6. Surgical treatment

Surgical resection of craniopharyngiomas is challenging due a number of different considerations, primary of which is the importance of the surrounding neurovascular structures. Risks of surgery include iatrogenic infarction, damage to the optic chiasm, cerebrospinal fluid (CSF) leak, anosmia, CN III–VI palsies, seizures, and a relatively high rate of incomplete resections and recurrences. Anatomic considerations play an especially important role when assessing the appropriate surgical approach. The location of CP can be described in relation to the optic chiasm, as either prechiasmatic (which displaces the chiasm posteriorly) or retrochiasmatic (which displaces the chiasm anteriorly) [6]. While prior classification schemes designed for transcranial surgery described CP in relation to the optic chiasm and the third ventricle, Kassam et al. developed a novel classification based on the infundibulum which was used for the expanded endoscopic approach. Craniopharyngiomas are grouped as pre-infundibular (Type I), trans-infundibular (Type II), or post-infundibular (Type III) locations and occasionally are located in the intraventricular region only (Type IV) [7]. Major variables that can also affect the outcome in these patients include the tumor configuration, patient's age, and medical comorbidities, as well as the surgeon and center experience and availability of essential facilities such as intra-operative imaging, ICU care, and multidisciplinary medical management under endocrinology and radiation oncology.

7. Modern case series

permanent diabetes insipidus [19].

Surgical resection can involve an open craniotomy or—alternatively—an endoscopic transnasal approach. A series of open surgical resection employing the frontolateral approach for extensive craniopharyngiomas greater than 4 cm in size reported by Gerganov et al. demonstrated a gross total resection rate (GTR) of 87.5% by microscopic inspection and 62.5% when based on post-operative MRI. Visual improvement was achieved in a significant number of patients (37.5%) in this study. Side effects included new hormonal dysregulation (56.2%) and new diabetes insipidus (75%) [9]. The rate of GTR resection in adults employing this approach is comparable to rates achieved in pediatric patients and compares well with studies employing various other open techniques [10–13]. A complex transpetrosal approach was

Figure 3. Recurrent cyst at 6 months follow-up. (A) Sagittal and coronal T1; (B) and (C) coronal T1 after transcortical

Modern Management of Craniopharyngioma http://dx.doi.org/10.5772/intechopen.74512 207

approach involving septostomy with fenestration of the lateral ventricles and third ventriculostomy.

A modern endoscopic series reported by Koutoursiou et al. of 47 adults and 17 children demonstrated comparable GTR, near-total, subtotal, and partial resection rates of 37.5, 34.4, 21.9, and 6.5%, respectively. Major complications reported in this series included CSF leak (23.4% initially and about 10% after the introduction of the modern endonasal flap) and again recurrence rates of 34.4% [15]. An analysis of the reported endoscopic series by Laws et al. found that endoscopic approaches for craniopharyngiomas are suitable especially if tumors are found to have a median intrasellar and subchiasmatic location, with no parasellar solid component and no growth along the pituitary stalk [16]. However, tumors that extend to the optic chiasm and the third ventricle may also be undertaken using the endoscopic approach if performed by experienced teams [17]. For patients requiring re-operation due to recurrence, the endoscopic approach was also shown to be effective, with no significant increase in the rates of complications according to some authors [18]. The endoscopic transsphenoidal approach offers a number of advantages including a surgical view in the axis of the tumor and the optic chiasm. Laws also suggest that while resection of craniopharyngioma is commonly associated with hypopituitarism, the transsphenoidal approach may offer the advantage of the reduced risk of

described by Al-Mefty et al. for CP located in the post-infundibular space [14].

The risk of recurrence is significant in patients with CP, especially if gross total resection (GTR) is not achieved. Regardless of improved surgical techniques, post-mortem studies performed by Bartlett et al. demonstrated tumor remnants that can remain attached to vital structures such as the optic chiasm, hypothalamus, and/or critical vascular. These remnants can act as a nidus for tumor growth post-surgery, leading to the relatively high rates of recurrence (about 33% within 36 months of surgery) observed in CP patients [8] (Figures 2 and 3).

Figure 2. (A) Type IV supra-infundibular craniopharyngioma with intraventricular extension and (B) post-operative MRI demonstrates near-total resection of tumor with the opening of the lamina terminalis.

Figure 3. Recurrent cyst at 6 months follow-up. (A) Sagittal and coronal T1; (B) and (C) coronal T1 after transcortical approach involving septostomy with fenestration of the lateral ventricles and third ventriculostomy.

## 7. Modern case series

of patients presenting with CP. In nearly 90% of patients who are present with hypopituitarism in the long term, there is a significantly higher mortality risk related to both cardiovascular and cerebrovascular mortality, with an especially higher risk in females compared to males. The evidence from multiple cohorts of patients suggests that the increased exposure to sex hormones also manifests as cardiovascular risk greater in females compared to males [5].

Surgical resection of craniopharyngiomas is challenging due a number of different considerations, primary of which is the importance of the surrounding neurovascular structures. Risks of surgery include iatrogenic infarction, damage to the optic chiasm, cerebrospinal fluid (CSF) leak, anosmia, CN III–VI palsies, seizures, and a relatively high rate of incomplete resections and recurrences. Anatomic considerations play an especially important role when assessing the appropriate surgical approach. The location of CP can be described in relation to the optic chiasm, as either prechiasmatic (which displaces the chiasm posteriorly) or retrochiasmatic (which displaces the chiasm anteriorly) [6]. While prior classification schemes designed for transcranial surgery described CP in relation to the optic chiasm and the third ventricle, Kassam et al. developed a novel classification based on the infundibulum which was used for the expanded endoscopic approach. Craniopharyngiomas are grouped as pre-infundibular (Type I), trans-infundibular (Type II), or post-infundibular (Type III) locations and occasionally are located in the intraventricular region only (Type IV) [7]. Major variables that can also affect the outcome in these patients include the tumor configuration, patient's age, and medical comorbidities, as well as the surgeon and center experience and availability of essential facilities such as intra-operative imaging, ICU care, and multidisciplinary medical management

The risk of recurrence is significant in patients with CP, especially if gross total resection (GTR) is not achieved. Regardless of improved surgical techniques, post-mortem studies performed by Bartlett et al. demonstrated tumor remnants that can remain attached to vital structures such as the optic chiasm, hypothalamus, and/or critical vascular. These remnants can act as a nidus for tumor growth post-surgery, leading to the relatively high rates of recurrence (about

Figure 2. (A) Type IV supra-infundibular craniopharyngioma with intraventricular extension and (B) post-operative MRI

33% within 36 months of surgery) observed in CP patients [8] (Figures 2 and 3).

demonstrates near-total resection of tumor with the opening of the lamina terminalis.

6. Surgical treatment

206 Brain Tumors - An Update

under endocrinology and radiation oncology.

Surgical resection can involve an open craniotomy or—alternatively—an endoscopic transnasal approach. A series of open surgical resection employing the frontolateral approach for extensive craniopharyngiomas greater than 4 cm in size reported by Gerganov et al. demonstrated a gross total resection rate (GTR) of 87.5% by microscopic inspection and 62.5% when based on post-operative MRI. Visual improvement was achieved in a significant number of patients (37.5%) in this study. Side effects included new hormonal dysregulation (56.2%) and new diabetes insipidus (75%) [9]. The rate of GTR resection in adults employing this approach is comparable to rates achieved in pediatric patients and compares well with studies employing various other open techniques [10–13]. A complex transpetrosal approach was described by Al-Mefty et al. for CP located in the post-infundibular space [14].

A modern endoscopic series reported by Koutoursiou et al. of 47 adults and 17 children demonstrated comparable GTR, near-total, subtotal, and partial resection rates of 37.5, 34.4, 21.9, and 6.5%, respectively. Major complications reported in this series included CSF leak (23.4% initially and about 10% after the introduction of the modern endonasal flap) and again recurrence rates of 34.4% [15]. An analysis of the reported endoscopic series by Laws et al. found that endoscopic approaches for craniopharyngiomas are suitable especially if tumors are found to have a median intrasellar and subchiasmatic location, with no parasellar solid component and no growth along the pituitary stalk [16]. However, tumors that extend to the optic chiasm and the third ventricle may also be undertaken using the endoscopic approach if performed by experienced teams [17]. For patients requiring re-operation due to recurrence, the endoscopic approach was also shown to be effective, with no significant increase in the rates of complications according to some authors [18]. The endoscopic transsphenoidal approach offers a number of advantages including a surgical view in the axis of the tumor and the optic chiasm. Laws also suggest that while resection of craniopharyngioma is commonly associated with hypopituitarism, the transsphenoidal approach may offer the advantage of the reduced risk of permanent diabetes insipidus [19].

However, the endoscopic approach has certain disadvantages in that it is not well suited for masses that are postchiasmatic or for lesions with prominent lateral extensions [16]. In situations of a recurrent craniopharyngioma after craniotomy, the trans-nasal approach may offer the distinct advantage of a previously untouched approach to the lesion, and an endoscopy enables the surgeon to assess the anatomy of the subchiasmatic and retrochiasmatic regions more closely. If preservation or restoration of vision is the primary goal, this should be strongly considered. Endoscopic approaches also offer the advantage of reducing morbidity associated with brain retraction typically employed during transcranial approaches [16].

large single-center series [24]. Conservative resection with adjuvant radiation was found to be a superior strategy in treating patients. Schoenfeld et al. reported a cohort of patients in which there was no significant difference between GTR and subtotal resection (STR) with radiation therapy (XRT) in terms of overall survival or progression-free survival at 2 years [25], with less

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The key to progression-free survival appears to be conservative surgery with subsequent radiation therapy. Radiation therapy can include various regimens employing conventional external beam radiation therapy, stereotactic radiosurgery, or proton beam therapy. Although radiation offers patients the possibility of treatment with reduced morbidity and mortality, side effects of radiation include enlargement of a cystic tumor, fatigue, skin effects, increased intracranial pressure, and transient or permanent optic neuropathy. Moreover, radiation may have longterm effects such as hypopituitarism in 30–50% of patients, cranial nerve palsies, cerebrovascular diseases, and secondary malignancies. Fortunately, radiation therapy offers excellent outcomes with progressive-free survival between 5 and 10 years of 90% and 100%, respectively [26].

As with many other cancers, targeted molecular therapies offer the promise of effective treatment without the need for extensive surgery or radiation. Genetic studies of aCP and pCP identified genetic characteristics of each subtype, that may eventually be targeted by specific molecular therapies for CP. Genomic analysis of aCP revealed mutations in CTNNB1 (βcatenin) in nearly all cases and BRAF mutations in most pCPs. These signaling pathways are currently being interrogated for targeted molecular therapies. Inhibitors of the BRAF protooncogene employing modern drugs such as Dabrafenib or Vemurafenib, or by prescribing MEK inhibitors, such as Trametinib, are already being studied as therapies for pCP. Inhibition of similar molecular pathways in melanoma, amelanoblastoma, hairy cell leukemia, and pleomorphic xanthoastrocytoma has already demonstrated the clinical promise of these therapies [27, 28]. Multicenter phase-2 clinical trials at the National Cancer Institute are currently under-

way evaluating BRAF/MEK inhibition in the treatment of craniopharyngioma [27].

this disease to allow patients improved quality of life.

Regardless of the therapeutic strategies that are utilized, it is evident that craniopharyngiomas continue to present a distinct oncologic challenge that still needs to be overcome. Quality of life is a key consideration in this disease, and long-term follow up, involving a multidisciplinary team, is a necessary element of care of these patients. The combination of minimally invasive surgery and radiosurgery will, in the near future, result in a minimally morbid approach to

Since Cushing's early writings, describing surgery for craniopharyngioma, our strategies to treat this challenging disease have evolved with modern technology to include endoscopic and

endocrinological side effects observed in the STR group.

9. Future directions

10. Conclusions

A comprehensive literature review performed by Komotar et al. claimed higher rates of GTR with endoscopic surgery compared to open resection (66 vs. 48%), higher likelihood of visual improvement (56 vs. 33%), although with a higher risk of CSF leak (18.4 vs. 2.6%). However, it is important to note that the paper suffers from systematic methodological flaws and selection bias since the mean follow-up time for the patients who underwent open resection in this study was 65 months, as opposed to 25.1 months for the endoscopically treated group [20]. More recent series comparing the two approaches were not able to establish similar significant differences in treatment outcomes.

In conclusion, the endoscopic approach may be most appropriate in certain patients who present with intrasellar and Type I lesions, whereas an open resection, employing a frontotemporal craniotomy, may be more suitable for intra-infundibular or post-infundibular lesions. In patients presenting with cystic CP, stereotactic management is appropriate to aspirate the cystic component of the mass before pursuing other avenues of treatment (e.g., radiation therapy).
