From the Annals of The University of Toronto, The Division of Neurosurgery
Craniopharyngiomas: Challenges and Controversies
Mohammed J. Asha, Selfy Oswari, Hirokazu Takami, Carlos Velasquez, Joao Paulo Almeida, Fred Gentili
Despite its benign histopathology, the treatment of cra-
niopharyngioma remains one of the most formidable chal-
lenges faced by skull base surgeons. The technical
challenges of tackling these complex central skull base
lesions are paralleled by clinical challenges related to
their unique tumor biology and the often-complex decision
making required. In this article, we critically appraise the
most recent literature to explore the challenges and con-
troversies surrounding the management of these lesions.
The role of curative resections and the shift in the surgical
paradigm toward the multidisciplinary goal-directed man-
agement approach are discussed.
INTRODUCTION
C raniopharyngiomas are rare, histologically benign (World
Health Organization grade I), predominantly sellar or
parasellar epithelial tumors that can occur in pediatric as
well as adult patients. The annual incidence is estimated at 0.5e2
per 100,000.1,2 The clinical manifestations and radiologic
appearances are variable according to the location, size, and
histologic subtype of the tumor as well as patient age-group.2,3
The management of these tumors poses significant challenges
on different levels. This characteristic is evident in the significant
morbidity associated with both the tumor itself and its surgical
management.4-6 Likewise, the relatively high recurrence rate dic-
tates a chronic course of multimodal interventions not only for the
disease but also equally for the resultant complications over the
course of its management.6-9
Understanding the various challenging aspects of this disease is
essential for formulating a holistic approach that addresses the
needs of the patient at every stage and maximizes the potential for
Key words
- Challenges
- Craniopharyngioma
- Goal-directed management
- Management
- Recurrence
Abbreviations and Acronyms
ACP: Adamantinomatous craniopharyngioma
GTR: Gross total resection
PCP: Papillary craniopharyngioma
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disease control with an acceptable level of added surgical
morbidity to preserve the quality of life for affected patients.
In this article, we attempt to encompass the various challenges
and controversies around the best management strategies for
craniopharyngiomas and discuss their implications on surgical
planning and postoperative outcome.
TUMOR CHARACTERISTICS
Craniopharyngioma Subtypes
Two main histologic subtypes have been identified: ada-
mantinomatous craniopharyngiomas (ACPs) and papillary
craniopharyngiomas (PCPs). ACPs account for most cases
(approximately 90%), with the predominance of ACPs over PCPs
being even greater in pediatric patients. A mixed type has been
also described, although it is less common.6,10
ACP characteristically occurs in a bimodal distribution, with a
peak in the pediatric age range and another in middle age. These
tumors tend to be more heteromorphous than PCPs, with cystic
components and calcifications as well as the characteristic wet
keratin components. However, the papillary variant tends to occur
mainly in adults and is composed of a more monomorphous solid
tumor with less common calcifications or cystic components.2,3,10
These morphologic differences have been attributed to different
embryologic origins.10,11
Two theories have been proposed to explain the histologic
differences between these 2 types of craniopharyngiomas. The
embryonic theory suggests that the tumors (mainly ACPs) arise
from neoplastic transformation of the epithelial remnants of the
hypophyseopharyngeal duct (Rathke pouch), which gives origin to
the primitive adenohypophysis.12 On the other hand, PCPs are
believed to arise as a result of squamous metaplasia of
adenohypophyseal cells in the pars tuberalis.13,14 These theories
might also explain the predilection of the tumors for specific
anatomic locations, with PCPs being commonly
Department of Neurosurgery, Toronto Western Hospital, University Health Network, Toronto,
Ontario, Canada
To whom correspondence should be addressed: Mohammed J. Asha, M.D.
[E-mail: masha@seha.ae]
Citation: World Neurosurg. (2020) 142:593-600.
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MOHAMMED J. ASHA ET AL.
suprachiasmatic, whereas ACPs can occur anywhere along the
craniopharyngeal tract.10,15
These topographic predilections seem to be correlated to
different patterns of clinical manifestations,10,16 with patients with
PCP presenting frequently with hypothalamic dysfunction and
features of increased intracranial pressure as a result of the
intimate relationship of the tumor to the hypothalamus and
third ventricle. On the other hand, the more common ACPs
seem to have more variable clinical presentations but tend to
carry a higher rate of visuoendocrine compromise compared
with PCP.17,18
Perhaps among the most challenging histologic features of
craniopharyngioma is the frequent adhesion to eloquent sur-
rounding neurovascular structures and the hypothalamus, which
can occur in up to two thirds of patients,19 and the presence of
calcifications, which can hamper the surgeon's ability to achieve
gross total resection (GTR). These findings are commonplace in
ACP, in contrast to PCP.
This situation has led some investigators to suggest that the
recurrence rate is higher in ACP compared with PCP,20 whereas
others have reported similar recurrence rates for both histologic
subtypes, concluding that the extent of resection per se is the
main determinant of recurrence, rather than histology.18
Although calcifications can be easily detected on preoperative
imaging, no reliable indicator is available to assess the degree
of adhesion to the surrounding structures. Consequently, it is
often difficult to quantify the surgical risks associated with
attempted radical resection of these tumors, although some
investigators have suggested a role for magnetic resonance
imaging and proposed specific criteria based on the position
of the tumor in relation to the hypothalamus, the appearance
of the pituitary stalk, and elliptic shape of the tumor as well
as the presence of calcifications as distinct markers for tumor
adhesiveness.21
Anatomic Considerations
The intimate relationship of these tumors to crucial adjacent
structures is the hallmark of the anatomic challenge. This factor is
underscored by the frequent entanglement with the major vessels
(internal carotid and basilar arteries), which has been shown in up
to 54% and 22%, respectively, of preoperative angiographic
studies22 and other rare manifestations, including complete
occlusion of the major vessels.23 The intimate relationship of the
tumor to the circle of Willis, coupled with the inevitable surgical
manipulation required in many cases (complicated by adhesions
and calcifications), is correlated with increased risks of
postoperative vascular complications, including aneurysmal
dilatations24,25 and cerebral vasospasm.26,27 Vasculopathy has
also been reported as a delayed complication of radiotherapy
and chemotherapy for these tumors.28,29
The close proximity to the optic chiasm also seems to pose a
particular surgical challenge. This characteristic is underscored by
the fact that up to one third of patients with craniopharyngioma
present with some degree of permanent visual loss.30 Prieto et al.
conducted an analysis of preoperative and postoperative
midsagittal magnetic resonance images obtained in 150 cases,
correlating their findings with preoperative and postoperative
visual status. These investigators showed that the preoperative
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CRANIOPHARYNGIOMAS: CHALLENGES AND CONTROVERSIES
location of the craniopharyngioma and its effect on the optic
chiasm as well as the appearance of the optic chiasm carry
significant consequences for the frequency of visual
compromise.31 The investigators were able to predict the visual
outcomes in 91.3% of cases. They concluded that the most
common location for craniopharyngioma was retrochiasmatic
and that patients with preoperatively stretched chiasms were less
likely to experience improvement in visual function than those
with compressed chiasms. This finding was also echoed by
postoperative studies, which showed that a persistent thinning
of the optic chiasm was a marker of poor visual outcome. The
thinning of the nerves is postulated to represent axonal loss and
might reflect the chronicity of venous congestion and
ischemia.32 Despite the best effort of the operating surgeon to
preserve the optic pathway and minimize its manipulation,
many of these patients have visual deterioration postoperatively
even in the absence of residual compressive disease. This
deterioration is likely related to added ischemic neuropathy
(especially in a previously compromised optic nerve) as a result
of small vessel injury during surgery or subsequently as a result
of adjuvant therapy.30-32
Up to 95% of parasellar craniopharyngiomas have been
shown to extend into the suprasellar compartment, although
only 20%e40% of these were exclusively suprasellar.10,33
However, most of the remainder had both sellar and
suprasellar components (75%).1,10 Purely intrasellar lesions
represent a small proportion of craniopharyngiomas and may
pose a diagnostic challenge, mimicking other sellar lesions,
especially cystic ones (e.g., Rathke cleft cysts and cystic
adenomas).34
The high prevalence of suprasellar extension of craniophar-
yngiomas is associated with an array of neurologic and endocri-
nologic as well as cognitive and psychological manifestations.2
Direct pressure on the hypothalamus and mammillary bodies
can lead to morbid obesity as well as cognitive and
psychological manifestations; extension into the third ventricle
and retrosellar space can lead to hydrocephalus and brainstem
compression, respectively.22,35,36
Retrochiasmatic and intraventricular craniopharyngiomas pose
particular difficulties for resection, and attempting GTR in these
cases may lead to significant neurocognitive sequalae.35 Surgical
insult to the posterior hypothalamus and mammillary bodies can
be troublesome36 and is associated with increased risk of
hypothalamic obesity as well as complex neurocognitive
impairments. Similarly, tackling tumor extensions in the
interpeduncular cistern puts the small perforating vessel from
the posterior circulation in jeopardy.35,37-39
In addition to the anatomic challenges based on the topog-
raphy of craniopharyngiomas, the size of these tumors also
adds further difficulty. Tumor diameter has been reported to be
>4 cm in 14%e20% of cases, 2e4 cm in 58%e76%, and <2 cm
in only 4%e28%.2 The relatively large size of some of these
lesions may dictate a degree of anatomic extension that may
be beyond the comfort level of a single surgical approach or
technique. This has been the rationale for combined or
staged approaches as well as an important factor in changing
the surgical philosophy to less aggressive function-preserving
partial resections.
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MOHAMMED J. ASHA ET AL.
CLINICAL MANIFESTATIONS AND PREOPERATIVE EVALUATION
The variable and clinically insidious course of craniopharyngioma
can be seen as an independent challenge, often resulting in well-
established deficits at the time of diagnosis. This delay in diag-
nosis and the presence of well-established wide-spectrum neuro-
hormonal deficits in the preoperative period is one of the major
challenges for this disease, with wider implications projecting
onto the clinical outcome in the postoperative period as well.
Many patients present with nonspecific manifestations,
including headaches (7%e81%), a degree of visual loss (35%e
79%), growth retardation and short stature (7%e93%), sexual
dysfunction (4%e24%), and memory and cognitive impairment
(3%e36%).1,2,6,8,18,40-42 Depending on the extent of these deficits,
the outcome can be, in some cases, adversely predetermined
despite optimal clinical management. Some investigators have
proposed a clinical grading system based on the degree of endo-
crinologic compromise, hypothalamic dysfunction, and visual
compromise as well as other manifestations of increased intra-
cranial pressure.43 Such clinical grading systems might be useful
in developing management paradigms tailored to patients' signs
and symptoms. However, this proposal is yet to be supported by
large-scale trials.
The presence of endocrinologic compromise of the anterior
pituitary has been reported in 35%e100% of patients with
craniopharyngioma. Conversely, a significant but smaller pro-
portion of patients (6%e38%) have evidence of posterior pi-
tuitary compromise (diabetes insipidus) at the time of
presentation.1-3 A temporal pattern of compromise of the
anterior pituitary hormones suggests different susceptibilities
for subpopulations of the adenohypophyseal cells, with a
pattern of early compromise of somatotrophs and gonado-
trophs, whereas the compromise of corticotrophs is often re-
ported late and is considered a more negative outcome
indicator in many cases.2,22,44
The preoperative evaluation of any visual compromise is para-
mount in formulating an effective management strategy and
anticipating the visual outcome of the proposed intervention.
Some investigators have examined the visual outcomes in their
patients and suggested correlations with baseline visual assess-
ment and early intervention,45 patient age,46 degree of tumor-
related optic tract edema,47 the pattern of optic chiasm
distortions in preoperative and postoperative radiologic
studies,31 and selected optical coherence tomography criteria.40
Neurocognitive deficits may be subtle and easily overlooked
compared with other clinical manifestations at the time of pre-
sentation and more so in the postoperative period in the presence
of more striking neuroendocrine complications. A myriad of
behavioral, cognitive, and psychosocial changes have been re-
ported in up to 57% of patients with craniopharyngioma.41,42,48
Researchers focusing on this aspect of clinical manifestations
are faced with considerable challenges in adopting a standardized,
reproducible, and quantifiable measure for assessing the impact of
the disease and its treatment on the affected patients.49 The
neurocognitive deficits associated with craniopharyngioma can
go unnoticed in many patients but can nevertheless lead to
significant behavioral difficulties, social dysfunction, reduced
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CRANIOPHARYNGIOMAS: CHALLENGES AND CONTROVERSIES
educational performance, low productivity, and, more
importantly, reduction in quality of life.42,50
AFFECTED POPULATIONSeSPECIAL CONSIDERATIONS
Pediatric Patients
The management of craniopharyngioma in pediatric patients
presents unique challenges, with most tumors in this population
being of the ACP subtype rather than the PCP subtype seen in
adults.51
This distribution pattern means that pediatric cases are often
more complex. The tumors are likely to be large heterogeneous
lesions and to have more extensive calcifications and mixed solid-
cystic components with frequent sellar-suprasellar extensions.
These less favorable tumor characteristics add further challenges
on top of the unique anatomic challenges of this age-group (small
nasal passages, less pneumatized paranasal sinuses, as well as the
delicate surrounding neurovascular structures) for the various
surgical approaches for this disease.
These challenges may explain the limited use of the endoscopic
approaches in pediatric patients and reliance mainly on open
techniques that are perhaps more invasive but more familiar.
Although some investigators have reported good outcomes using
the expanded endoscopic technique in the management of pedi-
atric craniopharyngiomas (including tumors with suprasellar ex-
tensions),52 many surgeons still see the role of expanded
endoscopic techniques as limited in pediatric surgery and
believe that they should be considered selectively, with the more
traditional open techniques being the first option in most
cases.53,54 It might be suggested that the lack of familiarity of
pediatric skull base surgeons with these endoscopic techniques
reflects the steep learning curve for neuroendoscopy in general
and especially in conjunction with the underdeveloped skull
base in this age-group.
In addition to the difference in technical challenges, the clinical
presentation seems to be slightly different in this age-group,
commonly involving a degree of growth retardation as well as
psychosocial developmental delay.48
Perhaps the most challenging aspect of the management of
pediatric craniopharyngioma is the decision making regarding
the role and extent of surgery. The surgical philosophy of
radical resections has come to face the reality of profound ef-
fects of the added morbidity and mortality at this young age.9,55
Perhaps the most devastating aspect of surgical morbidity in
this age-group is the risk of hypothalamic dysfunction (dis-
cussed in more detail in the Morbidity and mortality section),
which manifests as hyperphagia/hypothalamic obesity, thermal
dysregulation, and/or diabetes insipidus, as well as cognitive
and memory impairment.37
The impact of hypothalamic dysfunction is more devastating
when it occurs at a very young age. This reality has led to a more
conservative approach when considering the extent of any surgical
intervention. Along these lines, Puget et al.9,55 have proposed a
multimodal approach for the management of pediatric
craniopharyngioma that primarily focuses on preservation of the
pituitary-hypothalamic axis and tries to decompress the optic
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MOHAMMED J. ASHA ET AL.
apparatus to improve/preserve vision with minimal added surgical
risk.
The proposal of this approach marked a significant shift in the
surgical management of childhood craniopharyngiomas over the
last decade from a radical approach with the aim of total removal
to prevent recurrences to a more conservative philosophy that
focuses on preserving function and optimizing quality of life.
Residual disease is often treated with different radiotherapy
techniques. There is a certain agreement in the literature that the
combination of subtotal resection and adjuvant radiotherapy is a
valid strategy for the management of craniopharyngioma, because
some previous reports have suggested that progression-free and
overall survival are similar to those achieved with GTR but with
lower morbidity.56,57 This approach has been adopted by many
pediatric neurosurgeons, although the specific type of
radiotherapy and its timing remains a subject of
controversy.46,58,59
Adults and the Elderly
Although craniopharyngioma was once considered a congenital
disease identified in children or young adults, the concept of the
rarity of this disease in adults, including the elderly, has changed
with the introduction of magnetic resonance imaging and its wide
use as screening tool for patients with various neurologic pre-
sentations.60,61 As in the pediatric age-group, craniopharyngiomas
in adults constitute a distinct subset of this disease and are
associated with characteristic clinical problems. Hormonal de-
ficiencies and hydrocephalus seem to be less common pre-
sentations in adults, whereas mental health changes and visual
impairment seem to be the main presenting features.62
The clinical presentations in this age-group can be subtle and
may often be attributed to other conditions associated with aging,
such as cataracts, glaucoma, and diabetes, and their relationship
to visual compromise. Similarly, the less-specific signs of endo-
crinologic dysfunction can be easily missed in the context of other
chronic medical comorbidities and the generally different physi-
ologic demands of this age-group. Dementia, on the other hand,
might be overlooked as a common finding in older patients and
without the appropriate neuroimaging would be difficult to attri-
bute to craniopharyngioma, although mental health changes seem
to be a recognized clinical manifestation of this disease in this
population.39,61
Although the surgical management and techniques have
evolved, there is still a paucity of evidence about the clinical
manifestations of craniopharyngioma in adults, especially in older
patients, and its optimal management. The management of cra-
niopharyngioma in this group is often dictated by the patient's
baseline medical condition and comorbidities that may render
some of the standard surgical options too risky to pursue.
The surgical philosophy for management of craniophar-
yngiomas in the elderly population has evolved to favor the more
minimally invasive approaches, using endoscopic techniques for
partial debulking and cyst aspiration over traditional transcranial
surgery.63,64 The endoscopic approach has gained increasing use,
with reported better visual outcomes and quality-of-life improve-
ments with “minimal/acceptable” associated surgical morbidity.
Although the risk of recurrence remains high, the use of adjuvant
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CRANIOPHARYNGIOMAS: CHALLENGES AND CONTROVERSIES
radiation therapy has shown similar beneficial results to those in
children.65
SURGICAL TECHNIQUES
Despite significant advances in surgical techniques and support-
ing technologies, the surgical management of craniopharyngioma
still poses a substantial technical challenge. No single surgical
approach can be considered the gold standard or applicable to all
lesions, and each case should be considered separately, based
mainly on the radiologic and anatomic characteristics of the tu-
mor.10 Equally, patient characteristics (age, baseline status, and
the individual patient's wishes) are becoming increasingly
important when planning the extent of surgical intervention
and, consequently, the choice of surgical techniques. In our
companion article on surgical anatomy and
craniopharyngiomaresection,66 we presented a detailed study of
the anatomic and technical aspects of these tumors and their
resection as well as a critical analysis of the advantages and
disadvantages of various surgical techniques.
Various craniopharyngioma classification systems have been
developed, based on their growth patterns or relationships with
key anatomic structures, with the aim of helping guide surgeons
to identify the safest and most versatile surgical corridors.67-69
Expanded endoscopic techniques have gained increasing popu-
larity over the last few decades because of their relatively
less-invasive nature and the encouraging results compared with
the more extensive open techniques. Although reported cerebro-
spinal fluid rates remain higher for endoscopic approaches than
for open approaches, adoption of multilayer closure techniques
and the use of vascularized nasoseptal flaps to achieve watertight
closure of the osteodural defect have reduced this complication to
acceptable levels.68,69,70
The natural history of this disease mandates a long-term
multimodal strategy in which both open and endoscopic in-
terventions might be complementary and necessary in different
stages.
MORBIDITY AND MORTALITY
Despite its benign histology, as noted earlier, craniopharyngioma
is one of the most challenging types of skull base tumors, and
patients often present with complex medical and surgical
comorbidities that require ongoing management as chronic dis-
ease. Some of these associated conditions still present formidable
challenged despite all technical and therapeutic advances. In this
section, hypopituitarism and hypothalamic dysfunction are
addressed.
Hypopituitarism and Persistent Increase in Mortality
Hypopituitarism is common both preoperatively and post-
operatively in patients with craniopharyngiomas. The effects are
variable according to the degree of hormonal impairment and age-
group, and long-term sequelae, such as impaired growth, short
stature, and delayed or deranged sexual maturity, are often more
ominous in the young population. These endocrinologic deficits
seem to be alleviated by early detection and close follow-up.
Despite adequate hormonal replacement, long-term complica-
tions and increased standardized mortality ratios have been
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MOHAMMED J. ASHA ET AL.
reported in a meta-analysis of the outcome of long-term survivors
of craniopharyngioma.71 Female sex, childhood onset,
hydrocephalus, tumor recurrence, body mass index, and
panhypopituitarism were identified as the important predictors
for excess mortality. These long-term sequelae are mainly
related to metabolic disorders with increased risks for cardiovas-
cular complications.5
This situation raises the question of whether it is possible to
remove a craniopharyngioma totally and preserve all pituitary
function, which has direct implications on the proposed sur-
gical strategy. Although there are differing opinions in the
literature, it is the opinion of the senior author (F.G.), based on
the pathogenesis and embryology of this lesion and long clin-
ical experience, that, with rare exceptions, it is unlikely that a
craniopharyngioma can be totally removed without some loss of
pituitary function. This situation then mandates an in-depth
discussion with the patient and family in the preoperative
period to formulate the best management option for that
particular individual.
The decision to preserve or sacrifice the pituitary stalk is
perhaps one of the most complex issues related to the surgical
strategy. Studies that examine the impact of stalk preservation on
recurrence rates and the preservation of the hypothalamic-pituitary
axis are challenged by the fact that structural integrity of the stalk
does not equate to functional preservation because of ischemic
insults as a result of microvascular injury to the stalk. This fact has
been echoed by the findings of Ordóñez-Rubiano et al.,68 in which
despite structural preservation of the stalk, more than two thirds
of the patients had pituitary dysfunction and about half of them
developed diabetes insipidus.
Hypothalamic Dysfunction
Hypothalamic dysfunction is characterized by several clinical
manifestations including thermal dysregulation and neuro-
cognitive impairment as well as hormonal and metabolic disorders
(mainly diabetes insipidus).33,72
However, hypothalamic obesity is probably the most chal-
lenging (and most common, affecting up to 61% of patients) of
these complications.2 The full pathophysiology of its complication
are not fully understood but it is postulated that damage to the
anteromedial nuclei of the hypothalamus leads to a combination
of loss of homeostasis and damage to the satiety centers as well
as hormonal/metabolic dysregulation, leading to a state of
hyperinsulinism perhaps as a result of vagal nerve
overstimulation.2,38,73
The management of hypothalamic obesity remains an unsolved
challenge, with no fully effective remedy. The impact of hypo-
thalamic obesity is multifaceted, conferring increased risks of
diabetes mellitus, hypertension, and dyslipidemia, which collec-
tively increase the incidence of cardiovascular complications.
Moreover, hypothalamic obesity has been linked to reduced
quality of life and long-term depression as well as neurocognitive
impairment.37
The available management options include behavioral therapy,
strict dietary control, and surgical vagotomy as well as combina-
tions of different pharmacologic agents. However, the effective-
ness of these therapies remains less than desirable; a combination
of different modalities is often required in most cases and even
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CRANIOPHARYNGIOMAS: CHALLENGES AND CONTROVERSIES
this treatment yields only modest success rates.38,74 Recent trials
have suggested a promising role for oxytocin as an anorexic
agent producing sustained weight loss in these patients, but the
clinical implications of oxytocin therapy are yet to be fully
established.75,76
RECURRENCE
Recurrence of craniopharyngioma is common, with an incidence
reported between 9% and 62%,2,6,51 and its management remains
a major challenge. GTR rates for treatment of recurrence are
significantly lower than for initial resection: in the range of
0%e56% and often <25%.77 Nevertheless, some investigators
reported encouragingly high rates of GTR for repeat surgery
80%, with comparable extent of resection, visual outcomes,
and quality of life to primary surgery.74 Such findings advocate
offering repeat surgery as a valid alternative to radiotherapy as a
viable solution for selective recurrence cases, especially where
clear surgical targets can be defined preoperatively.
Nevertheless, surgery for recurrent craniopharyngioma is
considerably more difficult than in primary cases, and rates of
treatment-associated morbidity are also increased (11%e
24%).2,77,78
No consensus or standard treatment guidelines are available for
the treatment of these recurrent lesions, but a multidisciplinary
multimodality approach is often used.
The factors associated with recurrence of craniopharyngioma
include the degree of resection, tumor biology, adherence to
critical neurovascular structures, hypothalamic involvement, pa-
tient age at presentation (with recurrence being more common in
patients who presented as children than in those who first pre-
sented in adulthood), lack of adjuvant radiation, and duration of
follow-up.2,3,47,77,79
Future Trends: Genomics and Targeted Therapy
The differences in histology seem to be echoed by different mo-
lecular and genomic markers. The less common histologic variant
of PCP has been found to have a high rate of BRAF mutations,
with some investigators reporting BRAFv600e mutation in 92.8%
of specimens.44,80,81 This finding has allowed the use of previously
known BRAF inhibitors, which have been used effectively in the
management of malignant melanoma, in some cases of PCP.
However, the early results have not been uniformly effective, with
BRAF targeted therapy being used mainly to arrest growth or as
adjuvant therapy when other established management options
have been exhausted.26,80
On the other hand, the more common ACPs have been exclu-
sively found to harbor a high rate of the b-catenin gene muta-
tions.3,20,44 These mutations are postulated to play a direct role in
this subtype development and growth with the affected genes
(CNN1B and APC) being directly involved in cellular
proliferation, differentiation, and cell migration. Close
association of these mutations with the Wnt pathway and SHH
gene complex has been reported.79 Although there is no specific
targeted therapy for APC, recent advances in targeting these
pathways might pave the way for targeted therapy in the future,
with some investigators proposing a role for antiestrogen
antiinflammatory drugs for specific neoplasms (desmoid
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MOHAMMED J. ASHA ET AL. CRANIOPHARYNGIOMAS: CHALLENGES AND CONTROVERSIES

tumors) when Wnt signal mutations have been commonly CONCLUSIONS

detected.44,82 A similar application of such targeted therapies
has been suggested for ACP, although this remains short of
practical implications.1
BRAF and b-catenin mutations seem to be mutually exclusive,
which leaves most craniopharyngiomas (ACPs) without an effec-
tive targeted therapy.44,76
GOAL-DIRECTED MANAGEMENT
Although the evolution of more effective surgical techniques
and advances in technology have been of significant benefit in
the management of craniopharyngiomas, the ability to cure this
histologically benign World Health Organization grade I tumor
remains elusive. The traditional surgical philosophy of radical
resection at all cost has gradually been challenged by increasing
concerns over serious neurocognitive sequelae as well as evi-
dence of reduced quality of life and increased morbidity and
mortality on long-term follow-up. Most recent reports generally
favor more conservative resection in conjunction with radio-
therapy, with evidence of superiority over radical resection and
repeated surgical intervention for recurrences, especially in the
pediatric population.9,82 Akinduro et al.83 conducted a meta-
analysis examining the outcome of GTR versus partial resec-
tion in conjunction with radiotherapy and found that GTR
reduced the risk of recurrences compared with partial resection
but was associated with significantly higher rates of endocrin-
opathy and hypothalamic dysfunction. Merchant et al.,84
reporting on the St. Jude Children's Research Hospital
experience, reported a mean loss 9.8 points in full-scale IQ
for patients treated with radical resection, which was signifi-
cantly greater than the 1.25-point mean loss seen in patients
treated with limited resection and radiotherapy.
The management of craniopharyngioma remains a significant
surgical challenge, with high rates of surgical morbidity and
recurrence regardless of the surgical approach.
Understanding the tumor behavior and biology may help in the
planning of realistic treatment targets. Accordingly, craniophar-
yngioma should be considered a chronic disease with potentially
long-term survival. Although GTR may be associated with reduced
recurrence rates, the focus should be on quality-of-life issues in
long-term survivors. Aggressive surgical strategies that aim at total
excision may not be realistic in view of the tumor pathogenesis
and/or may not be the best options for many patients given the
potential for significant morbidity. There is increasing consensus
regarding the usefulness of partial resection in conjunction with
radiotherapy as a definitive management option.
When considering surgical approaches, the endoscopic
approach stands out as a valuable option; it provides a useful
complement to transcranial procedures in the overall management
of both primary and recurrent craniopharyngiomas. Careful pa-
tient selection can achieve results comparable to or better than the
best microscopic series especially in terms of less morbidity and
visual improvement. Endoscopic approaches have a significant
role to play in adults and the elderly, especially when more
aggressive open techniques are not viable.
Patients with craniopharyngioma are best served by the
formulation of a tailored, individualized surgical plan, based on
both patient and tumor factors, that aims to realistically and safely
achieve the proposed operative goals in a high-volume multidis-
ciplinary team setting.
ACKNOWLEDGMENTS
We acknowledge the contribution of Anne Stanford, E.L.S., who
provided professional editing services.

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Conflict of interest statement: The authors declare that the
article content was composed in the absence of any
commercial or financial relationships that could be construed
as a potential conflict of interest.
Received 11 April 2019; accepted 5 April 2020
Citation: World Neurosurg. (2020) 142:593-600.
https://doi.org/10.1016/j.wneu.2020.05.172
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