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, 87, 88, 89, 90). The duration of the symptoms until diagnosis ranges between 1 wk and 372 months (74, 89, 90, 91, 92, 93, 94). The commonest presenting clinical manifestations (neurological, visual, hypothalamopituitary) are summarized in Tables 2A and 2B. Headaches, nausea/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, 97, 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), Weber’s syndrome (ipsilateral III cranial nerve palsy with contralateral hemiplegia due to midbrain infarction) (105), and Wallenberg’s syndrome (signs due to occlusion of the posterior inferior cerebellar artery) (106).
The hypothalamo-pituitary function at presentation may 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 35–95% 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.
View this table:
[in this window]
[in a new window]
|
TABLE 3. Pituitary hormone deficits and hyperprolactinemia at presentation in children and adults with craniopharyngioma
|
|
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
|
|---|
Currently useful tools for the neuroradiological characterization of the craniopharyngiomas include plain skull x-rays, computed tomography (CT), magnetic resonance imaging (MRI), and occasionally, cerebral angiography.
Before the introduction of CT scans, air studies and carotid 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).
View larger version (127K):
[in this window]
[in a new window]
|
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 76:513–514, 2000 (70 ) with permission from the BMJ Publishing Group.].
|
|
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 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).
View larger version (90K):
[in this window]
[in a new window]
|
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 17:1427–1439, 1996 (43 ). © American Society of Neuroradiology.]
|
|
View larger version (131K):
[in this window]
[in a new window]
|
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 58:922–933, 2003 (250 ), with permission from the Royal College of Radiologists.]
|
|
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. 6–9).
View larger version (92K):
[in this window]
[in a new window]
|
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.]
|
|
View larger version (95K):
[in this window]
[in a new window]
|
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.]
|
|
View larger version (88K):
[in this window]
[in a new window]
|
FIG. 8. Unenhanced (A) and contrast-enhanced (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 17:1427–1439, 1996 (43 ). © American Society of Neuroradiology.]
|
|
View larger version (89K):
[in this window]
[in a new window]
|
FIG. 9. Nonenhanced (A) and contrast-enhanced (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 17:1427–1439, 1996 (43 ). © American Society of Neuroradiology.]
|
|
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 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).
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 45–57% 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 [41–54% in children (44, 74, 90, 118) and 12–30% 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 Rathke’s 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).
|
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 surgeon’s 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 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 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 (137, 138, 139, 140).
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 neurosurgeon’s 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) (25–100% 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, 143, 144, 145). 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 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 progression-free 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 relapse-free 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 ß-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 assessed the efficacy of various ß- and -emitting isotopes (mainly 32phosphate, 90yttrium, 186rhenium, and 198gold) (158, 159, 160, 161, 162, 163); because none of them has the ideal physical and biological profile [i.e., pure ß-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 ß 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 ß-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, 3–70); 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. 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 ß-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,
Top
Abstract
I. Introduction
