Rathke's cleft cysts (RCCs) are nonneoplastic sellar lesions derived from remnants of the embryonic Rathke's pouch¹⁾. Rathke's pouch normally closes in early fetal development, but failure of this pouch to regress upon formation of adenophysis and neurophysis can result in an RCC²⁾. They develop as cystic lesions located between the anterior and posterior lobes of the pituitary gland and are discovered intra and/or suprasellar lesions³⁾. RCCs are often clinically silent throughout life. According to a postmortem examination of 1,000 unselected autopsy specimens, 113 pituitary glands (11.3%) harbored incidental RCCs⁴⁾. As RCCs increase in size slowly with time, they may become clinically evident later in life. Typical symptoms are headaches, visual disturbances, and endocrinological dysfunction. However, as shown in a case study, there may be severe clinical consequences, such as pituitary apoplexy and aseptic meningitis⁵⁾. Although the prevalence of RCCs in adults is rather high, reported in up to 22% of subjects in routine autopsies, RCCs in children are rarer. In addition, most remain asymptomatic as determined by autopsy and magnetic resonance imaging (MRI) studies, and the asymptomatic RCCs that are identified in children are typically smaller than those found in adults^4,6,7,8).

With growing public interest in child growth and development and widespread availability of MRI, pediatric endocrinologists are expected to see increasing numbers of patients with radiological diagnosis of RCCs. Although there are many studies on the manifestations and prognosis of RCCs, most of the data are derived from case series of adult patients, and there are little data describing the presentation and outcome of RCCs in children. Several cases of RCCs were reported in a pediatric population, but the numbers of patients were small (Table 1)^{9,10,11,12,13,14)}. Thus far, the natural history and optimal treatment strategy for RCCs in children have not been clearly specified, especially in pediatric patients with endocrine disorders associated with growth delay. Given the relatively low likelihood of improvement and potential for worsened pituitary function after surgery, surgical intervention might not be a good option in this specific population if there are no evident symptoms due to mass effect of the cyst on adjacent structures such as visual loss or persistent headaches¹²⁾.

In the present study, we retrospectively analyzed children and adolescents with concomitant RCCs and endocrinopathy. The aims of our study were to investigate (1) the clinical characteristics of the children and adolescents with endocrine disorders in whom RCCs were incidentally identified, (2) the radiological characteristics of their RCCs as compared to RCC patients without endocrine dysfunction, and (3) the potential influence of RCCs on the treatment response of the patients with proven endocrine disorders.

In the present study, we evaluated the clinical characteristic of 26 children and adolescents, recruited from four tertiary hospitals, with endocrine disorders in whom RCCs were incidentally discovered and radiological features of their RCCs. Our patients had small, intrasellar RCCs (less than 20 mm), mostly of a cystic nature, on T1- and T2-weighted MRI (73.1%), and the prevalence of this MR pattern was significantly higher than in the RCC subjects without endocrinopathy. After treatment for 1 year, the treatment outcomes were similar compared to the matched controls.

Data from adult patients demonstrated that most RCC-related adenohypophyseal dysfunction, particularly panhypopituitarism, frequently fails to improve after surgical drainage, with a reported resolution rate of 14% to 20%, and that the response to surgery tends to vary according to the subtype of endocrinopathy^14,15,16,17). In contrast, the majority of patients with headaches or visual disturbances experienced an improvement^14,15,16,17). Likewise, recent case series of surgically treated pediatric RCCs also showed that pituitary dysfunction was not resolved in the majority of patients (Table 1)^{9,10,11,12,13,14)}. According to the reports, headaches and visual disturbances were more easily resolved by surgery, but some endocrine disorders were not. Moreover, most patients with CPP could be treated with medical treatment. In Korea, two studies describing the presentation and outcome of RCCs in children were published. In one study, a pediatric patient with surgically treated RCC presented with headaches and visual dysfunction¹⁴⁾. Lim and Yang¹⁰⁾ found that RCCs were responsible for pituitary disorders and that GHD and diabetes insipidus did not improve after surgical intervention, although hyperprolactinemia resolved in all patients. They also reported that some endocrine disorders developed after the surgery. In general, children with ISS exhibit a normal GH secretion pattern in response to a GH stimulation test, but GH neurosecretory dysfunction may result in reduced spontaneous 24 hours GH secretion^18,19). Although data on RCCs with concomitant ISS are lacking, our results showed that the size and MR patterns of RCCs accompanied by ISS were similar to the RCCs in other endocrine disorders (CPP and GHD). There have been controversies on which symptoms are related to RCC. Large RCCs accompanied by persistent headaches or temporal visual field defects are generally accepted as an indication for surgical intervention. However, the relationship between RCCs and endocrine disorders, especially specific subtypes, such as CPP and GHD, has not been established yet.

In some cases, GHD with concomitant RCC can be improved by surgical removal of the RCC. However, according to a few studies, the resolution rate was relatively low following surgery. Aho et al.²⁰⁾ reported that an improvement was seen in 14 of 78 patients (18 %) with GHD after removal of an RCC. In pediatric cases, symptoms of GHD were resolved in one of three patients with RCCs and concomitant GHD after surgery¹²⁾. In our study, all the patients with GHD were treated with hGH, and their clinical outcomes were similar to those of the control group, without any change in the cysts. In addition, recent case reports of RCCs with concomitant CPP suggested that they improved following treatment with either a GnRH agonist or conservative treatment alone^10,11,21). Considering the high prevalence of subjects harboring incidental RCCs, the low rate of recovery from endocrine dysfunction after surgery, and the potential for improvement without surgical drainage, the argument about the correlation between symptoms and RCCs has remained unresolved. Regardless of the true association between them, we revealed that RCCs in patients with concomitant GHD and CPP could be treated nonsurgically and that their clinical outcome was similar to those without RCCs.

As shown previously, the signal intensity of RCCs on MR images varies considerably, depending on the cystic contents²²⁾. Although no characteristic MRI features have been identified, many RCCs can be classified into one of the following two groups: RCCs with T1 hypointense/T2 hyperintense signals or RCCs with a high signal intensity on T1-weighted images and a variable signal intensity on T2-weighted images. Nishioka et al.²³⁾ found that adenohypophyseal dysfunction was associated with hyper- or iso-signal intensity on T1-weighted MR images rather than cyst size. The high protein or the mucus content within RCCs is believed to induce a tissue inflammatory response, and such stimulation participates in the development of symptoms, even in the case of small RCCs²⁴⁾. On the other hand, RCCs with cerebrospinal fluid-like signal intensity are thought to grow slowly and not to cause clinical symptoms until they become large²⁵⁾.

In our study, the cysts were all small, and no hyperintense T1 signal was observed in any of the cases. The equivalent treatment outcome of the study group and the control group might be due to the rather homogenous and unique MR pattern of our cohorts. Nevertheless, the six patients (26.9%) with RCCs that showed an iso-intense signal on the T1-weighted images all had a similar outcome (data not shown). Most RCCs were intrasellar lesions on the MR image, and they were slow growing. Larger RCCs can become suprasellar lesions. According to studies conducted among 151 RCC patients who were surgically managed, RCCs with a suprasella component more commonly presented with visual dysfunction and were associated with higher postoperative endocrine morbidity²⁶⁾. The RCCs in our patients were all intrasellar lesions, and most of the patients did not present with visual symptoms.

Our study has several limitations, which include its retrospective nature and the sample size, which is small, although it represents one of the largest series of pediatric RCCs to date. The small sample size likely reflects the rarity of RCCs in this population. In addition, a follow-up MRI scan was not performed in all the cohorts, and pathological confirmation of the RCCs could not be made. Although MRI cannot make a definitive distinction between pathological entities, the diagnosis of a RCC is commonly confirmed with MRI in daily clinical practice. In our study, RCCs were differentiated from other cystic tumor by the imaging features and the location of the cystic lesion and were confirmed by two or more radiological specialists. Finally, the follow-up duration was relatively short. However, during the follow-up period, no patient needed surgical intervention.

The findings from our series containing exclusively prepubertal/pubertal cohorts with endocrinopathies suggest that CPP and GHD patients with a small RCC (less than 20 mm) expressing cystic MR intensity can be managed with medical treatment. We believe that our findings provide valuable information for understanding the nature of pediatric RCCs and for developing an individualized therapeutic strategy. However, it is still unclear whether this specific population would have a positive clinical outcome during an extended follow-up period or whether RCCs with different MR signal intensity patterns would show similar outcomes. To answer these questions, well-designed, large scale, prospective clinical trials are warranted.