Craniopharyngioma treatment

General

Team involved

Neurosurgery paediatric oncology, radiation oncology, endocrinology, neuroradiology, and neuropathology

Except in occasional surgical emergencies, offer delayed definitive surgical or radiotherapeutic treatment until confirmatory preoperative or perioperative tissue histopathology or cyst fluid cytology is available

Management of paediatric craniopharyngioma - UK guidelines

hoong-wei-gan-national-uk-guidelines-for-the.pdf

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Specific tumour types

Papillary craniopharymgioma

Surgery resection + radiotherapy

Safe total surgical resection is the goal when feasible.
Adjuvant radiation or techniques such as proton beam therapy are considered for residual disease.

Targeted therapy using BRAF and MEK inhibitors is a therapeutic option currently being evaluated in clinical trials.

Adamantinomatous craniopharyngioma

Treatment strategies are debated, ranging from gross total resection to limited surgery focused on preserving hypothalamic and visual integrity.

Radiotherapy and hypothalamus-sparing surgical approaches are often recommended to maintain quality of life.

Surgery resection + radiotherapy

Cystic component of craniopharyngioma commonly presents a problem for radiotherapy and radiosurgery

Tumour growth and cyst enlargement can be independent:

Solid component can usually be controlled by radiation
Cystic component may require treatment with

Stereotactic aspiration (e.g. acute presentation or poor surgical candidate)
Placement of Ommaya reservoir allowing intermittent aspiration pf a cyst that cannot be completed resected
Sclerosis of cyst wall by chemotherapy agents for treatment-resistant cysts (e.g. bleomycin, interferon alpha)
Internal irradiation (brachytherapy) with implanted radioisotopes for treatment resistant cysts (Phosphorus-32)

Surgical resection/debulking

General

1st line of treatment

Surgery (complete or subtotal resection or cyst aspiration) has better overall and progression-free survival compared with conservative management alone

Central diabetes insipidus and ACTH deficiency are associated with late mortality, preoperative hypothalamic grading is important in determining the overall surgical treatment strategy

Choice of operative approach

Depends on

Position of optic chiasm

Rhoton et al studied 50 sellae specimens

75% normal
10% prefix, 15% postfix

Sella expansion

Third ventricle involvement

Hypothalamus

Avoid long term endocrine and hypothalamic morbidities

Preserve superior hypophyseal artery

Supplies infundibulum, ON, chiasm

Surgical options

Gross total resection if possible

Hard to get gross total resection because of hypothalamic damage → causing endocrine abnormalities (diencephalic syndrome)

Gross total resection results in better overall survival and progression-free survival than subtotal resection alone, with subtotal resection resulting in poor local control rates and potentially increasing the risk of visual deterioration

Consider not proceeding with complete resection of paediatric craniopharyngiomas where there is clear evidence of hypothalamic involvement on grading

Subtotal resection + RT

Similar outcomes in total resection vs subtotal resection + RT

Importance of RT in tumour control
GOSH series: 72% PFS in 10 yrs
RT induced optic neuropathy ~1-2%

Subtotal resection can be salvaged with adjuvant radiotherapy (gross total resection 5-year progression-free survival 77% vs subtotal resection plus radiotherapy 5-year progression-free survival 73%) without the increased risk of long-term morbidity and central diabetes insipidus, particularly in tumours with hypothalamic involvement.

Cyst aspiration +/- Ommaya reservoir for instillation

Paris classification for craniopharyngiomas

Description

puget2007.pdf

423.9 KB

MR imaging grading of pre op and post op paediatric craniopharyngiomas patient.

Pre op predict which patient will have a higher chance of hypothalamic injury
Post op predict which patient will have higher chance of hypothalamic injury

Aim to help decide whether resection should be done by balancing risk of damage to hypothalamus

A collage of images of a brain AI-generated content may be incorrect.

Grade	Pre op	Post op
0	No hypothalamic involvement	No hypothalamic damage
1	Hypothalamus displaced by the tumor	Minimal hypothalamic damage
2	Hypothalamic involvement	Severe hypothalamic damage

Outcome

The higher the grade the more obese patients are.

MRI Grade	Postop BMI Z Score (in SD ± SD)	p Value
Preop grade	ㅤ	ㅤ
0	1 ± 1.6	0.007
1	2.4 ± 1.6	ㅤ
2	2.8 ± 1.8	ㅤ
Postop grade	ㅤ	ㅤ
0	1.2 ± 1.4	0.001
1	2.6 ± 1.5	ㅤ
2	3.1 ± 1.9	ㅤ

* Values are presented as the SD ± SD. The BMI Z score is itself representative of an SD of the norm.
BMI: body mass index

The higher the grade the lower the quality of life (QoL) score

MRI Grade	Postop HUI2 Score (± SD)	p Value
Preop grade	ㅤ	ㅤ
0	0.92 ± 0.08	0.001
1	0.86 ± 0.11	ㅤ
2	0.51 ± 0.31	ㅤ
Postop grade	ㅤ	ㅤ
0	0.82 ± 0.24	0.003
1	0.80 ± 0.14	ㅤ
2	0.52 ± 0.35	ㅤ

HUI2 (Health Utility Index Mark 2) score: defines patient health status within seven categories (sensation, mobility, emotion, cognition, self-care, pain, and fertility. A marker for QoL

Algorithmn

Paris classification algorithm

puget2007.pdf

423.9 KB

Preserving hypothalamic function trumps total excision.

Pre-operative work up

Endocrine evaluation: as for pituitary tumour.

Hypoadrenalism may be corrected rapidly, but hypothyroidism takes longer, either condition can increase surgical mortality
8am cortisol and 24hr urine free cortisol
Free TSH
Prolactin
Gonadotrophins (FSH, LH) and sex steroids (oestradiol, testosterone)
IGF-I
Fasting blood glucose

Ophthalmology assessment

As baseline
Usually bitemporal hemianopia

Imaging

MRI
CT
CTA: Look for Carotids

Surgical approaches

Right frontotemporal

As low as possible along base of frontal fossa (lateral sphenoid wing rongeured/drilled). Approach to tumour is extra-axial, whether subfrontal or frontotemporal. All tumours should be aspirated (even if they look solid on imaging).
Then, with microscope, possible approaches include:

Subchiasmatic: through space between optic nerves and anterior to chiasm (question of "prefixed chiasm")
Opticocarotid (between right ICA and right optic nerve/tract)
Lamina terminalis (tumour often needs to be brought down and removed Subchiasmatically)
Lateral to carotid artery

Pure transsphenoidal:

If dark fluid is aspirated with no CSF evident, it is possible to leave a stent from the tumour cavity to the sphenoid air sinus to allow continued drainage

Transcallosal:

Strictly for tumours limited to the third ventricle

Combined subfrontal/pterional approach gives you advantages of a head positioned with slight lateral rotation)

ㅤ	Pterional/FTOZ	Bifrontal interhemispheric	Transcallosal transventricular	Transfrontal transventricular	Endoscopic TSS
Pros	- Familiar approach - May need to open ON and falciform ligament, drill ACP - Can open lamina terminalis to go into 3ʳᵈ vent - Good for prefix chiasm - Good for intra/suprasellar, pre/post chiasmatic exposure	- Good for postfix chiasm - May need to drill tuberculum - Open lamina terminalis - Can see ON and tracts clearly	- Good for normal size lat vent - Direct access to lat vent and FM and ant 3ʳᵈ vent - May need subchoroidal/transchoroidal/interforniceal exposure - No cortical incision	- Good for enlarged lat vent - Minimal retraction - Less draining vein and pericallosal a. injury	- Good for sella/suprasellar - ONs and perforating a. seen - Can be part of combined surgery - Less risk of ON injury
Cons	- Cannot see contralat. opticocarotid or retrocarotid space - Difficult to see ipsi hypothalamic wall and post 3ʳᵈ vent - Risk of injury to fornix and supraoptic nuclei	- Frontal sinus exposure - Olfactory tract damage	- Pericallsoal a. injury - Retraction to frontal lobes - Frontal draining veins to SSS injury - Fornix/anterior commissure injury	- Cortical disruption → seizures - Still risks to fornix, deep veins	- CSF leak

Post operative

Steroids

For cortisol replacement

All patients are hypoadrenal.

Reduce aseptic (chemical) meningitis
Reduce brain swelling

Hydrocortisone

Greenberg: give hydrocortisone in physiological doses (for mineralocorticoid activity) in addition to dexamethasone
Perioperative hydrocortisone cover for at least 48 h in cases where selective adenomectomy is not possible
Patients with proven intact preoperative adrenal function and small pituitary masses undergoing non-resective surgery (eg, ventricular–peritoneal shunt insertion), can discontinue hydrocortisone 24–48 h postoperatively, with monitoring of morning serum cortisol and ACTH concentrations

Dexamethasone (to treat oedema as glucocorticoid)

Taper steroids slowly to reduce risk of aseptic (chemical) meningitis
Offer children and young people with cerebral oedema and those undergoing craniotomy or wide opening of the cerebrospinal fluid space transsphenoidally rapidly tapered perioperative (48–72 h) dexamethasone neuroprotection

Diabetes insipidus

Often shows up early.

May be part of triphasic response.

Phase 1:

Injury to pituitary reduces ADH level for 4-5 days, polyuria and polydipsia

Phase 2:

Cell death releases ADH for next 4-5 days, and there is transient normalisation of even SIADH-like water retention

Phase 3:

Reduced or absent ADH secretion results in transient or prolonged DI

DI management:

Mild

Drink to thirst

Severe

DDAVP PO, Nasal, IV

Best managed initially with fluid replacement.
If necessary, use short acting vasopressin (prevents iatrogenic renal shutdown if a SIADH like phase develops during vasopressin therapy)

Outcome

5-10% mortality in most series, most from hypothalamic injury

Five year survival is 55-85% (range from 30-93% has been reported)

Recurrence:

Most recurrences are in < 1 year
Few > 3 yrs
Morbidity/mortality higher with re-operation
Some systematic reviews have found no significant difference in rate of recurrence for GTR vs STR + XRT (PMID:29267973)

Radiotherapy

External beam radiotherapy

General

Controversial

Recommendation

Consider upfront external beam radiotherapy where tumour resection is incomplete

Probably helps prevent regrowth when residual tumour is left behind.

Upfront adjuvant radiotherapy after gross total resection confers no additional benefit

Side effects:

Endocrine dysfunction
Optic neuritis
Dementia/cognitive side effects

In children it may be best to delay RXT (to minimise effects on IQ), recognising that reoperation may be needed for recurrence

Dosage

Radiotherapy using a dose fractionation of 50·4–54·0 Gy administered in 28–30 fractions over 6 weeks

Outcome

Changes in tumour volume can occur between 3 months and 5 years postradiotherapy
Radiotherapy can also cause cyst expansion before shrinkage that might not always require intervention
Recurrence is more likely if radiotherapy is omitted from second-line treatment
STR + RT vs GTR

Yang et al 2010 and Clark 2012 Similar 5 year progression free survival (67–77% vs 69–73%)
Based on complications associated with a aggressive resection and proven efficacy of radiation for CPS, several authors recommend subtotal resection and RXT as acceptable alternative to GTR.

Further support from this because although neurological deficits and endocrine dysfunction due to radical resection can be managed, the associated psychological consequences for paediatric patients significantly affect quality of life

High-energy proton beam therapy

Postulated reduction in risk of irradiating healthy brain tissue, and thus the risk of cognitive deficits

Retrospective studies indicate no difference in overall survival or progression-free survival for proton beam therapy versus conventional photon therapy

SRS

Delivers a single, large radiation dose of 12–14 Gy to a small volume with high precision.

Unlike in adults, there is no good quality evidence comparing stereotactic radiosurgery to other treatment modalities in children

SRS as a primary treatment has shown higher tumour control rates in single type tumours compared to mixed tumours (solid-cystic)

Solid tumours and solid portions of mixed tumours may be less responsive to brachytherapy than cystic tumours, hence a combination of radioisotope instillation and SRS has been suggested as primary treatment for mixed solid- cystic tumours

Chemotherapy

Intracyst chemotherapy

Bleomycin

A group of five nitrogen atoms arranged in a square-pyramidal conformation binds divalent metals including iron, the active ligand, and copper, an inactive ligand → Molecular oxygen, bound by the iron, can produce highly reactive free radicals and Fe(III) → The free radicals → DNA single-strand breaks at 3'-4' bonds in deoxyribose.

Interferon alfa-2b (IFNα)

Is increasingly used in monocystic disease in light of the lower risk of neurotoxicity from leakage compared with bleomycin or radioisotopes
Interferon alfa-2b is proinflammatory
Only be considered as a primary treatment within a research setting as there is currently insufficient evidence for efficacy

Systemic IFNα

Should only be considered in a research setting

Side effects

Pyrexia, neutropenia, transaminitis, fatigue, rashes, seizures, insomnia, and anxiety

Management of associated disease

Hypopituitarism

Consider recombinant human growth hormone in replacement doses in children and young people with confirmed growth hormone deficiency to re-establish normal linear growth, as this treatment does not increase the risk of tumour progression

Diabetes insipidus

Hydrocephalus

CSF diversion Options

Ventricular–peritoneal shunts
External ventricular drains
Transventricular endoscopic cyst drainage
Transsphenoidal endoscopic cyst drainage
Insertion of an Ommaya reservoir into a craniopharyngioma cyst

Follow up

Radiological

Follow-up MRI within 3–6 months of treatment

Visual

Offer repeat formal visual acuity and, if age appropriate, visual field assessment within 3 months of definitive tumour treatment

Endocrine

Offer basal and combined dynamic anterior pituitary function tests off any replacement therapy within 6 weeks of completion of initial treatment to assess the integrity of the growth hormone, ACTH, TSH, and, if age-appropriate, gonadotrophin axes
Consider using dynamic function testing as per local guidelines on several occasions over time to differentiate long-term recovery from dexamethasone-induced ACTH suppression due to permanent ACTH deficiency
Offer lifelong endocrinology follow-up for evolving hypopituitarism

Neuropsychological

12% of children are affected by sleep disturbances after surgery for craniopharyngiomas, with problems including sleep disordered breathing, sleep fragmentation, reduced sleep efficiency, sleep onset latency, and obstructive sleep apnoea, particularly in individuals with hypothalamic obesity and a history of previous radiotherapy

Recurrence management

Offer further surgery to avoid or reduce the radiation field before radiotherapy in children and young people with cystic or solid recurrences after a radiologically complete resection without previous irradiation

Primarily cystic progressions should be aspirated before irradiation to the whole tumour volume

Offer further cyst drainage before radiotherapy in children and young people with progressive, primarily cystic recurrences following initial incomplete resection without previous irradiation

Offer radiotherapy with further surgery to reduce the radiation field in children and young people with progressive, primarily solid recurrences following initial incomplete resection without previous irradiation

Offer a repeat course of conventional radiotherapy for the treatment of disease progression or recurrence after previous irradiation only in exceptional cases and only after all other therapeutic modalities have been explored, given its high morbidity

Gamma knife radiosurgery for recurrent or progressive craniopharyngiomas should only be considered in a research setting

Intracystic IFNα via an indwelling catheter could be considered instead of aspiration alone for recurrent cystic craniopharyngiomas

IFNα should only be considered in a research setting

Prognosis

10 years of follow-up

60-93% of patients were recurrence free
64-96% were alive

30 year survival 80%

Factor associated with recurrence

Extent of surgical resection

Lesions > 5 cm in diameter carrying a markedly worse prognosis
Trend towards less radical extirpation in order to avoid hypothalamic injury
Radiotherapy is widely used in incompletely resected tumours

Histological evidence of brain invasion

Adamantinomatous>papillary
Does not correlate with a higher recurrence rate in cases with gross surgical resection

Better prognosis for the papillary variant

Rare for Malignant transformation of craniopharyngioma to squamous carcinoma

Favorable prognostic factors for risk of recurrence/ regrowth in craniopharyngioma include:

Size (< 4 cm)
Favorable location
Complete surgical removal
Age (> 5 years carries favourable prognosis)
Absence of severe hypothalamic involvement