TOPIC REVIEW

Rathke’s cleft cysts: review of natural history and surgicaloutcomes

Seunggu J. Han • John D. Rolston •

Arman Jahangiri • Manish K. Aghi

Received: 31 July 2013 / Accepted: 9 October 2013

� Springer Science+Business Media New York 2013

Abstract Rathke’s cleft cysts (RCCs), also known as pars

intermedia cysts, represent benign lesions formed from

remnants of the embryologic Rathke’s pouch. Commonly

asymptomatic, they are identified in nearly 1 in 6 healthy

volunteers undergoing brain imaging. When symptomatic,

they can cause headaches, endocrine dysfunction, and,

rarely, visual disturbances. A systematic review of the

published English literature was performed focusing on

large modern case series of RCCs to describe their natural

history, clinicopathologic features, radiographic features,

and surgical outcomes, including rates of recurrence. The

natural history of asymptomatic RCCs is one of slow

growth, suggesting that observation through serial mag-

netic resonance imaging is appropriate for smaller

asymptomatic RCCs. Symptomatic RCCs can be treated by

surgical resection with low morbidity, usually through an

endonasal transsphenoidal corridor using either a micro-

scope or an endoscope. Surgical treatment frequently pro-

vides symptomatic relief of headaches and visual

disturbances, and sometimes even improves endocrine

dysfunction. Rates of recurrence after surgical treatment

range from 16 to 18 % in large series, and higher rates of

recurrence are associated with suprasellar location,

inflammation and reactive squamous metaplasia in the cyst

wall, superinfection of the cyst, and use of a fat graft into

the cyst cavity.

Keywords Rathke’s cleft cyst � Suprasellar �Recurrence rates � Rathke’s pouch � Pars intermedia

cyst

Introduction

Rathke’s cleft cysts (RCCs) are also known as pars inter-

media cysts, and their tissue of origin is that of remnants of

the embryonic Rathke’s pouch. Thus they develop as cystic

lesions located between the anterior and posterior lobes of

the pituitary gland [1]. RCCs occupy the sellar space, but

can have suprasellar extension. They are common inci-

dental findings in 4–33 % of autopsy cases [2–5], but

RCCs account for 6–10 % of symptomatic sellar and

suprasellar lesions [6]. When these lesions grow, they can

cause mass effect on surrounding structures, such as the

pituitary gland, hypothalamus, and optic chiasm and

become symptomatic [7]. Thus, they can present with

headaches, visual disturbances, or pituitary dysfunction [8–

10]. While asymptomatic RCCs are typically followed by

serial imaging [8], symptomatic RCCs are managed by

surgical decompression, usually through a transsphenoidal

corridor achieved through the use of a microscope or

endoscope. The primary goal of surgery is to aspirate the

cyst contents, thereby alleviating the mass effect of the

cyst. Here, we present an overview of the pathophysiology,

S. J. Han � J. D. Rolston � A. Jahangiri � M. K. Aghi (&)

Department of Neurological Surgery, University of California

at San Francisco (UCSF), 505, Parnassus Avenue Room M779,

San Francisco, CA 94143-0112, USA

e-mail: AghiM@neurosurg.ucsf.edu

S. J. Han

e-mail: hansj@neurosurg.ucsf.edu

M. K. Aghi

Center for Minimally Invasive Skull Base Surgery (MISB),

505, Parnassus Avenue Room M779, San Francisco,

CA 94143-0112, USA

M. K. Aghi

The California Center for Pituitary Disorders (CCPD),

505, Parnassus Avenue Room M779, San Francisco,

CA 94143-0112, USA

123

J Neurooncol

DOI 10.1007/s11060-013-1272-6

natural history, surgical treatment, and clinical outcomes of

RCCs.

Methods

A PubMed search (http://www.ncbi.nlm.nih.gov/pubmed/)

of the keywords ‘‘Rathke’s cleft cyst’’, ‘‘outcomes’’,

‘‘surgery’’, and ‘‘endoscopic’’ alone and in combination

was performed. The query yielded 280 total citations, and

the articles that were selected for review of surgical out-

comes included those (1) with a large number of patients

([50 patients) (2) who were treated with surgery, and (3)

included clinical outcome data, including endocrinologic

outcomes and recurrence rates.

Pathophysiology

Rathke’s cleft cysts are remnants of Rathke’s pouch, which

is ectodermal in origin. The Rathke’s pouch normally

develops during the fourth week of gestation, and extends

caudally to fuse with the infundibulum around week eight

of gestation, forming the craniopharyngeal duct [2, 11, 12].

The infundibulum gives rise to the neurohypophysis or

posterior lobe of the pituitary gland. Rathke’s pouch gives

rise to the pars distalis and the pars intermedia in the sella,

and the pars tuberalis in the suprasellar cistern. In the sella,

the pars distalis comprises the anterior lobe or adenohy-

pophysis. The pars intermedia is also known as the inter-

mediate lobe of the pituitary gland. In the suprasellar

cistern, Rathke’s pouch gives rise to the pars tuberalis, a

structure that resides above the anterior lobe and the di-

aphagrama sella. During this time, a cleft, also known as

Rathke’s cleft, is formed in the region of the pars inter-

media, which normally regresses. Failure of the cleft to

regress leaves an adult with a persistent remnant of the

embryologic Rathke’s cleft. The remnant can fill with fluid

over time, leading to the formation of a Rathke’s cleft cyst

(Fig. 1a–c) [6, 13]. In the same regard, the purely supra-

sellar RCCs are thought to arise from a remnant of Rath-

ke’s pouch within the pars tuberalis in the suprasellar

cistern (Fig. 1g). RCCs and craniopharyngiomas are

thought to be within the continuum of the same disease

process, as both have ectodermal origin [13, 14].

Histology

Histologically, RCCs consist of single pseudostratified

ciliated cuboidal or columnar epithelium. Some RCCs

exhibit inflammatory contents and squamous metaplasia,

and this metaplasia is thought to be the reaction to the

chronic inflammation [15]. The fluid inside an RCC can

vary. It can be clear, similar to cerebrospinal fluid with low

protein content, in which case the cyst will rarely cause

symptoms. Or it can be filled with mucinous fluid with high

protein content, which is more frequently seen in symp-

tomatic patients. A number of the latter type of cysts have

been found to be superinfected, with typical organisms

including Staphylococcus epidermidis and Propionibacte-

rium acnes [16]. The exact mechanism of superinfection

remains unclear, but one speculation is based on the shared

venous drainage of the sphenoid sinus and sellar contents

allowing dissemination of local infection from the sinus

space to the RCCs [16].

Clinical presentation

The median age of a patient presenting with and diagnosed

with symptomatic RCC is in the late 30s [17], but they

have been reported in numerous pediatric patients [18] and

as well as elderly patients in their 70s and 80s [17]. The

typical symptoms include headache, visual loss and endo-

crinologic dysfunction (Fig. 2). In the published literature,

headache was described in 44–81 % of symptomatic cases

[9, 19], visual loss in 11–67 % of symptomatic cases [8,

19, 20] with nearly all examples of RCCs with visual loss

exhibiting suprasellar extension [21], and endocrinologic

dysfunction in 30–60 % of symptomatic cases [6, 7, 22,

23]. In as many as 16 % of patients, sudden onset severe

headaches have been described [9]. Although no clinical,

Fig. 1 Development of RCCs. a The pituitary gland is derived from

two sources. The anterior lobe originates from an upgrowth of

ectoderm from the roof of the stodeum (pharyngeal epithelium), while

the posterior lobe (along with the rest of the diencephalon) originates

from a downgrowth of neurectoderm. In the middle of the fourth week

of gestation, a diverticulum, Rathke’s pouch, begins as a dorsal

evagination from the pharyngeal epithelium, then grows upwards

from the roof of what will become the mouth towards the developing

brain. As the upgrowth contacts a ventral evagination or downgrowth

from the diencephalon of the brain, the infundibular process, it begins

to pinch off from its connection with the stomodeum. b By the sixth

week the connection between Rathke’s pouch and the oral cavity of

the pharyngeal epithelium degenerates, after which c the cells of

Rathke’s pouch proliferate to form the pars distalis (also called the

anterior pituitary or adenohypophysis), while the infundibular process

forms the neurohypophysis (the posterior lobe of the pituitary gland).

d The cells of Rathke’s pouch also extend up the anterior aspect of the

infundibulum as the pars tuberallis. The posterior surface of Rathke’s

pouch forms the pars intermedia. The infundibulum having grown

down from the floor of the diencephalon, expands as the axons of

diencephalon cells grow down into it. While Rathke’s pouch normally

closes early in fetal development, a remnant often persists as Rathke’s

cleft in the pars intermedia in between the anterior and posterior

lobes. A Rathke’s cleft (persistent material from Rathke’s pouch) can

sometimes expand to form a Rathke’s cleft cyst, which can be found

in a purely sellar location centered in the pars intermedia (e), a sellar

location with suprasellar extension (f), or a purely suprasellar

location, likely reflecting origin from persistent suprasellar Rathke’s

pouch cells that gave rise to the pars tuberalis (g). Abbreviations used:

Och optic chiasm, Mb mammillary bodies

c

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radiographic or histopathologic correlation has been made

with this type of headache presentation, it has been

hypothesized that this phenomenon may represent cyst wall

infarction, cyst hemorrhage, or leakage of inflammatory

cyst contents [24]. It has also been noted by many authors

that inflammatory hypophysitis is commonly seen with

RCCs, whether or not patients have acute onset of symp-

toms [24–28]. In a series reported by Komatsu and col-

leagues, only two of eleven patients with hypophysitis on

pathology had presented with acute symptoms; however,

the authors also noted higher rates of endocrine dysfunc-

tion, both of the adeno and neurohypophyseal axes in

patients with evidence of hypophysitis [24]. Interestingly,

hypophysitis in the setting of RCCs rarely seem to be

associated with visual deficits, and this observation has

lead to some authors to believe that the symptoms stem

from the inflammatory response to the hypophyseal tissue

after rupture of leakage of cyst contents, rather than direct

expansion and mass effect [28–31]. Consistent with this

theory, other studies have also suggested a higher likeli-

hood of finding evidence of an inflammatory reaction in the

surrounding pituitary gland in patients symptomatic with

RCCs [25]. While indicating a need for surgical interven-

tion, acute presentation is only an emergency if it is

associated with acute visual loss, similar to that seen with

apoplexy of a pituitary adenoma.

Depending on the age and gender of the patient, the

endocrinologic symptoms may differ. A commonly

described finding among men is hypogonadism, resulting

in fatigue and decreased libido, while premenopausal

women tend to suffer from menstrual irregularities and

galactorrhea, and postmenopausal women tend to present

with symptoms of panhypopituitarism, such as fatigue and

altered mental status [9]. Diabetes insipidus is also a rel-

atively common presenting finding in patients with RCCs,

when compared to pituitary adenomas, with reported rates

for RCC patients ranging from 2.3 % to as high as 37 % of

patients [7, 13, 17, 22, 32]. Previous authors have attributed

this higher rate of diabetes insipidus to the cysts’ propen-

sity for inflammation and infiltration of the surrounding

pituitary gland that is found on histopathologic analyses

[33].

Imaging features and differential diagnosis

On MRI, RCCs will typically appear hyperintense on T2.

However, their appearance on T1-weighted imaging can be

either hyperintense, consistent with proteinaceous mucin-

ous cyst contents that often represent presence of inflam-

mation, or hypointense, consistent with clear, low-protein

cyst contents (Fig. 3). An intracystic nodule having high

signal intensity on T1-weighted images and low signal

intensity on T2-weighted images has been reported in over

75 % of RCCs [34]. These intracystic nodules are fre-

quently found to be yellow, waxy, solid masses during

surgery, and their pathologic analysis reveals mucin

clumps. The main differential diagnosis of RCCs includes

pituitary adenoma, pituitary cyst and intrasellar cranio-

pharyngioma. The key feature distinguishing RCCs from

an adenoma is the midline location of RCCs without stalk

deviation, as well as the position of the cyst between the

anterior and posterior glands when viewed from sagittal

cuts.

Natural history of untreated RCCs

The incidence of incidentally discovered RCCs has risen as

neuroimaging has become more widely applied and

advanced [8]. Of a series of 61 incidentally discovered

RCC cases reported by Aho and colleagues [8], 42 cases

(69 %) did not show any growth over a 9 year follow-up

period. In another series of 139 incidentally discovered

RCCs reported by Sanno and colleagues [35], only 5.3 %

of these cases were found to have any documented growth,

while 76.5 % of cysts remained unchanged in size. In

15.9 % of cases, the cysts actually decreased in size. Little

published data exist regarding the progression of symptoms

Fig. 2 Mechanisms by which symptoms can arise from RCCs.

Suprasellar extension can result in mass effect on the optic chiasm,

and visual disturbances (1). Within the sella, mass effect on the

anterior pituitary can result in hypopituitarism (2), and diabetes

insipidus by mass effect on the posterior pituitary (3)

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in already symptomatic cases, as these patients likely

underwent immediate treatment and were not observed for

a long duration. Within the series published by Aho and

colleagues [8], development of new visual loss, endocri-

nopathy, or significant cyst growth ([1.5 cm) occurred in

31 % of patients observed through serial imaging over a

9-year period.

Surgical management

Surgical drainage is the mainstay for symptomatic RCCs,

and it is typically achieved via a transsphenoidal exposure.

Historically, RCCs were treated with cyst wall fenestration

for decompression along with biopsy sampling of the cyst

wall to confirm the diagnosis [2]. More recently, some

authors have advocated for the need for removal of the

entire cyst wall, quoting lower rates of cyst recurrence with

this more aggressive approach [36–38]. Unfortunately,

similarly to craniopharyngiomas, complete cyst removal

has been found to be associated with higher rates of post-

operative endocrine dysfunction [8, 9]. Some authors have

also described the technique of marsupialization, whereby

after the decompression, the cyst wall is opened up widely

and left open [39]. Unfortunately, no study to date has

compared the efficacy of marsupialization over simple

decompression.

The largest published experiences with surgically trea-

ted RCCs come from Benveniste et al. in 2004 [9], Aho

et al. [8] in 2005, and Lillehei et al. [19] in 2010. In the

work described by Aho and colleagues, complete cyst

decompression was achieved in 97 % of patients, resulting

in improved vision in 97 % of patients with preoperative

visual impairments. The series by Lillehei and colleagues

included 82 cases, and show postoperative improvements

in headaches in 71 % and vision in 83 % of cases, as well

as improvement in various endocrinopathies in 33–94 % of

patients. Benveniste and colleagues reported a series of 62

surgically treated cases, in whom complete cyst decom-

pression was achieved in 53 % cases, resulting in

improvement in headaches in 91 % and visual symptoms in

70 % of cases. In the published literature, the experience

with endoscopic endonasal approach is much more limited,

as the largest experience is a series of 22 patients published

by Frank and colleagues [37]. In this series, all patients had

improvement in their vision and headaches, as well as their

hyperprolactinemia, if present. Interestingly, when hypo-

pituitarism was present preoperatively, there no improve-

ment was seen after endoscopic resection [37].

Morbidity of surgery

The morbidity of surgical treatment of RCCs must include

considerations of those involved with the transsphenoidal

approach, including cerebrospinal fluid leaks, surgical site

infections, as well as possible injury to the carotid artery or

the optic apparatus. Among the three large clinical series

described above, which include 262 surgically treated

cases, there has not been a single reported case of new

postoperative neurological deficit or visual decline [8, 9,

19]. Considerations specific to RCCs are mainly based

around the development of postoperative diabetes insipi-

dus; in modern series of cases treated with cyst drainage,

the rates of permanent postoperative diabetes insipidus

have been reported to range from 0 to 9 % [8, 9, 19]. With

more aggressive strategies at attempted complete cyst wall

resection, the rates of new-onset diabetes insipidus are

Fig. 3 Imaging features of RCCs. Sagittal T1 weighted MRI images

showing (a/b) a Rathke’s cleft cyst with T1 isointense cyst contents,

suggestive of low protein cyst contents that will resemble water at

surgery, as seen on pre-contrast (a) and post-contrast (b) images with

the contrast causing the anterior lobe of the gland to brighten, but not

the cyst contents; and c an example of a Rathke’s cleft cyst with

intrinsically T1 bright cyst contents, suggestive of proteinaceous cyst

contents that will resemble mucus at surgery and can be potentially

consistent with inflammation

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reported to be higher, ranging from 19 % to as high as

69 % [8, 9, 38]. With the endoscopic approach, rates of

cerebrospinal fluid leaks reached 9 %, and one of 22

patients developed a new postoperative diabetes insipidus

(5 %) [37].

Recurrence rates after surgical treatment

The reported rates of cyst recurrence after surgical resec-

tion in the published literature vary greatly. Some studies

report very low rates, as low as 0 % [7], and some reports

describe high rates, up to 42 % [40]. Overall, among the

three largest surgical series, the studies by Aho and col-

leagues and Benveniste and colleagues [8, 9] have reported

rates of 18 % recurrence at 5 years, and 16 % recurrence at

2 years, respectively. The endoscopic series reported one

case of recurrence after a mean follow up of 33 months

[37]. Factors associated with higher rates of recurrence in

case series include a purely suprasellar location (3-year

recurrence rates of 29 % vs. 0 % in purely sellar lesions in

same series) [21], inflammation and reactive squamous

metaplasia in the cyst wall (odds ratio 2.6–3.7) [8, 9],

superinfection of the cyst (13–31 % recurrence rates) [16],

and repair strategy using a fat graft in the cyst cavity,

which some feel may prevent cyst marsupialization and

lead to reaccumulation (odds ratio, 17.3) [8, 21] (Fig. 4).

The use hydrogen peroxide of alcohol irrigation in the cyst

cavity, which is thought to kill the single-cell epithelial

lining of the cyst, has been adopted by a number of sur-

geons; however, strong evidence supporting the utility of

this strategy in lowering recurrence rates has yet to be

established [8, 19].

Conclusion

Rathke’s cleft cysts are benign lesions that form from

remnants of the embryologic Rathke’s pouch. While usu-

ally asymptomatic, RCCs, particularly those whose con-

tents are inflammatory, can cause symptoms such as

headaches, endocrine dysfunction, and, rarely, visual dis-

turbances. Symptomatic RCCs warrant surgical resection,

usually through an endonasal transsphenoidal corridor.

Resection via an endoscopic approach appears to have

equivalent rates of symptom resolution, endocrinologic

outcomes and recurrence rates, as results published with

the microscopic approach. While surgery is associated with

minimal morbidity, the natural history of asymptomatic

RCCs is one of slow growth, suggesting that observation

through serial magnetic resonance imaging is appropriate

for smaller, asymptomatic RCCs. For symptomatic RCCs,

surgical resection provides good symptomatic relief of

headaches and visual disturbance, and can even improve

endocrine dysfunction. Recurrence rates are generally low

after resection, on the order of 16–18 %.

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