15.1 Introduction

Rathke’s cleft cysts (RCC) represent the most common sellar lesion in adults and have been described to occur in up to one-third of individuals studied at autopsy. ¹ Despite this, RCCs are often incidental findings and account for less than 10% of surgically treated sellar lesions. ¹ Unlike their high prevalence in the adult population, these congenital lesions are uncommonly diagnosed in pediatric patients. While the prevalence of pediatric RCC is not precisely defined, less than 200 cases of symptomatic pediatric RCCs have been reported in the literature. In imaging studies of asymptomatic patients, cystic lesions of the pituitary were seen in 1.2% of patients younger than 15 years. ² However, with increased access to advanced imaging, the diagnosis of smaller, incidental RCCs is rising, underscoring the need for the pediatric neurosurgeon or pituitary specialist to be familiar with their optimal diagnosis, natural history, and management. In this chapter, we will review the pathophysiology, diagnosis, and optimal management of these benign sellar lesions.

15.2 Pathophysiology

During development, Rathke’s pouch develops from pharyngeal ectoderm that rises cranially to fuse with the descending infundibulum of neuroectodermal origin. Rathke’s pouch forms the pars tuberalis within the suprasellar cistern, the pars distalis, and the pars intermedia. The pars distalis ultimately differentiates to become the anterior lobe of the pituitary, whereas the posterior lobe arises from the pars nervosa of the descending neuroectoderm. ¹ In most instances, Rathke’s pouch regresses. In some, however, a remnant persists and can become filled with cerebrospinal fluid (CSF) or proteinaceous fluid that leads to the development of an RCC. As such, RCCs are commonly sellar in location and are bound by the adenohypophysis anteriorly and the neurohypophysis posteriorly. RCC can expand into the suprasellar space or infrequently arise exclusively in the suprasellar cistern as remnants of the pars tuberalis. RCCs can enlarge and cause compression of the optic chiasm, leading to visual field deficits, or can disturb normal pituitary function, leading to a variety of hormonal syndromes.

15.3 Natural History

Much debate exists within the literature regarding the optimal management and natural history of RCCs. The majority of longitudinal studies of asymptomatic RCCs are relegated to the adult population. Culver et al reported a series of 75 patients who underwent conservative management for RCC. ³ Over a median follow-up of 24 months, 57% of the cysts had no growth and 11% of the cysts decreased in size. Aho et al similarly examined the natural history of incidental RCCs less than 1 cm in diameter. ⁴ In this series, 69% of patients had no growth of the cyst 9 years from the time of diagnosis. Thus, in the majority of patients with asymptomatic, incidental RCCs, watchful waiting with serial imaging studies is a reasonable strategy. Indeed, Amhaz et al reported 51 patients treated with RCC over a 9-year period. ⁵ Twenty-nine patients were managed conservatively, and serial imaging showed involution of RCCs in nine patients. Interestingly, of the seven patients who had presented with headaches, five had subjective improvement in symptoms at the time the cyst was found to have decreased in size. This response rate is similar to outcomes reported by Zada et al, who published an 88% response rate for headaches following cyst fenestration. ⁶ Not all RCCs have a benign course, however. In Aho et al’s study, 31% of the patients at 9-year follow-up had developed an enlarging cyst, vision deficits, or pituitary hormonal dysregulation. ⁴ As such, surgical intervention may be warranted in some individuals.

In the pediatric population, headache, endocrinologic disturbance, and visual change are the most common manifestations of RCC. Disorders of the HPA in children frequently present with precocious puberty or growth delay, unlike the adult population, who exhibit pathology of the HPA via decreased libido, fatigue, menstrual irregularities, or altered mental status. ^{1 ,​ 7} Aseptic meningitis or apoplexies have been reported in patients with RCC, but these presentations are relatively rare. ⁷ There have been several published retrospective literature reviews on RCCs in the pediatric population that are briefly summarized in ▶ Table 15.1. Of the 163 patients who have been previously described, 53% were females, the median age at the time of diagnosis was 10.9 years, and the median cyst size was 0.8 cm in maximum diameter. Pooled analysis of the reported cases shows that 47% of patients presented with headache, 50% presented with an underlying endocrinopathy, and 9% presented with visual disturbance. 16% of the lesions were incidental findings. In total, 37% of pediatric patients with a diagnosis of RCC in the literature underwent surgery, with the most common approach being via the transsphenoidal corridor.

15.4 Diagnosis and Management of RCC

RCCs are generally described as non–contrast-enhancing, midline cystic lesions of the sella situated between the anterior and posterior lobes of the pituitary. They are noncalcified and can have suprasellar extension in up to 30% to 50% of cases. ^{8 ,​ 9} Diagnosis of an RCC on radiologic imaging alone can be challenging in some instances, given the variable appearance of cystic components on T1- and T2-weighted imaging (WI) on MRI. Although some heterogeneity does exist, RCCs generally are hyperintense on T2-WI MRI, whereas the T1-WI intensity is dependent upon whether or not the cystic contents are highly proteinaceous (hyperintense) or bland (hypointense). The major differential diagnosis on radiologic imaging for RCCs in the pediatric population is a cystic craniopharyngioma (CC), which is usually of the adamantinomatous subtype. The incidence of craniopharyngiomas in individuals younger than 18 years is greater than that of RCCs, and being able to differentiate between the two is imperative, as the optimal management for these two entities differs widely. ⁸ Classically, CCs, unlike RCCs, tend to have a contrast-enhancing nodular solid component, and the vast majority extend to the suprasellar space, with cystic components resembling cerebrospinal fluid on T1-WI and T2-WI. To further delineate differences between RCCs and CCs, Hayashi et al. performed a comparative study of RCCs and CCs based on MRI findings and concluded that RCCs tended to be smaller in size than CCs, regular in shape, and without calcification. ⁸ Byun et al further described that the presence of an intracystic nodule that was hyperintense on T1-WI and hypointense on T2-WI was characteristic of RCCs and represented deposits of cholesterol and protein on biochemical analysis. ⁹

Histopathologic differentiation of RCCs versus CCs can likewise be difficult, and some have suggested that RCCs can progress toward CC formation via an intermediate entity known as RCC with squamous metaplasia. ⁸ RCCs resemble ectodermal tissue on histologic section and are characterized by the presence of a single layer of columnar or pseudostratified ciliated cuboidal epithelium. ¹ CCs are divided into adamantinomatous and papillary subtypes. Both are characterized by proliferative stratified epithelium; however, the adamantinomatous subtype exhibits calcification and contains keratin debris with cholesterol clefts, while the papillary subtype is characterized by numerous papillae without dense keratin or calcification. ¹⁰ The papillary variant of RCC can be especially difficult to differentiate from RCCs, and genetic testing is important in their differentiation in certain cases. Papillary CCs contain the BRAF V600E mutation, while adamantinomatous variants of CC are characterized by intranuclear beta-catenin staining. ¹¹ RCCs do not typically contain these genetic and molecular hallmarks, and thus their absence aids in the diagnosis of RCCs.

In the pediatric population, surgical intervention has been reported in approximately 60 cases, with the two largest individual series being documented by Jahangiri et al ² and by Zada et al. ⁶ Jahangiri described 14 cases of pediatric RCCs treated by microsurgical transsphenoidal surgery for cyst fenestration. ² Half of their reported cases described headaches, and one of the 14 patients endorsed visual disturbance. Postoperative outcomes were not documented for these patients, but the authors did note a 21% postoperative rate of diabetes insipidus (DI) and noted that none of the three patients with preoperative growth hormone (GH) or insulin-like growth factor (IGF-1) deficiencies had normalization of their GH or IGF-1 levels postoperatively. Zada et al described 10 cases of RCC treated by a transnasal transsphenoidal approach for cyst fenestration and aspiration. ⁶ Eighty-eight percent of the patients in their series with headaches had improvement of their symptoms postoperatively. Only one of their patients had visual disturbances preoperatively, and this patient had modest improvement following surgery. Two of the six patients with preoperative HPA dysfunction had improvement of their underlying endocrinopathy postoperatively, while three patients developed new hormonal deficiencies. Surgical outcomes for adults are better described in the literature, with improvements in headaches being documented in 70% to 90% of cases and visual field improvements being noted in 70% to 80% of cases. ¹ Given the sparse data on surgery for pediatric RCCs, the 60 surgically described cases of RCC were pooled and collectively analyzed and are summarized in ▶ Table 15.2. In brief, 25% of patients had an improvement in a preoperative endocrinopathy; however, 27% had new anterior pituitary dysfunction postoperatively and an additional 27% had postoperative DI. Gross total resection was achieved in 82% of reported cases, and by the end of a 31-month follow-up, there was an 18% recurrence rate.

RCCs are not characterized by rapid division of multiplying cells, and as such, they are not sensitive to traditional chemotherapy or radiation. Medical therapy is mainly directed toward treating the underlying hormone excess or deficiency associated with an RCC, if any. In the pediatric population, this is most commonly aimed at treating GH deficiency (GHD) or precocious puberty. While some have advocated for surgery in these instances, surgical success in correcting underlying endocrinopathy as a result of RCC is limited, as noted earlier. Medical management for GHD involves GH supplementation, while gonadotropin-releasing hormone (GnRH) antagonists have been used to treat precocious puberty. ⁷ Oh et al showed that out of 26 pediatric patients with endocrinopathy associated with an underlying RCC, 27% were diagnosed with GHD, while 46% were diagnosed with central precocious puberty. At 1 year of treatment with either GH agonists or GnRH antagonists, outcomes were similar for age-matched controls with idiopathic GHD or central precocious puberty. ⁷

Taking all of this into account, surgical resection for pediatric RCCs seems most reasonable in instances with optic chiasmal compression with concurrent visual symptoms, instances of severe medical refractory headaches, progressive cyst growth toward the optic chiasm, or in cases where diagnostic uncertainty is present. Medical therapy is directed at treating the underlying hormonal excess or deficiency in patients with RCCs, if present.