Craniopharyngioma Pathology

Craniopharyngiomas are low-grade (World Health Organization [WHO] grade I) circumscribed epithelial tumors that most commonly arise in the suprasellar region.

Craniopharyngioma comprises 5%-10% of all childhood brain tumors and 1.2%-4.6% of brain tumors in adults (0.5-2.5 new cases per million population per year). ^[1]  The reported incidence of craniopharyngioma is particularly high in Nigeria and Japan. ^{[2, 3]}

The peak incidence is in children aged 0 to 19 years. A second peak occurs later in life, between ages 40 and 79 years. ^[4]  There is no sexual predilection. ^[1]  Black persons may have an increased relative risk for craniopharyngioma, although this has been inconsistently reported. ^[4]

Craniopharyngioma comprises two clinically, histologically, and biologically distinct subtypes: adamantinomatous (most common) and papillary. ^{[5, 6, 7, 8, 9]} Rare hybrid forms have also been reported. ^[10] Papillary craniopharyngioma occurs almost exclusively in adults, whereas adamantinomatous craniopharyngioma occurs in both adults and children. Adamantinomatous craniopharyngioma presumably arises from remnants of the Rathke pouch and the craniopharyngeal duct.

The close histopathologic and immunohistochemical resemblance among adamantinomatous craniopharyngioma, adamantinoma of the jaw, and calcifying odontogenic cyst suggests an odontogenic epithelial differentiation for these tumors. ^[11] Collision lesions of the sellar region, including pituitary adenoma associated with Rathke cyst and pituitary adenoma associated with craniopharyngioma, have been described. ^[12] Complex sellar lesions consisting of pituitary adenoma intimately admixed with Rathke cyst and metaplastic squamous epithelium have also been reported. ^[13]

The current hypothesis is that pituitary adenoma, adamantinomatous craniopharyngioma, and Rathke cyst share a common ancestry from involuted remnants of the Rathke pouch and the craniopharyngeal duct. In elderly persons, squamous metaplasia of adenohypophyseal cells of the pituitary stalk or gland has been postulated as a possible origin for the papillary variant of craniopharyngioma. ^[14]

Craniopharyngiomas most commonly arise in the suprasellar region, with a variable intrasellar component. Other more rare locations include isolated infrasellar, intraventricular (third ventricle), corpus callosal, posterior fossa, and postclival sites. ^{[15, 16, 17, 18, 19]}

Clinical features of craniopharyngiomas may include visual disturbances (from compression of the optic chiasm and adjacent nerves and tracts), endocrine abnormalities, and signs of increased intracranial pressure. Endocrine abnormalities may take the form of hormonal deficiencies or of diabetes insipidus. Cognitive and personality changes have also been observed.

Adamantinomatous craniopharyngioma

Magnetic resonance imaging (MRI) typically shows an adamantinomatous craniopharyngioma as a complex solid/cystic lesion with heterogeneous signal intensity. The cysts are often filled with fluid of a high protein content (thus, they are hyperintense on T1-weighted images). Solid areas reveal enhancement following gadolinium administration. Peripheral calcification is often prominent on computed tomography (CT) scans.

Papillary craniopharyngioma

MRI of a papillary craniopharyngioma characteristically depicts an enhancing, predominantly solid, circumscribed mass without the calcification or complex cystic architecture of the adamantinomatous variant. The papillary architecture may sometimes be evident.

Although the imaging descriptions of the two morphologic variants are typically described as above, note that overlap and exceptions occur. In addition, there is overlap between the imaging characteristics of craniopharyngiomas of both subtypes and other sellar/suprasellar mass lesions of this anatomic neighborhood; thus, tissue examination is generally required for definitive diagnosis.

Adamantinomatous craniopharyngioma is a partly cystic mass filled with dark greenish-brown fluid that has traditionally been compared in terms of color and consistency to "machinery oil." The characteristic white speckled appearance of "wet" keratin nodules typical of the adamantinomatous variant are frequently grossly visible and provide the neurosurgeon advance notice of the diagnosis before the pathologist even sees the surgical specimen.

In contrast to the adamantinomatous variant, which tends to insinuate tongues around nerves and blood vessels, the papillary subtype is comparatively more well-circumscribed and typically lacks the complex multicystic architecture and fluid-filled spaces upon sectioning.

Cytopathology

The cytologic smear of adamantinomatous craniopharyngiomas show compact nodules of "wet" keratin, calcifications, macrophages, multinucleated giant cells, cholesterol crystals, and amorphous debris in the background. Cellular, cohesive sheets of epithelial cells with peripheral palisading are prominent, in addition to individual epithelial cells. More recently, the presence of inflammatory mediators has been demonstrated in the solid component and cyst fluid of adamantinomatous craniopharyngiomas, indicating an inflammatory cytokine and chemokine expression pattern. ^[20]

The cytologic smear of papillary craniopharyngiomas reveals tissue fragments composed of benign squamoid cells, with only rare individual cells. Small cellular whorls are often seen.

Histology

With adamantinomatous craniopharyngiomas, a complex epithelial lesion with cysts and calcified "wet" keratin is seen. The epithelium has central stellate reticulum with prominent peripheral palisading. Rarely, ciliated cells and goblet cells are encountered. Even more rare are calcification and enamel formation in an abortive attempt to form "toothlike" structures. The adjacent neural parenchyma may show granulomatous reaction with cholesterol clefts. In some cases, there is perilesional piloid gliosis with Rosenthal fibers. A biopsy or frozen section sample from this area can be potentially misleading. (See the images below.)

 

With papillary craniopharyngiomas, an epithelial lesion composed of mature squamous epithelium without surface maturation, a keratohyaline granular layer, or keratin formation is noted. Focal tissue dehiscence with resultant pseudopapillary architecture is often present, as are small whorls. Although basal peripheral palisading is also seen, this feature is not as prominent as with the adamantinomatous variant. The most characteristic features of the adamantinomatous subtype are absent, including nodules of "wet" keratin, "stellate reticulum," and calcification. (See the image below.)

Ultrastructure

Electron microscopic studies are virtually never needed for making the diagnosis of craniopharyngiomas, but when they are performed, these studies show the expected ultrastructural features of epithelial differentiation, including prominent numbers of desmosomes and associated cytoplasmic tonofilaments. ^[21]

Craniopharyngioma tumor cells display immunoreactivity to epithelial membrane antigen (EMA) and cytokeratin. ^[22]  Membranous claudin-1 expression is displayed most strongly in papillary craniopharyngiomas, but it is also seen in the adamantinomatous subtype and Rathke cleft cysts. Low claudin-1 expression has been reported to correlate with a more invasive growth pattern, regardless of the craniopharyngioma subtype. ^[23]

Most adamantinomatous craniopharyngiomas show aberrant nuclear expression of beta-catenin, a feature that is not observed in papillary craniopharyngiomas. ^[24]  Nuclear beta-catenin expression is also observed in the shadow cells of pilomatricoma and calcifying odontogenic cysts. ^[25]  In contrast, most papillary craniopharyngiomas harbor BRAF V600E mutations, which can be demonstrated immunohistochemically. ^{[8, 9, 26]}  Adamantinomatous craniopharyngiomas also express various enamel proteins, including amelogenin, enamelin, and enamelysin, thereby supporting the postulated odontogenic differentiation. ^[27]

Most of the adamantinomatous craniopharyngiomas harbor a mutation of the beta-catenin gene (CTNNB1). ^{[9, 28, 29]}  Almost all mutations involve exon 3, which encodes the degradation targeting box of beta-catenin. This mutation results in nuclear accumulation of beta-catenin protein and dysregulation of the Wnt signaling pathway, with activation of downstream targets such as Axin-2. ^{[9, 30]} Papillary craniopharyngiomas and other sellar region lesions do not exhibit this mutation. ^[29]

BRAF V600E mutations have been demonstrated in up to 95% of papillary craniopharyngioma cases. ^[29] This is a well-studied activating mutation of a serine-threonine kinase involved in cell division and differentiation via the MAP-kinase/ERK signaling pathway, which has been implicated in a variety of other neoplasms including melanoma, colorectal carcinoma, and papillary thyroid carcinoma. Although much more common in papillary craniopharyngiomas, the mutation may not be exclusive to this subtype.

A study reported two cases of adamantinomatous craniophargynioma exhibiting BRAF V600E mutations; however, in both cases a concomitant CTNNB1 beta-catenin mutation was also present. ^[31]  In the vast majority of cases, however, BRAF V600E and beta-catenin mutations segregate by subtype—papillary and adamantinomatous, respectively. Thus, the two subtypes of craniopharyngiomas are genetically distinct lesions, and identification of these mutations by molecular studies or immunohistochemistry may aid in the diagnosis of histologically challenging cases. ^[32]

Relatively recent studies have also demonstrated that papillary and adamantinomatous craniopharyngiomas have distinct DNA methylation profiles. ^[32]  Chromosomal imbalances are very rare in both subtypes. ^[33]

Craniopharyngiomas are World Health Organization (WHO) grade I tumors. However, rare cases of craniopharyngioma seeding along the surgical access route and through the cerebrospinal fluid (CSF) pathways have been reported. ^{[34, 35]}

Although classified as World Health Organization (WHO) grade I tumors, craniopharyngiomas often demonstrate an aggressive local behavior after treatment and may require adjuvant radiotherapy. ^{[9, 36]} The recurrence rate is related to the extent of surgical resection and tumor size (>5 cm). ^[37] Some studies have shown a better prognosis for the papillary subtype, whereas other reports have failed to confirm this finding. ^[10] Malignant transformation into squamous cell carcinoma following irradiation has been documented in both adults and children. ^{[38, 39]}

Alternate diagnoses to consider include other cystic sellar lesions, including the following:

• Epidermoid cyst

• Rathke cyst

• Xanthogranuloma