Craniopharyngioma (CP) is a rare suprasellar tumor arising from remnants of Rathke’s pouch epithelium. Histologically, it is classified as a benign tumor of WHO grade I.
It accounts for 1.2–4.6% of all intracranial tumors, with an estimated annual incidence of 0.5–2.5 per million population. In adults, it is 0.5–2 cases per million person-years, with no sex, racial, or geographic differences 1). The age distribution is bimodal, with peaks at 5–14 years and 50–74 years 1).
Histologically, it is mainly classified into two types.
The ophthalmologic significance stems from the tumor’s anatomical location. Craniopharyngioma arising in the suprasellar region is adjacent to the optic chiasm, optic nerves, and pituitary gland, making visual impairment one of the main initial symptoms. 40–70% of patients experience visual symptoms, and in adults, visual impairment is the most common chief complaint (40–84%) 1).
The tumor arises in the suprasellar region (directly below or around the optic chiasm) and compresses the optic chiasm and optic nerves. It is often asymptomatic until the tumor grows to 3 cm or more, and visual impairment is often the first noticeable symptom.
Craniopharyngioma compresses the optic chiasm from above downward. Therefore, among the crossing fibers of the chiasm, the inferonasal retinal nerve fibers are preferentially damaged, resulting in bitemporal hemianopsia starting from the lower quadrant. This contrasts with pituitary adenoma, which compresses the chiasm from below and causes upper quadrant-dominant temporal hemianopsia. In advanced cases, junctional scotoma, optic neuropathy, and rarely optic tract damage may occur.
Cavernous sinus invasion can cause ophthalmoplegia.
Craniopharyngioma compresses the optic chiasm from above, resulting in bitemporal hemianopia starting from the inferior field. Pituitary adenoma compresses the chiasm from below, causing superior temporal hemianopia. This difference is an important point in differential diagnosis.
Craniopharyngioma is thought to arise from remnants of the epithelium of the craniopharyngeal duct during development from the stomodeum to the base of the brain 5). No specific risk factors have been identified, and genetic predisposition is not clear.
The molecular biological background differs greatly depending on the histological type.
Adamantinomatous type (ACP)
Gene mutations: Activating mutations in exon 3 of the CTNNB1 gene are found in up to 96% of cases 1).
Signaling pathways: Constitutive activation of the WNT signaling pathway via nuclear accumulation of β-catenin. EGFR and SHH signaling pathways are also upregulated.
Age of onset: All age groups. More common in children.
Papillary type (PCP)
Gene mutations: BRAF V600E mutation is found in 95–100% of cases 1)2).
Signaling pathway: Constitutive activation of the MAPK signaling pathway (Ras/Raf/MEK/ERK).
Age of onset: Almost exclusively in adults (40–55 years).
These mutations in ACP and PCP are essentially non-overlapping. Epigenomically, they form clearly distinct clusters, and the methylation profiles of adult and pediatric ACP are similar to each other 1).
Some ectopic craniopharyngiomas (occurring in the fourth ventricle, paranasal sinuses, orbit, etc.) are explained by the translocation theory, involving abnormal migration of neural crest cells 4)5).
MRI is the first choice. Contrast-enhanced head MRI evaluates soft tissue, cystic components, tumor location, and adjacent structures.
The table below summarizes the main differences in MRI and CT findings between the two histological types.
| Finding | ACP | PCP |
|---|---|---|
| T1 signal | High signal (cystic component) | Tendency toward low signal |
| Shape | Irregular, lobulated | Smooth, spherical |
| Calcification | Common | Rare |
T1 hyperintensity is useful for differentiating ACP from PCP, with reported sensitivity of 73.3% and specificity of 75% 1). The presence or absence of calcification is more clearly confirmed on CT, with reported sensitivity of 83.3% and specificity of 100% 1).
All patients with CP undergo evaluation of anterior and posterior pituitary hormones. Immunostaining (β-catenin, BRAF V600E) and MIB-1 labeling index (proliferative activity measurement) are used for treatment planning and recurrence prediction 1).
The first choice of treatment is surgical resection. Craniopharyngiomas often adhere strongly to the optic chiasm, pituitary gland, and hypothalamus, making total resection difficult. It should be noted that postoperative visual function recovery is often less favorable compared to pituitary adenomas.
The main surgical approaches are as follows:
Endoscopic Endonasal Transsphenoidal Surgery (EET)
Indications: Sellar and suprasellar tumors. Its use has been increasing with recent technological advances1).
Features: Minimally invasive. Provides good access to the undersurface of the optic chiasm.
Transcranial Surgery
Types: Pterional, subfrontal, transcallosal, etc.1).
Features: Selected based on tumor size, location, and degree of adhesion.
Comparing gross total resection (GTR) and subtotal resection (STR), GTR has a lower recurrence rate (GTR 9.9–25% vs STR 33–94.2%), but the risks of diabetes insipidus, visual impairment, and hypopituitarism are higher1). The 5-year recurrence-free survival rate has been reported as 75.0% for GTR vs 25.0% for STR1). If hydrocephalus is present, consider shunt surgery preoperatively.
It is recommended to perform baseline visual field testing and OCT before surgery.
Used for residual tumor after subtotal resection or for recurrence. Proton beam therapy is recommended as it can spare adjacent structures. Compared to photon therapy, it is said to reduce the incidence of secondary tumors by up to 15-fold. A retrospective study of 91 adults reported 5-year and 10-year local control rates of 100% and 94%, respectively1).
The recurrence rate after surgical resection is high, ranging from 9% to 51%. In addition to regular imaging, continued ophthalmologic evaluation with visual field testing and OCT is important. The 5-year survival rate is reported as 83.9%, and the 2-year survival rate as approximately 89.5%.
Timely tumor removal may alleviate or improve visual function. It is reported that 38–42% of adults experience visual improvement after surgery. However, in cases with advanced optic atrophy, the prognosis is often poor, and recovery is generally less favorable compared to that after pituitary adenoma surgery.
The optic chiasm is located directly above the pituitary gland, with nasal retinal fibers crossing and temporal retinal fibers passing uncrossed. Craniopharyngioma compresses the optic chiasm from the suprasellar region from above downward. Therefore, the inferonasal retinal fibers running on the ventral (lower) side of the chiasm are preferentially damaged, resulting in bitemporal hemianopia starting from the lower temporal visual field.
As the condition progresses, uncrossed fibers become damaged, and visual field defects extend to the nasal side. If the tumor extends to the optic tract, contralateral homonymous hemianopia occurs, and a relative afferent pupillary defect (RAPD) may appear in the contralateral eye.
Combination therapy with BRAF inhibitors and MEK inhibitors is attracting attention for BRAF V600E-mutant papillary craniopharyngioma (PCP).
Yu et al. (2024) administered vemurafenib 960 mg twice daily plus cobimetinib 60 mg once daily (28-day cycle) to a 45-year-old man with third ventricular PCP 2). The tumor dramatically shrank from 2.3×2.3×3.0 cm to 0.4×0.3×0.3 cm, and remained stable for 29 months after treatment discontinuation. Main adverse effects were diarrhea, nausea, and hypertension.
A phase II clinical trial (NCT03224767) evaluating the efficacy of vemurafenib plus cobimetinib in PCP patients is ongoing 2). Its use as neoadjuvant therapy is also being considered 1).
This treatment is only applicable to BRAF V600E mutation-positive PCP and is not indicated for adamantinomatous craniopharyngioma (ACP).
The target is papillary CP (PCP) with BRAF V600E mutation positivity. Approximately 95–100% of PCPs are reported to have this mutation. Adamantinomatous CP (ACP) does not have this mutation, so BRAF/MEK inhibitor therapy is not indicated 2). Currently, this is an investigational treatment and is not part of standard therapy.
