2.4.2 Craniopharyngiomas

Craniopharyngiomas are rare tumours with a reported incidence of 0.13 cases per 100 000 person-years. They account for 2–5% of all the primary intracranial neoplasms, 5.6–15% of the intracranial tumours in childhood populations, in which they are the commonest lesion involving the hypothalamo-pituitary region. They may be detected at any age, even in the pre- and neonatal periods and almost half of the total cases have been described in adults. They show a bimodal age distribution with peak incidence rates in children aged 5–14 and adults aged 50–74 years (1).

Craniopharyngiomas are epithelial tumours arising along the path of the craniopharyngeal duct (the canal connecting the stomodeal ectoderm with the evaginated Rathke’s pouch). Neoplastic transformation of embryonic squamous cell rests of the involuted craniopharyngeal duct or metaplasia of adenohypophyseal cells in the pituitary stalk or gland are the proposed theories (1). B-catenin gene mutations have been identified in the adamantinomatous subtype affecting exon 3, which encodes the degradation targeting box of B-catenin; this is compatible with an accumulation of nuclear B-catenin protein (a transcriptional activator of the Wnt signalling pathway). Strong B-catenin expression has been shown in the adamantinomatous subtype indicating re-activation of the Wnt signalling pathway, which is implicated in the development of several neoplasms (2).

Craniopharyngiomas are grade I tumours according to the WHO classification. Rare cases of malignant transformation (possibly triggered by previous irradiation) have been described. Two main pathological subtypes have been reported: the adamantinomatous and the papillary, but transitional or mixed forms have also been described (1, 3).

The adamantinomatous type is the most common subtype and may occur at any age. Macroscopically these tumours have cystic and/or solid components, necrotic debris, fibrous tissue and calcification. The cysts may be multiloculated and contain liquid ranging from ‘machinery oil’ to shimmering cholesterol-laden fluid consisting of desquamated squamous epithelial cells, rich in membrane lipids and cytoskeleton keratin. They tend to have sharp and irregular margins, 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. The epithelium of the adamantinomatous type is composed of three layers of cells: a distinct palisade basal layer of small cells with darkly staining nuclei and little cytoplasm (somewhat resembling the basal cells of the epidermis of the skin), 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 plate-like squamous cells (Fig. 2.4.2.1). The flat squames are desquamated singly or in distinctive stacked clusters and form nodules of ‘wet’ keratin, which are often heavily calcified and appear grossly as white flecks. The keratinous debris may elicit an inflammatory and foreign body giant cell reaction. The presence of the typical adamantinomatous epithelium or of the ‘wet’ keratin alone are diagnostic, whereas features only suggestive of the diagnosis in small or non-representative specimens include fibrohistiocytic reaction, necrotic debris, calcification, and cholesterol clefts (1).

The papillary variety has been almost exclusively described in adult populations (accounts for 14–50% of the adult cases and for up to 2% of the paediatric ones). Calcification is rare and the cyst content is usually viscous and yellow. It is generally well circumscribed and infiltration of adjacent brain tissue by neoplastic epithelium is less frequent than in the adamantinomatous type. It consists of mature squamous epithelium forming pseudopapillae and an anastomosing fibrovascular stroma without the presence of peripheral palisading of cells or stellate reticulin (Fig. 2.4.2.2). The differential diagnosis between a papillary craniopharyngioma and a Rathke’s cleft cyst may be difficult, particularly in small biopsy specimens, as the epithelial lining of the Rathke’s cysts may undergo squamous differentiation; however, the lack of a solid component and the presence of extensive ciliation and/or mucin production are suggestive of Rathke’s (1, 3).

Most of the craniopharyngiomas 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%), whereas the purely intrasellar ones represent the least common variety (5–6%). Other rare locations include the nasopharynx, the paranasal area, the sphenoid bone, the ethmoid sinus, the intrachiasmatic area, the temporal lobe, the pineal gland, the posterior cranial fossa, the cerebellopontine angle, the midportion of the midbrain, or completely within the third ventricle (1, 4).

Imaging tools for the diagnosis of craniopharyngiomas include plain skull X-rays, CT, MRI, and occasionally, cerebral angiography. Plain skull X-rays, although seldom used nowadays, may show calcification and abnormal sella (1). CT is helpful for the evaluation of the bony anatomy, the identification of calcifications and the discrimination 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 (1) (Fig. 2.4.2.3). The MRI is particularly useful for the topographic and structural analysis of the tumour. The appearance of the craniopharyngioma depends on the proportion of the solid and cystic components, the content of the cyst(s) (cholesterol, keratin, haemorrhage) and the amount of calcification present. A solid lesion appears as iso- or hypointense relative to the brain on precontrast T₁-weighted images, shows enhancement following gadolinium administration and is usually of mixed hypo- or hyperintensity on T₂-weighted sequences. Large amounts of calcification may be visualized as areas of low signal on both T₁- and T₂-weighted images. A cystic element is usually hypointense on T₁- and hyperintense on T₂-weighted sequences. On T₁-weighted images a thin peripheral contrast-enhancing rim of the cyst is demonstrated. Protein, cholesterol, and methaemoglobin may cause high signal on T₁-weighted images, while very concentrated protein and various blood products may be associated with low T₂-weighted signal (1) (Fig. 2.4.2.4).

The size of craniopharyngiomas has been reported to be more than 4 cm in 14–20% of the cases, 2–4 cm in 58–76%, and less than 2 cm in 4–28%. Their consistency is purely or predominantly cystic in 46–64%, purely or predominantly solid in 18–39% and mixed in 8–36%. Calcification has been demonstrated in 45–57% and is probably more common in children (78–100%). The calcification patterns vary from solid lumps to popcorn-like foci or less commonly, to an eggshell pattern lining the cyst wall. Hydrocephalus has been reported in 20–38% and is probably more frequent in childhood-diagnosed disease (41–54%). There is no agreement on the radiological features discriminating the two histological subtypes. The differential diagnosis includes a number of sellar or parasellar lesions, including Rathke’s cleft cyst, dermoid cyst, epidermoid cyst, pituitary adenoma, germinoma, hamartoma, suprasellar aneurysm, arachnoid cyst, suprasellar abscess, glioma, meningioma, sacroidosis, tuberculosis, and Langerhans cell histiocytosis. Differention from a Rathke’s cleft cyst (typically small, round, purely cystic lesion lacking calcification), or from a pituitary adenoma (in the rare case of a homogeneously enhancing solid craniopharyngioma) may be particularly difficult (1, 4–7).

Patients with craniopharyngioma may present with a variety of clinical manifestations attributed to pressure effects on vital structures of the brain (visual pathways, brain parenchyma, ventricular system, major blood vessels and hypothalamo-pituitary system). Their severity depends on the location, the size, and the growth potential of the tumour. The duration of the symptoms until diagnosis ranges between 1 week to 372 months (1). The presenting clinical manifestations (neurological, visual, hypothalamo-pituitary) and the pituitary function in a large series of cases are shown in Tables 2.4.2.1 and 2.4.2.2. Headaches, nausea/vomiting, visual disturbances, growth failure (in children) and hypogonadism (in adults) are the most frequently reported.

Surgery combined with or not combined with adjuvant external beam irradiation is currently one of the most widely used first therapeutic modalities for craniopharyngiomas. These remain challenging tumours, even in the era of modern neurosurgery. This is mainly attributed to their sharp, irregular margins and to their tendency to adhere to vital neurovascular structures making surgical manipulations potentially hazardous to vital brain areas. The attempted extent of excision has been a subject of significant debate and depends on the size (achieved in 0% of lesions >4 cm) and location (particularly difficult for retrochiasmatic or within the third ventricle) of the tumour, the presence of hydrocephalus, of greater than 10% calcification and of brain invasion, as well as on the experience, the individual judgement during the operation and the general treatment policy (aggressive or not) adopted by each neurosurgeon (1, 6, 7). 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%) (6). The perioperative morbidity ranges between 1.7% and 5.4% for primary operations (1, 4, 5, 8). The irradiation of cystic craniopharyngiomas carries the risk of enlargement, which may later regress or necessitate further intervention (4, 9).

Recurrent tumors may arise even from small islets of craniopharyngioma cells in the gliotic brain adjacent to the tumour, which can remain even after gross total resection. The mean interval for their diagnosis after various primary treatment approaches ranges between 1 and 4.3 years and relapses as late as 36 years after initial therapy have been reported. Remote recurrences after apparent successful removal have been described with possible mechanisms including transplantation during the surgical procedures and dissemination by meningeal seeding or cerebrospinal fluid spreading (1, 4).

Series with radiological confirmation of the extent of resection show that the recurrence rates following gross total removal range between 0 and 62% at 10 years follow-up. These are significantly lower than those reported after partial or subtotal resection (25–100% at 10 years follow-up). In cases of limited surgery, adjuvant radiotherapy improves significantly the local control rates (recurrence rates 10–63% at 10 years follow-up). Series with statistical comparisons of the recurrences achieved by gross total removal or combination of surgery and radiotherapy have not provided consistent results. Finally, radiotherapy alone, which, however, can be offered to selected tumours, provides 10-year recurrence rates ranging between 0 and 23% (1, 4–14) (Table 2.4.2.3). In cases of predominantly cystic tumours, fluid aspiration provides relief of the obstructive manifestations and facilitates the removal of the solid tumour portion; the latter should not be delayed for more than a few weeks, as there is significant risk of cyst refilling (reported in up to 81% of the cases at a median period of 10 months) (4, 6). The interpretation of the data on the effectiveness of each therapeutic modality has to be done with caution, since the published studies are retrospective, nonrandomized and often specialty-biased. Although not widely accepted, it has been suggested that the tumor control correlates with the irradiation dose and doses of and below 5400 cGy are associated with poorer outcome. The growth rate of craniopharyngiomas varies considerably and reliable clinical, radiological, and pathological criteria predicting their behaviour are lacking. Thus, apart from significant impact of the treatment modality, attempts to identify other prognostic factors (age group at diagnosis, sex, imaging features, pathological subtypes, immunoreactivity of the tumor proliferation marker MIB1) have not provided consistent data (1).

The management of recurrent tumours remains difficult, as scarring/adhesions from previous surgeries or irradiation decrease the chance of successful excision. In such cases, total removal is achieved in a significantly lower rate when compared with primary surgery (0–25%) and is associated with increased perioperative morbidity and mortality (10.5–24%), suggesting that for many recurrent lesions palliative surgery is the most realistic target. The beneficial effect of radiotherapy (preceded or not by second surgery) in recurrent lesions has been clearly shown (1, 4, 13, 14).

Intracavitary irradiation (brachytherapy) is a minimally invasive approach involving stereotactically guided instillation of b-emitting isotopes into cystic craniopharyngiomas and delivering higher radiation dose to the cyst lining than the one offered by external beam radiotherapy. It causes destruction of the secretory epithelial lining leading to elimination of the fluid production and cyst shrinkage. A number of b- and γ-emitting isotopes (mainly phosphate-32, yttrium-90, rhenium-186, gold-198) have been used; as none of them has the ideal physical and biological profile (i.e. pure b emitter with short half-life and with tissue penetrance limited to cover only the cyst wall), there is no consensus on which is the most suitable therapeutic agent. Based on studies with the largest series of patients and with relatively long follow-up periods, brachytherapy seems to offer a good prospect for the reduction/stabilization of cystic craniopharyngiomas. This combined with its reported low surgical morbidity and mortality render intracavitary irradiation an attractive option for predominantly cystic tumors, and particularly the monocystic ones. Its impact on the quality of survival and long-term morbidity (particularly vision, neuroendocrine, and cognitive function) remain to be assessed (1, 15, 16).

The intracystic installation of the antineoplasmatic agent bleomycin has been proposed for the management of cystic tumours. However, in published reports the tumour control rates range between 0 and 100%. Direct leakage of the drug to surrounding tissues during the installation procedure, diffusion though the cyst wall or high drug dose have been associated with various toxic (hypothalamic damage, blindness, hearing loss, ischaemic attacks, peritumoral oedema) or even fatal effects. The value of this treatment option in the tumour control or even in the delaying of potentially harmful surgery and/or radiotherapy, as well as the optimal protocol and the clear-cut criteria predicting the long-term outcome remain to be established in large series with appropriate follow-up (1, 17, 18).

Stereotactic radiosurgery delivers a single fraction of high-dose ionizing radiation on precisely mapped targets keeping the exposure of adjacent structures to a minimum. Tumour 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. Published studies suggest that it achieves tumour control in a substantial number of patients with small volume lesions (complete/partial resolution: 67–90%). Stereotactic radiosurgery may be particularly useful for well-defined residual disease following surgery or for the treatment of small solid recurrent tumuors, particularly after failure of the conventional radiotherapy. In cases of large cystic portions multimodality approaches with instillation of radioisotopes or bleomycin may offer further benefits. Studies with long-term follow-up evaluating the optimal marginal dose, its role in the prevention of tumour growth and its effects on the neurocognitive and neuroendocrine functions are required (1, 19–21).

Systemic chemotherapy has been offered in a limited number of patients mainly with aggressive tumours with relative success (1). Its application remains rather experimental and its place, particularly in the treatment of aggressive tumours, remains to be assessed.

Patients with craniopharyngioma suffer from significant long-term morbidity (mainly endocrine, visual, hypothalamic, neurobehavioural, and cognitive) attributed to the damage of critical neuronal structures by the primary or recurrent tumour and/or to the adverse effects of the therapeutic interventions (Table 2.4.2.4). Notably, the severity of the radiation-induced 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 (1).

In series including subjects with various treatment modalities and follow-up periods, the frequency of pituitary hormone deficits ranges between 88% and 100% for growth hormone, 80–95% for follicle-stimulating hormone/luteinizing hormone, 55–88% for adrenocorticotropic hormone, 39–95% for thyroid-stimulating hormone and 25–86% for antidiuretic hormone (ADH). Apart from symptomatic diabetes insipidus, which is probably more common in surgically treated patients, the long-term endocrine morbidity is not affected by the type of tumour therapy. Interestingly, restoration of pre-existing hormone deficits after surgical removal is absent or uncommon. The phenomenon of growth without growth hormone has been reported in some children with craniopharyngioma, who show normal or even accelerated linear growth, despite their untreated growth hormone deficiency. The pathophysiological mechanism has not been clarified; the obesity-associated hyperinsulinaemia or the presence of hyperprolactinaemia have been proposed as factors stimulating growth by affecting serum concentrations of insulin-like growth factor 1 (IGF-1) or by binding directly to the IGF-1 receptor. Finally, a number of studies support the view that growth hormone replacement in children and adults does not increase the risk of tumour recurrence (1, 4, 22, 23). Compromised vision has been reported in up to 62.5% of the patients treated by surgery combined with or not combined with radiotherapy during an observation period of 10 years. The visual outcome is adversely affected by the presence of visual symptoms at diagnosis and by daily irradiation doses above 2 Gy (1).

Hypothalamic damage may result in hyperphagia and uncontrollable obesity, disorders of thirst and water/electrolyte balance, behavioural and cognitive impairment, loss of temperature control and disorders in the sleep pattern. Obesity is the most frequent manifestation affecting 26–61% of the patients treated by surgery combined or not with radiotherapy. It is a consequence of the disruption of the mechanisms controlling satiety, hunger, and energy balance, and it often results in devastating metabolic and psychosocial complications. This necessitates provision of dietary and behavioural modifications, encouragement of regular physical activity, psychological counselling, and antiobesity drugs. Diabetes insipidus 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. In this group of patients, the maintenance of the osmotic balance has been shown to be precarious with recurrent episodes of hyper- or hyponatraemia contributing to morbidity and mortality. Careful fluid balance in and out and regular weighting are important. Factors associated with significant hypothalamic morbidity have been proposed to be young age at presentation in children, manifestations of hypothalamic disturbance at diagnosis, hypothalamic invasion, tumour height greater than 3.5 cm from the midline, attempts to remove adherent tumour from the region of hypothalamus, multiple operations for recurrence and hypothalamic radiation doses greater than 51 Gy (1, 4, 5, 7).

The compromised neuropsychological, and cognitive function in patients with craniopharyngioma contributes significantly to poor academic and work performance, disrupted family and social relationships, and impaired quality of life. In a series of 121 patients treated by surgery with or without adjuvant radiotherapy and followed up for a mean period of 10 years, 40% had poor outcome (the assessment was based on motor and visual deficits, dependence for activities of daily living, Karnofsky Performance Scale, school and work status, debilitating psychological or emotional problems) (5). It has also been shown that the mean morbidity scores (based on endocrine deficiencies, vision, motor disorders and epilepsy, learning difficulties, behavioral problems, IQ, hypothalamic dysfunction) of children with additional surgery for recurrence were higher than the ones after their initial surgery and higher than those of children without recurrence (7). There is no consensus on the therapeutic option with the least adverse impact on the neurobehavioural outcome necessitating prospective studies with formal neuropsychological testing and specific behavioural assessment prior and after any intervention (1). These data are particularly important for young children, in whom the uncertainties 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 overall mortality rates of patients with craniopharyngioma have been reported to be three to six times higher than that of the general population with survival rates ranging between 83% and 92.7% at 10 years. Apart from the deaths directly attributed to the tumour (pressure effects to critical structures) and to the surgical interventions, the risk of cardio-/cerebrovascular and respiratory mortality is increased. It has also been suggested that in childhood populations the hypoadrenalism and the associated hypoglycaemia, as well as the metabolic consequences of ADH deficiency and absent thirst may contribute to the excessive mortality. The impact of tumour recurrence on the long-term mortality is widely accepted and the 10-year survival rates in such cases range between 29% and 70% (depending on the subsequent treatment modalities) (1, 4, 24).

The proposed treatment algorithm, which is based on the significant available literature, is shown in Fig. 2.4.2.5 (1). Surgical removal is suggested for all craniopharyngiomas causing compressive signs or symptoms (if a predominantly cystic lesion, the resection may be facilitated by previous aspiration of the cyst fluid). Gross total removal is a reasonable aim provided it is performed by experienced neurosurgical hands and hazardous manipulations to vital brain structures are avoided. If residual tumour remains following surgery, adjuvant irradiation is recommended; this is because of the high risk of recurrence and its adverse impact on morbidity and mortality. Although this strategy may be debated for the young children, the radiation toxicity to the developing brain needs to be balanced with the consequences of relapse and subsequent possible multiple surgical procedures. In small tumours not causing pressure effects (visual, neurological, hypothalamic), radiotherapy (preceded by biopsy for confirmation of the diagnosis) is an attractive approach avoiding the risks of surgery. In predominantly cystic tumours, previous fluid aspiration may reduce the adverse sequelae of possible cyst enlargement during irradiation.

The treatment of recurrent disease depends on the previous interventions and the severity of the clinical manifestations. In recurrent lesions not previously irradiated, radiotherapy provides satisfactory local control rates. In view of the high morbidity and mortality of a second surgery, such an intervention is advocated only in cases of acute pressure effects. The treatment of further recurrence(s) should be individualized and could include gamma-knife radiosurgery, cyst-controlling procedures, surgical debulking (for significant solid life-threatening component), and systemic chemotherapy (1).