Pediatric craniopharyngioma in association with familial adenomatous polyposis

Abstract

Familial adenomatous polyposis (FAP) is a cancer predisposition syndrome driven by germline loss-of-function of the APC gene and phenotypically manifests with intestinal polyposis and a variety of extra-intestinal bone and soft tissue tumors. Craniopharyngioma is not a well-described FAP-associated tumor, however, six cases have been reported in adults, all demonstrating ectopic location and adamantinomatous histology. We report the first case of craniopharyngioma associated with FAP in a pediatric patient. A seven-year-old girl who presented with headache and vomiting was found on magnetic resonance imaging to have a suprasellar mass with cystic extension to the pre-pontine space. The tumor represented an adamantinomatous craniopharyngioma (aCP) with nuclear β-catenin expression. Whole exome sequencing confirmed a CTNNB1 activating point mutation and a germline APC frameshift variant. This case represents the first FAP-associated craniopharyngioma in childhood…. expanding our understanding of the molecular underpinnings driving tumorigenesis in this unique patient.

Introduction:

Familial adenomatous polyposis (FAP) is an autosomal dominant cancer predisposition syndrome driven by germline loss-of-function of the APC gene. The classic phenotype of FAP involves development of hundreds of intestinal adenomas by the second or third decades of life with progression to colorectal adenocarcinoma at a young age in the absence of prophylactic colectomy[1]. Several phenotypic variants of FAP have been described, though all are now genetically defined as a spectrum of pathogenic APC-associated conditions. The eponymous Gardner syndrome consists of intestinal polyposis accompanied by extra-intestinal bone and soft tissue tumors, including osteomas, epidermal cysts, Gardner-associated fibromas, and desmoid tumors[1, 2]. Turcot syndrome historically described the concurrence of intestinal adenomas with primary central nervous system tumors (CNS)[3]. In patients with underlying APC perturbations, the associated CNS tumors are typically medulloblastomas, whereas patients with intestinal polyposis as a consequence of Lynch syndrome are at increased risk for high-grade astrocytomas[3, 4]. Craniopharyngiomas are not classically amongst the CNS tumors predisposed to by APC-associated or other hereditary polyposis conditions.

Craniopharyngiomas are World Health Organization (WHO) grade I tumors that, with rare exception, originate in the suprasellar region and are thought to arise from the epithelial remnants of the vestigial craniopharyngeal duct or Rathke’s pouch[5]. Craniopharyngiomas may be histologically and molecularly subdivided into adamantinomatous (aCP) and papillary (pCP) subtypes[5]. Childhood craniopharyngiomas are almost universally of the aCP subtype characterized by WNT pathway activation, while the pCP subtype is largely exclusive to adults and is molecularly distinguished by BRAF V600E[6, 7]. Six cases of craniopharyngioma have been reported in patients with FAP[8], all of which exhibit a predilection for ectopic sites of disease and adult age of onset[8–14]. We here report the first case of FAP-associated craniopharyngioma in a pediatric patient and discuss the potential molecular underpinnings of this association.

Case Report:

A seven-year-old girl presented to the pediatric gastroenterology clinic to establish care for a known diagnosis of maternally inherited FAP stemming from a pathogenic frameshift mutation in the APC gene [p.R976fs]. At the time of her initial presentation, she reported intermittent occipital headaches of over two years duration. While travelling she experienced an acute worsening of her symptoms with accompanying vomiting, right facial droop, and mild ataxia leading to evaluation in a local Emergency Department.

Initial head CT demonstrated a partially calcified, cystic mass involving the posterior fossa with secondary obstructive hydrocephalus. Subsequent MRI further defined a primary suprasellar mass with cystic extension to the pre-pontine space (Figure 1). The patient underwent fenestration of the dominant cyst and experienced no significant surgical complications. She quickly returned to her neurologic baseline. Endocrine and ophthalmologic evaluations were unremarkable.

Figure 1. T1 weighted post-gadolinium MRI.

Axial (A) and sagittal (B) MR imaging demonstrates predominately cystic mass arising from the suprasellar region. Lobulated cystic component extends posteriorly and inferiorly into the prepontine cistern. The tumor exerts significant mass effect on the brainstem with resultant obstructive hydrocephalus. Corollary CT demonstrated coarse midline calcifications (not shown).

Histopathology of the cyst wall shows a tumor with well differentiated palisading basaloid epithelium, stellate reticulum, wet keratin and calcifications; changes consistent with adamantinomatous craniopharyngioma. In addition, the tumor expresses focal nuclear immunoreactivity for β-catenin (Figure 2A&B). The patient was enrolled on PEDS-MIONCOSEQ, a precision oncology study involving whole exome (paired tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Clinically-integrated sequencing was performed according to previous published methodology[15]. Nucleic acid preparation, high-throughput sequencing, and computational analysis were performed using standard protocols in the sequencing laboratory in the Michigan Center for Translational Pathology, which adheres to the Clinical Laboratory Improvement Amendments (CLIA). This identified an activating point mutation to CTNNB1 (NM_001904.3: c.122C>T, p.Thr41Ile) as well as recapitulation of her germline APC perturbation. There was no loss of heterozygosity in APC by copy loss, insertion/deletion, or other mutation detected in the tumor. No other significant somatic indels, fusions, or copy number aberrations were detected. Whole transcriptome sequencing demonstrated overexpression of multiple Wnt/β-catenin and sonic hedgehog pathway-associated genes as have been previously described in aCP[16, 17](Figure 2C). Interestingly, we also noted upregulation of Hippo pathway modulator LATS1 and DNA methylation regulator TET2, both alternative mechanisms associated with β-catenin pathway activation[18, 19].

Figure 2. Adamantinomatous craniopharyngioma demonstrates Wnt/β-catenin pathway activation.

A. Hematoxylin and Eosin staining shows a lobular tumor with finger like projections of well differentiated epithelium composed of basaloid layer (BL), stellate reticulum (SR) and nodules of wet keratin (WK). B. Beta-catenin staining shows nodules of nuclear accumulation. C. Expression histograms from RNA sequencing demonstrating enrichment in multiple Wnt/β-catenin and sonic hedgehog pathway genes.

Discussion:

Six cases of craniopharyngioma arising in patients with FAP have been previously reported[9–14]. These reports describe tumors occurring exclusively in young adult patients (ages 20–34). Of the five tumors with available histopathologic subtyping, all were described as aCP. These FAP-associated aCPs also exhibit a consistent propensity for ectopic sites of disease within the posterior fossa, in contrast to the typical suprasellar site of origin in sporadic craniopharyngiomas[8]. Four are described as arising at the cerebellopontine angle[11–14], while the remaining two originated within the fourth ventricle[9, 10]. Our patient presented at a younger age than has been previously described, and yet despite the suprasellar origin of her tumor, the prominent posterior extension of the dominant cyst emulates this idiosyncratic ectopic phenotype.

The wild-type APC gene on chromosome 5q22.2 codes for a protein which acts as a negative regulator of canonical Wnt signaling via binding to cytosolic β-catenin as part of a degradation complex, targeting it for ubiquitination and subsequent proteosomal destruction[3]. Loss of this tumor suppressor function through inactivating truncations, deletions, or rearrangements leads to an increase in nuclear translocation of β-catenin and consequent unchecked transduction of Wnt-mediated signaling[3, 20]. Somatic mutations to exon 3 of the β-catenin gene CTNNB1, the genetic alteration observed in at least 70% of aCPs[21], result in loss of the Ser and Thr residues that are targeted for phosphorylation by the APC-containing degradation complex, likewise leading to escape of cytosolic β-catenin from ubiquitin-mediated degradation and constitutively active Wnt-mediated signaling[6].

Given the similar effect of germline APC mutation (in FAP) and somatic CTNNB1 mutation (in sporadic aCP) on canonical Wnt signaling at the level of cytosolic β-catenin regulation, it is curious why aCPs are not more commonly observed in patients with FAP. Precedence for these divergent disruptions leading to a common disease exists in desmoid tumors, where 85% of sporadic tumors harbor somatic mutations to exon 3 of CTNNB1[22], while the <10% of desmoids which are associated with FAP are uniformly driven by characteristic APC mutations[23]. Despite the similar propensities for activating mutations of β-catenin amongst sporadic disease, desmoid tumors are well recognized as a classical sequela of FAP, while FAP-associated craniopharyngiomas remain limited to a small number of case reports. It is possible that craniopharyngioma is underrecognized as a sentinel lesion for a subset of attenuated FAP phenotypes, or it is possible that regulatory elements within the developmentally unique epithelium from which aCP arises abrogate the pathogenic potential of APC loss. The two-hit Wnt/β-catenin signaling perturbation observed in our patient would indeed suggest that loss of APC alone was insufficient for neoplastic transformation. Previously published reports of FAP-associated craniopharyngioma have not included matched tumor and germline sequencing, so it is unclear how often these CTNNB1 and APC mutations co-occur. Regardless, this observation of craniopharyngioma in a pediatric patient with FAP carries implications both for the appropriate anticipatory genetic counseling of these families as well as the diagnostic evaluation of a child with FAP and clinical suspicion for a CNS tumor.