The clinical picture of symptomatic Rathke cleft cysts in children

Introduction

Rathke cleft cysts (RCC) are benign cystic remnants of Rathke’s pouch, typically located in the pars intermedia between the anterior and posterior pituitary lobes and usually regress during embryonic development [1]. They are often asymptomatic and incidentally discovered on cranial imaging. Diagnosing RCCs can be challenging due to the similarity of cystic lesions of the sellar region, including pituitary adenomas, craniopharyngiomas, and arachnoid cysts [2], 3]. RCCs are rare in the pediatric population [4]. The prevalence ranges from 1.2 % in asymptomatic children [5] to 13.5 % in children suffering from endocrine disorders [6]. Like adults, the most common presenting symptoms include headaches and endocrinological symptoms with varying frequencies across studies [6], [7], [8], [9].

The current literature contains limited information about the natural course and long-term outcomes, particularly in children who undergo conservative management. In the present study, we aim to analyze the clinical symptoms, endocrine dysfunction, and clinical course of pediatric RCC patients treated at a single institution.

Patients and methods

Results (median, range)

Initial hormonal assessment

The endocrinological diagnostic work-up at presentation revealed pituitary insufficiency in 10 patients (71.4 %, Figure 1). Five patients had GHD. Three of them had a combination of GHD and central hypothyroidism or hypocortisolism; one patient had GHD and AVP-D, and another patient had isolated GHD. All five patients with GHD were prepubertal males. Five out of 14 patients had AVP-D, either alone (n=1) or in combination with central hypothyroidism (n=2) or hypocortisolism (n=2). Six patients had a TSH deficiency on diagnostic work-up, mostly in combination with other hormonal disturbances; only one patient exhibited isolated central hypothyroidism. Three patients (2 m, 1 f) had hyperprolactinaemia with a median level of 50.4 ng/mL (range 28.5–52.6). Two of the three patients with pituitary stalk dislocation (No. 7 and 11, Table 1) had multiple pituitary hormone deficiencies, whereas Patient No. 5 presented with no endocrine disturbances.

Figure 1:

Prevalence of isolated or combined hormonal dysfunction in this cohort of 14 patients with Rathke cleft cysts. GH, growth hormone; AVP, arginine vasopressin.

Discussion

In the present study, we analyzed the clinical symptoms and endocrine disorders at presentation and during follow-up of 14 children and adolescents with symptomatic RCCs diagnosed over 18 years in our institution.

The diagnosis of RCC was made radiologically based on the characteristic appearance on MRI in all patients. It should be noted that a definitive diagnosis can only be made by histopathological examination of the cyst membrane [3]. It has been pointed out that in cases where membrane resection is not performed to preserve hypophyseal function, histological examination is incomplete, and the definitive diagnosis of the cyst remains uncertain [14]. The diagnosis was confirmed through microscopic pathological analysis of the membrane in five patients who had undergone surgery.

The number of our patients aligns with most published pediatric studies [8], [15], [16], [17], [18]. However, one study from South Korea reported the largest series of 93 children and adolescents from a single institution to date [19]. The authors found a slight female predominance (female to male ratio: 1.16) and a mean age of 10.9 years at diagnosis. The slight female-to-male predominance was also reported in a cohort of 24 children from a single institution [8] and found in 31 children with a histopathological diagnosis of RCC after surgery [20]. The smaller number of subjects studied could explain our lower female-to-male ratio. Our patients’ median age of 12 years at diagnosis matches well with data from the literature [8], 20].

Headaches have been reported as the most common symptom in pediatric studies, with prevalence ranging from 21 % [7] to 79 % [9]. In our study, eight of 14 patients (57 %) reported headaches as the presenting symptom, including all five surgically treated patients. The size of the cyst did not correlate with headaches. Even the patient with the smallest cyst size (Patient No. 6) in our cohort reported headaches and had signs of AVP-D. Recent data suggest that chronic adenohypophyseal inflammation may be the key to understanding why some patients with small RCCs experience severe headaches [21].

Our data confirm the low frequency of visual symptoms reported in other pediatric studies [7], 18]. In contrast, adult studies report visual impairments of up to 75 % [22].

Growth retardation and clinical signs of AVP-D were the most common endocrine abnormalities at presentation [15], 20]. Lee et al. report that endocrine abnormalities were more prevalent in the surgery group than in the observation group [19]. However, in the present study, we could not confirm these results. Patients with symptomatic RCC may display a variable degree of endocrine dysfunction. Our series revealed hormonal deficiencies in up to 71 % of the children at diagnosis. This study’s high frequency of GHD aligns with previous pediatric studies [7], 23], 24]. In contrast, AVP-D incidence was higher than previously reported in the literature [7], 8]. Arginine vasopressin deficiency was found in all five patients treated surgically (before surgery: n=4, after surgery: n=1), and only in one of the nine followed conservatively. Arginine vasopressin deficiency did not improve during the follow-up. Our results confirm the data of Lim HH et al., who stated that none of their 29 conservatively managed pediatric patients had AVP-D, whereas 40 % of surgically managed patients had AVP-D [23].

Hyperprolactinemia was reported as adults’ most common hormonal disturbance [25], whereas it seems to be rare in children [6], 20]. Hyperprolactinemia was found in three patients at diagnosis (2 m, 1 f) and in two patients at last visit (1 m, 1 f). None of the patients had galactorrhea, and the female patient (Pat. No. 9) had no menstrual irregularity. Our data do not confirm the reports of a high rate of precocious puberty, which has been reported between 4 and 37 % in other studies [7], 23]. This finding might be attributable to ethnic differences, the older age of the subjects, and the small number of female subjects in our study.

The data from the literature on complete resolution of prior hormone deficiencies after surgery range from 14.6 % [19] to 50 % [20]. In our cohort, endocrine deficits did not improve during our patients’ follow-up period. Moreover, at the last visit, five patients, including two patients of the observation group, developed hypogonadotropic hypogonadism during the clinical course as additional endocrine dysfunction.

The RCCs in childhood are usually small and typically located in the pars intermedia [26]. Previous studies reported that the median cyst diameter data varied between 5.5 mm [15] and 8 mm, ranging between 6 and 30 mm [8]. The median cyst size of our cohort was comparable to the literature. In five of our 14 patients, RCC showed a suprasellar extension on MRI. A former study suggested that suprasellar extension is associated with TSH, ACTH deficiencies, and AVP-D [23]. We did not observe a similar association; in fact, two of the patients with suprasellar RCC (Patients No. 5 and 12, Table 1) had a normal hormonal status at presentation.

The natural course of pediatric RCC remains unclear since most reported series do not provide long-term follow-up as in this study. In our observation group, all nine patients with RCC were diagnosed radiographically, differentiated from other cystic lesions by the location and lack of calcification [27]. The cyst size remained unchanged in seven and decreased in two. Of the five patients treated surgically, the cyst size increased in four; three required a second operation. Recurrence rates have been reported between 0 and 22 % [26]. Headache and hyperprolactinemia were the leading findings of cyst recurrence in our patients. In our cohort, two patients with recurrence had squamous metaplasia described in the histopathological examination. One of them had a postoperative cerebrospinal fluid leak. The other patient had a residual cyst demonstrated on postoperative MRI.

A recent systematic review and meta-analysis of 190 children with RCCs identified from 12 retrospective cohort studies compared surgical and conservative management approaches [28]. The authors reported that the conservative group demonstrated a broader age distribution than the surgical group, that headaches were more prevalent in surgical patients than in conservative patients, and that surgical patients exhibited higher rates of visual disturbances and endocrine dysfunction compared to conservative patients. Due to the relatively small number of patients in our cohort, we were unable to confirm these results.

Our data suggest that most pediatric RCC patients can be managed successfully. This finding is compatible with the study of Jung et al., in which only 7.5 % of patients were managed surgically, although 94.4 % were symptomatic [7]. While commonly accepted criteria for surgery include visual field deficits, radiographic evidence of chiasma compression, and medically refractory headaches, some authors suggest that the latter is a subjective surgical indication, as more than half of conservatively managed patients show spontaneous resolution of headaches [8]. None of our patients had headaches at the last visit. All five patients who underwent surgery had medically refractory headaches before surgery; we observed a complete resolution of headaches after the operation in all of them. However, the initial findings of endocrine deficiencies did not resolve; on the contrary, new hormonal deficiencies arose during follow-up in both observation and surgery groups. A recent study conducted on adult patients with RCC supports our findings [29]. The authors reported that the patients with presurgery pituitary dysfunction had the longest RCC diameter and that pituitary dysfunction did not improve after surgery. In our study, all five who had surgery had the largest RCC maximal dimension. The surgery led to an improvement of headache and hyperprolactinemia.

There are some limitations in the present study. We identified only 14 symptomatic patients with RCC over an 18-year period who fulfilled the criteria. Due to the retrospective design and the small number of subjects, detailed comparison analysis could not be performed, and thus, definitive conclusions cannot be drawn. Secondly, there might be selection bias, as we see the symptomatic patients referred to a tertiary university center due to further explanation of persistent headaches and hormonal disturbances. This might also be the explanation for the higher frequency of pituitary insufficiencies. Thirdly, the RCC diagnosis was based on the characteristic appearance of the MRI, and data on cyst size or location were extracted from the medical files.

The strengths of our study include its relatively long follow-up period. Only a few studies report the natural course of RCC during childhood. We demonstrated long-term outcomes and the factors associated with a recurrence. Secondly, we performed a detailed endocrine work-up in our cohort with stimulation tests. Lastly, a histopathological examination was performed on all surgically managed patients, allowing us to make a definitive diagnosis.

In conclusion, symptomatic RCCs are rare in children and are accompanied by a high frequency of endocrine disturbances, with GHD and AVP-D being the most common. Neither the size nor the location of RCC will help to define signs and symptoms. Surgery has benefits in improving headaches and visual disturbances, but not in improving endocrine deficiencies. Our findings suggest that most patients can be managed conservatively, and the cyst may shrink or even disappear entirely in the natural course. Residual cysts on postoperative MRI, recurrence of headache, and hyperprolactinemia might suggest a relapse.