Craniopharyngeoma D44.4

According to Einhaus et al. (1999), Zenker was the first to describe a cystic, suprasellar lesion with cholesterol crystals and squamous epithelium in 1857. According to German-language sources, however, Engel was the first to describe this tumor in 1839 (Linsenmann 2010).

The term "craniopharyngioma" was introduced in 1931/1932 by Frazier, Alpers and Cushing (Linsenmann 2010).

Craniopharyngeoma (CP [Dias 2022]) is a low-malignant (Bächli 2018) brain tumor that originates from cell remnants of the Radtke pouch (precursor of pituitary parts [Uhlenbrock 2007]) (Herold 2025). The craniopharyngeoma develops during the embryonic period from remaining cell remnants along the craniopharyngeal duct (Lehnert 2015). CPs are slow-growing tumors with a proliferation index < 1% (Bächli 2018).

A histological distinction is made between craniopharyngioma of the:

• Adamantinomatous type (ACP [Müller 2019]):

This type occurs predominantly in childhood and adolescence and is characterized by frequent cyst formation. It is often associated with mutations in the beta-catenin gene. In this type, tumor extensions into adjacent brain tissue are often found, which do not allow complete resection (Bächli 2018). At 95%, the adamantinomatous type is the most common type in children (Uhlenbrock 2007).

• Papillary type (PCP [Müller 2019]):

The papillary type usually only manifests itself in adulthood. It can be accompanied by calcifications and has more solid than cystic parts. Mutations are found in the BRAF gene (Bächli 2018). The papillary type is found in only 5 % of affected children. In adulthood, however, in up to 35% (Uhlenbrock 2007).

• Mixed types (Bächli 2018)

See also histology

The incidence is 0.5-2 per 10 to the power of 6 per year. CP thus represents 1.2 - 4 % of all intracranial tumors in childhood (Bächli 2018). Uhlenbrock (2007) speaks of 5-10 % of all intracranial tumors in childhood.

Embryonic theory:

ACP, the most common subtype, is explained according to the embryonic theory as follows: cells of the Radtke pouch form the so-called craniopharyngeal duct during embryonic development, which normally regresses in the 7th week of gestation. If this regression is not complete, a CP can develop from the remnants (Slide 2022).

Metaplastic theory:

The metaplastic theory is mainly used for PCP, which predominantly occur in adulthood. These tumors are caused by metaplasia of the adenohypophysis cells. The metaplasia gives rise to differentiated squamous cell networks. This theory is based on the detection of epithelial cell nests in healthy adult pituitary glands along the pars tuberalis (slide 2022).

Craniopharyngiomas originate from ectodermal remnants of the Radtke pouch and are therefore dysontogenetic malformations with a space-occupying character (Bächli 2018).

Symptoms of craniopharyngioma are particularly common in school-age children (Ertl-Wagner 2007) between the ages of 10 and 14. Boys are more frequently affected than girls. A second age peak occurs in adulthood between 40 - 60 years (Uhlenbrock 2007). However, a diagnosis can even be made at an advanced age between 75-80 years (Lehnert 2015).

The craniopharyngioma is usually located prechiasmally, retrochiasmally and very rarely also in the area of the sphenoid sinus (Ertl-Wagner 2007).

In about 20% of cases the tumors are exclusively suprasellar, in 5% exclusively intrasellar. Extension into the anterior cranial fossa is found in 30% and into the middle cranial fossa in 23% (Bächli 2018).

Clinical symptoms depend very much on the location, size and growth rate of the tumor, as increasing growth also leads to ingrowth into neighboring brain structures.

Hypothalamic structures, for example, are particularly affected by suprasellar growth. Typical symptoms are then:

• Behavioral disorders
• Impairment of cognitive performance
• Disturbances in sleep and temperature regulation (Lehnert 2015)

According to Lehnert (2015), pituitary insufficiency is particularly associated with:

• Fatigue
• Performance insufficiency
• Lack of sex hormones
• Obesity
• Polyuria and polydipsia with the occurrence of diabetes insipidus (found in approx. 20% of those affected)

Typical symptoms of a craniopharyngioma are therefore:

• Visual disturbances in 62-84 %
• Endocrine deficits in 52-87 %
  • growth hormone deficiency at 75%
  • of gonadotropins at 40%
  • TSH at 25%
  • ACTH also at 25%
  • Occurrence of diabetes insipidus at 17 % (Bächli 2018)
• Headaches
• Polydipsia / polyuria
• Eating disorders in up to 50 % (Bächli 2018)
• Bitemporal hemianopsia resulting from lower bitemporal quadrant anopsia (Berlit 2014)
• Growth retardation (Ertl-Wagner 2007)
• Neurological deficits in the form of:
  • Attention deficit
  • Memory disorders
  • Disorders of socialization and motivation (Bächli 2018)
  • Cranial pressure symptoms with displacement of the foramina Monroi (Berlit 2014)

The actual diagnosis is made using imaging (see below). Multiple hormone deficiencies are found in up to 75% of patients (Lehnert 2015).

The anterior pituitary insufficiency should also be checked:

• Checking the fluid balance
• Determination of sodium in serum and urine
• Determination of osmolality and specific gravity in the urine (Lehnert 2015)

In addition, preoperative

• ophthalmological examinations are recommended, in particular with fundus assessment and visual field examination (Lehnert 2015)
• Neurological examinations to examine cranial nerve function, increased susceptibility to seizures, signs of increased intracranial pressure and internal hydrocephalus (Lehnert 2015)
• Psychoneurological examinations often show restrictions in quality of life, concentration and memory disorders in adults. In children, behavioral abnormalities and reduced intellectual performance are often found (Lehnert 2015)

CT

Up to 70% (up to 90% according to Ertl-Wagner 2007) of CT scans show calcifications (Gerok 2007), especially in adamantine craniopharyngiomas, but only rarely in papillary craniopharyngiomas (Ertl-Wagner 2007).

MRI

The cystic part of the tumor can sometimes be depicted with a high signal in the T1 image on MRI. However, it can also appear hypodense and show an increased signal in the T2 image (Gerok 2007).

Solid tumor parts can be depicted isodense. They also show enhancement after the administration of contrast agents (Gerok 2007).

Calcifications are found in up to 80 - 90 % of cases. They are hypodense (Uhlenbrock 2007).

Postoperatively, the following tests should be performed after 3-6 months to exclude or detect hormonal deficiencies:

• CRF test
• LHRH test
• Growth stimulation tests (2019 guideline)

The following checks are recommended annually if the results are normal:

• Serum electrolytes
• IGFBP-3 or IGF-1
• TSH
• fT4
• prolactin
• DHEAS
• Cortisol daily profile in serum or saliva
• Cortisol excretion in 24-hour urine collection (2019 guideline)

In the case of previously undiagnosed diabetes insipidus and the occurrence of polyuria, polydipsia, further examinations should be carried out in the form of:

• Export
• Specific gravity in morning urine
• Serum electrolytes
• Osmolality
• DDAVP test (2019 guideline)

If obesity is present, the following annual checks should also be carried out:

• HbA1c
• GTT
• Serum lipids
• Blood pressure (2019 guideline)

If secondary hypothyroidism is suspected, the following should be determined or carried out:

• Free T4
• Free T3
• FSH
• ACTH
• LH

• TRH test (Siegenthaler 2000)

A histological distinction is made between a craniopharyngioma of the:

• Adamantinomatous type

This type occurs predominantly in childhood and adolescence and is characterized by frequent cyst formation (Bächli 2018).

• Papillary type

The papillary type usually only manifests itself in adulthood. It can be accompanied by calcifications and has more solid than cystic parts (Bächli 2018).

The tumor consists of solid and cystic parts. Calcifications are detectable in up to 70% of cases (Gerok 2007). Papillary craniopharyngiomas, which are predominantly more homogeneous and solid, are found much less frequently (Ertl-Wagner 2007).

• Hypothalamic or chiasmal astrocytomas
• Germ cell tumors
• Pituitary macroadenomas
• dermoids
• Rathke's pocket cysts
• Epidermoids
• Suprasellar arachnoid cysts (Ertl-Wagner 2007)
• Colloid cysts of the 3rd ventricle
• Inflammatory diseases
• Germinomas
• Pituitary adenomas
• Aneurysms
• Langerhans cell histiocytosis
• Xanthogranulomas (Bächli 2018)

Craniopharyngioma is a low-malignant tumor, but due to its anatomical proximity to the pituitary gland, hypothalamus and optic nerve, it often not only has serious late effects, but also impairs quality of life, such as hypothalamic obesity (Bächli 2018).

The tumor can also lead to secondary hypothyroidism (Siegenthaler 2000).

Treatment takes the form of neurosurgery (Bächli 2018) and postoperative beta-gamma irradiation. Proton beam therapy is often used in children to protect healthy tissue (Diaz 2022).

Radioiodine therapy and brachytherapy (Diaz 2022) are usually used for incompletely resected tumors or recurrent craniopharyngiomas (Lehnert 2015).

Intracystic chemotherapy is used for monocystic ACP (Müller 2017).

In most cases, however, resection of the tumor cannot correct the hormone deficiencies, meaning that around 98% of CP patients have a pituitary hormone deficiency and need to be substituted accordingly (Diaz 2022).

During surgical removal, the tumor should be removed as completely as possible. Nowadays, this is usually achieved in designated centers using a transnasal-transcranial approach (Lehnert 2015).

Postoperatively, there are sometimes:

• excessive obesity in up to 50 % of patients due to impairment of hypothalamic structures (Lehnert 2015).
• Complete anterior pituitary insufficiency is not uncommon. Diabetes insipidus occurs postoperatively in around 80 % of patients (Lehnert 2015).

The prognosis is relatively good, with approx. 97% of patients surviving after 3 years and approx. 93% after 10 years (Bächli 2018). Diaz (2022), on the other hand, speaks of a variable prognosis with 5-year survival rates between 54-96% and 10-year survival rates between 40-93%. The 20-year survival rate in relation to affected children is given as 62 %. The considerable morbidity due to long-term consequences must also be taken into account (Diaz 2022).

Craniopharyngiomas have a high recurrence rate. However, malignant transformation is very rare. Possible tumor seeding along the surgical access route has been described, usually after transcranial surgical access (Lehnert 2015).

Postoperatively, the following tests should be performed after 3-6 months to exclude or detect hormonal deficiencies:

• CRF test
• LHRH test
• Growth stimulation tests (2019 guideline)

The following checks are recommended annually if the results are normal:

• Serum electrolytes
• IGFBP-3 or IGF-1
• TSH
• fT4
• prolactin
• DHEAS
• Cortisol daily profile in serum or saliva
• Cortisol excretion in 24-hour urine collection (2019 guideline)

In the case of previously undiagnosed diabetes insipidus and the occurrence of polyuria, polydipsia, further examinations should be carried out in the form of:

• Export
• Specific gravity in morning urine
• Serum electrolytes
• Osmolality
• DDAVP test (2019 guideline)

If obesity is present, the following annual checks should also be carried out:

• HbA1c
• GTT
• Serum lipids
• Blood pressure (2019 guideline)

If secondary hypothyroidism is suspected, the following should be determined or carried out:

• Free T4
• Free T3
• FSH
• ACTH
• LH
• TRH test (Siegenthaler 2000)

• Bächli H, Lütschg J, Messing-Jünger M (2018) Pediatric neurosurgery. Springer Verlag Berlin 458-469
• Berlit P (2014) Basic knowledge of neurology. Springer Medizin Verlag Berlin / Heidelberg 169 - 170
• Diaz M J, Kwak S H, Root K T, Fadil A, Nguyen A, Ladehoff L, Batchu S, Lucke-Wold B (2022) Current Approaches to Craniopharyngioma Management. Front Biosci (Landmark Ed). 27 (12) doi: 10.31083/j.fbl2712328.
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• Ertl-Wagner B (2007) Pediatric Neuroradiology. Springer Verlag Berlin / Heidelberg / New York 277
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• Lehnert H (2015) Rational diagnostics and therapy in endocrinology, diabetology and metabolism. Georg Thieme Verlag Stuttgart / New York 68-71
• Guideline (2019) Craniopharyngioma in childhood and adolescence. AWMF online. AWMF Registry No. 025/026 doi: https://register.awmf.org/assets/guidelines/025-026l_S1_Kraniopharyngeom-im-Kindes-und-Jugendalter_2019-01-abgelaufen.pdf
• Linsenmann T (2010) The neonatal craniopharyngioma. A casuistic contribution and literature review. Inaugural dissertation for the degree of Doctor of Medicine of the Julius-Maximilians-University of Würzburg.
• Müller H L, Merchant T E, Warmuth-Metz M, Martinez-Barbera J P, Puget S (2019) Craniopharyngeoma. Nat Rev Dis Primers. 5 (1) doi: 10.1038/s41572-019-0125-9.
• Siegenthaler W (2000) Siegenthaler's differential diagnosis: internal diseases - from symptom to diagnosis. Georg Thieme Verlag Stuttgart / New York 1975
• Uhlenbrock D, Forsting M (2007) MRI and MRA of the head: indication - choice of examination parameters - interpretation of findings. Georg Thieme Publishers Stuttgart / New York 123-124