2018 NPA-02

This case was originally published in 2018. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A previously-well 13-year-old girl presented with a one-year history of intermittent and increasing clumsiness, visual loss, and headaches. The patient was small for age and had below-normal levels of cortisol and free T3/T4. Ophthalmologic exam revealed asymmetric, bilateral loss of vision in the temporal fields. MRI revealed a proteinaceous cyst measuring 3.5 x 2.5 x 2.4 cm and occupying the sella and suprasellar spaces (Image A). The patient underwent a craniotomy with partial resection of the cyst wall and aspiration of the cyst contents (Image B, Image C, and Image D). Following reaccumulation and drainage of cyst contents over the ensuing year, another resection of cyst wall was performed (Image E, Image F, Image G, and Image H).

Tissue Site
Suprasellar mass

The whole slide image provided is an H&E stained slide of suprasellar cyst from an excision.

The most appropriate diagnosis for this case is papillary craniopharyngioma (PCP), WHO grade I. The micrographs from the first resection show ciliated pseudostratified columnar epithelium adjacent to adenohypophysis (Image B), fibrous cyst wall (Image C), and overlying focal nonkeratinizing squamous differentiation (Image D). A diagnosis of Rathke cleft cyst was made, but the presence of papillary craniopharyngioma was not recognized. Micrographs of the second resection specimen show expansion of the squamous component, still with overlying respiratory epithelium (Image E and Image F). The squamous component shows membranous beta-catenin immunostaining without nuclear expression (Image G). Immunostaining for BRAF V600E shows reactivity in cytoplasm of the squamous component and in the cilia of the columnar component (Image H). Pyrosequencing confirms the presence of a BRAF V600E mutation. Such testing on the initial resection specimen would have identified the coexisting papillary craniopharyngioma. Rathke cleft cyst and craniopharyngioma, as dual pathology, can be found in a minority of cases.

A suprasellar cystic lesion may be one of several different pathologic entities. The morphologic features of adamantinomatous craniopharyngioma (ACP) - peripheral nuclear palisading, “wet” keratin, and stellate reticulum - are absent in this case. Immunostaining for β-catenin shows only cytoplasmic membranous expression and no nuclear expression in the squamous epithelia. These findings make the diagnosis of ACP unlikely. Epidermoid cysts are lined by squamous epithelium which displays a granular layer and matures into dry, flaky keratin that fills the cavity, features not present in this case. Teratomas occur in the suprasellar area and may include keratinizing or nonkeratinizing squamous cysts, but they should also contain multiple other tissue types from multiple germ layers. Both Rathke cleft cysts and nasopharyngeal mucosa can be lined by respiratory epithelium, and both may undergo squamous metaplasia focally, but neither should harbor the BRAF V600E mutation.

WHO grade I craniopharyngiomas can be divided into two types, adamantinomatous and papillary. More than 90% of craniopharyngiomas are of the adamantinomatous type, which have a median age of onset at around 25 years and a bimodal distribution of incidence that peaks in childhood and in the sixth decade. Loss of peripheral vision and endocrine deficiencies are the two most common clinical features at presentation. ACPs are usually cystic and show calcifications on CT imaging. Microscopically, the neoplastic cells are rimmed by palisading tall basal cells that outline irregular nests of dense squamous epithelium and loose “stellate reticulum.” Epithelial elements are interspersed with eosinophilic and frequently calcified nodules of anucleate “wet” keratin that show the ghost-like outlines of polygonal squamous cells. The cystic component of ACPs frequently contains xanthogranulomatous debris, a mixture of cholesterol crystals, macrophages/siderophages, and multinucleate giant cells. Although this element in ACPs is similar to xanthogranuloma of the sella, evidence in the literature suggests that most xanthogranulomas arise from Rathke clefts cysts, probably as a result of hemorrhage.

PCPs are substantially less common than ACPs and almost exclusive to adult patients; yet, as illustrated in this case, they may rarely occur in children. Histologically, neoplastic cells in PCPs are usually arranged in thicker and more solid bands/nests than seen in the present case, with the epithelium often distributed in a geographic pattern around thick, fibrovascular cores. The stratified epithelium is nonkeratinizing and overtly squamous with incomplete maturation towards surface (lacking stratum granulosum and stratum corneum). Whereas ACPs have tall basal cells that form peripheral palisades around cell nests, the basal cells in PCPs are flatter and similar to that of epidermis or squamous mucosa. PCPs are reported to be less likely than ACPs to show histologic evidence of brain invasion, but only have an inconsistent association with better outcomes.

Craniopharyngiomas are locally aggressive and invade the surrounding brain, giving its surgical resection a high risk of damage to the pituitary stalk and the hypothalamus. To avoid such damage, many craniopharyngiomas are incompletely resected and have an increased risk of postsurgical recurrence. Many craniopharyngioma patients experience life-long hypopituitarism that requires hormone replacement therapy. The primary prognostic factors in craniopharyngiomas are extent of resection and size of tumor at presentation with incomplete resection and size >5 cm associated independently with higher rates of recurrence. Following incomplete resection or recurrence, radiation therapy is typically pursued.

ACPs and PCPs are each consistently associated with specific genetic abnormalities; most ACPs have CTNNB1 exon 3 mutations, and most PCPs have BRAF V600E mutations. In most cases, the histologic findings are straightforward, yet in others there may be hybrid ACP/PCP features, or, as in this case, may overlap histologically with nonneoplastic lesions. DNA-based testing detects these mutations in difficult cases. IHC serves as surrogate tests for both mutations: focal nuclear β-catenin expression in ACPs and cytoplasmic BRAF V600E expression in PCPs.

• Papillary craniopharyngiomas are less common and usually occur in older patients than adamantinomatous craniopharyngiomas.
• The vast majority of papillary craniopharyngiomas harbor BRAF V600E mutations, whereas adamantinomatous craniopharyngiomas usually have CTNNB1 mutations in exon 3.
• Although WHO grade I, craniopharyngiomas are associated with high rates of morbidity due to hypopituitarism.
• Papillary craniopharyngiomas may coexist with nonneoplastic lesions such as Rathke cleft cysts.

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