R E V I E W A R T I C L E

Rathke’s cleft cysts

Raluca Trifanescu*, Olaf Ansorge†, John A. H. Wass*, Ashley B. Grossman* and Niki Karavitaki*

*Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital and †Neuropathology

Department, John Radcliffe Hospital, Oxford, UK

Summary

Rathke’s cleft cysts (RCCs) are benign, sellar and/or suprasellar

lesions originating from the remnants of Rathke’s pouch. Although

a common finding in routine autopsies (12–33% of normal pitui-

tary glands), symptomatic cases are rare and comprise 5–15% of all

surgically resected sellar lesions. Small, asymptomatic RCC do not

require surgical intervention, and their natural history is not clear.

In series of nonoperated presumed RCCs, 26–94% did not progress

during follow-up periods up to 9 years. In symptomatic ones, sur-

gery is indicated, aiming to drain the cyst content and safely

remove as much of the capsule as possible. Following surgical inter-

vention, headaches and visual field defects improve or resolve in a

significant number of patients (40–100% and 33–100%, respec-

tively) and partial hypopituitarism recovers in 14–50%. Data on

relapse rates published in the last 15 years are based on variable fol-

low-up periods and show wide variation (between 0% and 33%).

The lowest relapse rates have been described in reports with rela-

tively short mean observation periods (<3 years), whereas in those

with longer follow-up the relapse rates increase. Most of the

relapses occur within 5–6 years, suggesting that follow-up is

required for at least 5 years after surgery. Risk factors for relapse

include the presence of squamous metaplasia in the cyst wall, cyst

size and the presence of inflammation. Long-term sufficiently pow-

ered studies aiming to clarify the natural history of asymptomatic

RCCs and of those relapsing postoperatively are required.

(Received 31 July 2011; returned for revision 17 August 2011;

finally revised 19 September 2011; accepted 20 September 2011)

Introduction

Rathke’s cleft cysts (RCCs) are benign, sellar and/or suprasellar

lesions1 originating from the remnants of Rathke’s pouch.2 They

are named after the German anatomist Martin Heinrich Rathke,

who described the evagination process of the anterior foregut in

1838.3 Luschka in 1860 and then Goldzieher in 1913 published the

first cases of RCCs as incidental postmortem findings. Although a

common finding in routine autopsies (12–33% of normal pituitary

glands), symptomatic cases are relatively rare.4 Their presenting

manifestations are associated with the compression of adjacent

structures (usually headaches, visual disturbance and pituitary hor-

mone deficits).5–10 Treatment of the symptomatic cases is surgical.

The incidental detection of RCC has increased because of the

improvements in imaging techniques and the increased frequency

of brain scans, but at present their natural history and optimal

management protocols have not been clearly established.

In this review, we will highlight the clinical and laboratory char-

acteristics of RCCs, evaluate the current literature on their treat-

ment and propose a management protocol.

Epidemiology

Rathke’s cleft cysts are the most common incidentally discovered

sellar lesions, followed by pituitary adenomas. In routine autopsies,

they are encountered in 13–33% of normal pituitary glands.11,12 In

a retrospective review of 2598 subjects undergoing at least one pitu-

itary MRI scan from 1999 to 2009 in a tertiary pituitary centre,

nonadenomatous sellar masses accounted for 18% of visible

lesions, of which the most frequent were RCCs (19%).13 They have

been reported in all age groups, with a peak frequency between the

4th and 6th decades.8,14–19 Data from a nonselected autopsy series

suggested that RCCs measuring >2 mm were found in up to 4% of

subjects older than 30 years.12 Cases in paediatric populations have

been reported,20,21 but are generally rare. This may be attributed to

the fact that RCCs grow slowly with time and therefore, become

clinically evident later in life. Notably, in 44 autopsy specimens

from children aged <9 years, no RCC measuring >2 mm was

reported.12 However, MRIs performed in 341 children aged

<15 years revealed cystic pituitary lesions in four of them (1Æ2%);

these were sharply demarcated and situated just posterior to the

anterior pituitary lobe, highly suggestive of RCCs.20

Published reports have suggested a female preponderance with a

female/male ratio up to 3.9,10,14–16,18,19,22–24 Menstrual irregularity

may lead to earlier detection in women, possibly explaining this

finding.10 Furthermore, apoplexy of the pituitary gland on the

background of a RCC has been described more commonly in

women (female/male ratio of 15:5).25 No ethnic differences have

Correspondence: Niki Karavitaki, Department of Endocrinology, Oxford

Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital,

Old Road, Headington, Oxford OX3 7LJ, UK. Tel.: +44 186 585 7307;

Fax: +44 186 585 7311; E-mail: nikikara@doctors.org.uk

Clinical Endocrinology (2012) 76, 151–160 doi: 10.1111/j.1365-2265.2011.04235.x

� 2011 Blackwell Publishing Ltd 151

been recognized. Symptomatic cases are rare and constitute 5–15%

of all surgically resected sellar lesions.5,7,8,15,16,19,26–29.

Pathogenesis

Rathke’s cleft cysts originate from embryonic remnants of Rathke’s

pouch,30 which appears on the 24th day of embryonic life as a dor-

sal diverticulum from the ectodermal stomodeum (primitive oral

cavity) and is lined by simple ciliated columnar epithelium. Rath-

ke’s pouch extends cranially to form the craniopharyngeal duct

while, simultaneously, the infundibulum forms from the dienceph-

alon as a downgrowth of the neuroepithelium. By the 5th week of

gestation, Rathke’s pouch comes into contact with the infundibu-

lum,2,31 and by the 7th week, it separates from the oral cavity.

Between the 3rd and the 5th month, cells in the anterior wall of

Rathke’s pouch proliferate rapidly to form the pars anterior of the

pituitary and cells in the posterior wall differentiate into the pars

intermedia. Meanwhile, the infundibulum gives rise to the median

eminence, the pituitary stalk and the posterior pituitary lobe.32

Obliteration of the craniopharyngeal duct is associated with invo-

lution of the pouch. Failure of obliteration of the lumen results in

the development of a cyst between the pars distalis and the pars

nervosa.19,31,33 Remnants in the craniopharyngeal canal may result

in a spectrum of cystic lesions ranging from simple RCCs to com-

plex craniopharyngiomas. Notably, it has been proposed that

craniopharyngiomas and RCCs may represent a continuum of

ectodermally derived epithelial masses (also including neuro-

epithelial cysts, epidermoid and dermoid cysts).34

Other theories on the pathogenesis of RCCs propose an origin

from the neuroepithelium35 or from metaplasia of anterior pitui-

tary cells,36 but these explanations seem unlikely.32 Despite the

reported association of RCCs with pituitary adenomas, there is no

evidence for a direct metaplastic origin of these cystic lesions from

adenomas or vice versa.37

Pathology

Rathke’s cleft cysts are benign cystic lesions with a reported size

ranging from a few mm to 5 cm.15,32,38 Their content is usually a

thick, mucoid material consisting of cholesterol and protein,1

which in surgical series has been described as yellowish (15–37%),

mucoid (51–70%) or gelatinous (10%).5,8–10,22 Cerebrospinal

fluid-like or light brown and motor oil-like or milky contents have

also been reported.9,28

The cyst wall is lined by simple cuboidal or columnar epithelium

with or without cilia and occasionally goblet cells secreting mucous

into the cyst (Fig. 1).39 Pseudostratified, columnar, ciliated respira-

tory-type epithelium may be present in up to 49% of cases.8,9,28.

Squamous metaplasia (making them occasionally indistinguishable

from craniopharyngiomas)9 and nodules (at surgery, yellow, waxy,

solid masses) of mucinous material (containing mainly cholesterol

and protein) connected or not with the cyst wall8,11,14,40 may also

be seen. Notably, it has been demonstrated that the Ki-67 index

[the fraction of Ki-67 positive cells (Ki-67 protein: cellular marker

for proliferation)] of the squamous epithelium is higher than that

of the simple or pseudostratified epithelium observed in other parts

of the cyst.27 Other reported pathological findings include choles-

terol clefts (up to 23%), necrotic debris and fibrosis (up to 15%),

keratin nodules, haemosiderin and blood (when presenting with

haemorrhage). An inflammatory reaction penetrating the cyst

(a) (b)

(c) (d)

Fig. 1 The typical epithelial lining consists of tall epithelial cells with cilia (a, arrow). The epithelium expresses cytokeratins (b, Cam5.2 antibody, brown

reaction product, arrow) and may be mucin-rich (c, PAS, arrow). Long-standing cyst epithelium may show pressure atrophy (d, arrows), resulting in flat

epithelium without cilia (note clefted cyst contents). In some instances, squamous metaplasia may be pronounced, making distinction from other epithelial

lesions difficult. All magnifications · 600.

152 R. Trifanescu et al.

� 2011 Blackwell Publishing Ltd, Clinical Endocrinology, 76, 151–160

epithelium or subjacent stroma has been reported in up to 50% of

symptomatic RCCs. In such cases, the cyst wall undergoes changes

from a single-layered to stratified epithelium, depending on the

stage of inflammation.41 The inflammation is a foreign-body reac-

tion to the cystic content with the most prominent histological

findings at sites of rupture of the cyst wall, suggesting secondary

hypophysitis.5,9,41,42 Hypophysitis has been described sometimes

associated with pregnancy.42,43 The presence of inflammation and

associated oedema may result in destruction of the adjacent pitui-

tary gland, and it has been proposed that inflammation rather than

simple compression is responsible for the development of pituitary

hormone deficits.5,6,8,9,41 The formation of an abscess in the cyst

has been also reported.44

Overlapping pathological features between RCC and cranio-

pharyngiomas may pose difficulties in the differential diagnosis of

these two lesions. The distinction between a papillary craniophar-

yngioma and a RCC may be difficult, particularly in small biopsy

specimens, because of the capacity of the epithelial lining of the

RCCs to undergo squamous differentiation; in such cases, the lack

of a solid component and the presence of extensive ciliation and/or

mucin production are suggestive of Rathke’s.45 Furthermore, it has

been proposed that RCCs show a cytokeratin expression pattern

distinct to that of craniopharyngiomas: in contrast to craniophar-

yngiomas, RCCs express cytokeratins 8 and 20 (as also the pars

intermedia)46 and craniopharyngiomas show aberrant nuclear

staining for b-catenin37,47; these findings may be useful in the

differential diagnosis.

Co-existence of RCCs with pituitary adenomas has been

reported: GH secreting pituitary adenomas48 and prolactino-

mas9,10,49,50 are the most frequently described, followed by cortico-

troph4,9,37,49,51 or nonfunctioning pituitary adenomas.4,8,49 In a

large series of pituitary adenomas, co-existence with RCC has

been reported in 0Æ5–1Æ7% of the cases52; this is probably merely

co-incidental.

Location

Rathke’s cleft cysts typically present as intrasellar and/or suprasel-

lar cysts, rarely occupying only the suprasellar region.53 They typi-

cally lie in the pars intermedia, between the anterior and posterior

pituitary lobes.20,54 In a nonselected autopsy series of one thou-

sand pituitary glands, 87% of all medially situated lesions (33/38)

were RCCs; in contrast, 74% (17 out of 23) of the laterally located

ones were pituitary adenomas.12 Suprasellar extension has been

demonstrated in 16–97% of RCCs.5,8,10,15,17,27,49 Rare cases in

which the lesion is intrasphenoidal or with lateral extension into

the cavernous sinus, or extending into the frontal area, have been

reported. Interestingly, a tumour located in the cerebellopontine

angle and a second one with a giant retroclival RCC extending to

the lower prepontine cistern with brain stem compression have

also been published.38

Presenting manifestations

Small cysts are asymptomatic and their detection is usually inciden-

tal. When they are large enough to cause pressure effects on adja-

cent structures, they result in chronic clinical manifestations

mainly headaches, visual disturbance and pituitary dysfunction.

Occasionally, acute symptoms and signs may be present mimicking

pituitary apoplexy.8,18,25,49,55 The mean duration of clinical mani-

festations until diagnosis ranges from 3 days to 156 months (most

commonly between 9 and 24 months).4,8,10,14,25,39,49 The reported

signs and symptoms at presentation are shown in Table 1.

Headache is the most prevalent manifestation both at diagnosis

as well as in cases of recurrence, with reported frequencies between

33% and 81%.4,6,8–10,14–19,21,22,24,28,39,49,51,56 Frontal, episodic,

nonpulsating, bilateral headache or deep retroorbital pain are the

most common, but pain may also affect the occipital or temporal

region or involve the whole head.22 Chronic and/or continuous

headache is present in about 60% of the cases, and it may be the

only presenting manifestation in 40%.9,22 Headaches do not usually

correlate with the cyst size, location or the presence of pituitary

dysfunction, but are related to either high or isointense content on

T1-weighted MRI, mucous cyst content or intense chronic cyst wall

inflammation.9,22 Given that inflammation may result in pituitary

damage,8,9,28,41 it has been suggested that episodic frontal head-

aches may indicate an intermittent inflammatory reaction,22 and

surgical treatment is required to prevent further irreversible

endocrine dysfunction.22 Major visual field defects have been

demonstrated in up to 75% of the cases4,8–10,14–16,18,22,24,26,39,49 and

correlate with cyst size.9 Cranial nerve palsies have been rarely

described.18

Anterior pituitary hormone deficits at presentation vary widely

between 19% and 81% depending on the number of the affected

reported axes and the diagnostic tests used.6,8–10,14–

Table 1. Manifestations at presentation in patients with Rathke’s cleft cysts

References

No of

patients

Headache

(%)

Visual

disturbances

(%)

Pituitary

hormone

dysfunction

(%) (one or

more axes

affected)

Trifanescu et al.49 33 67 58 58

Xie et al.65 23 65 39 26

Wait et al.24 73 75 39 49

Madhok et al.17 35 81 – 19

Nishioka et al.22 46 59 35 24

Nishioka et al.9 37 49 38 24

Aho et al.26 118 – 49 66

Benveniste et al.5 62 71 20 55

Kim et al.8 53 81 47 –

Kasperbauer

et al.56

29 55 – 66

Isono et al.15 15 33 33 60

Shin et al.10 26 65 38 81

Mukherjee

et al.412 50 75 25

(panhypopituitarim)

Eguchi et al.6 19 – 47 47

Ross et al.23 43 44 12

Volker et al.19 155 49 56 39

Rathke’s cleft cysts 153

� 2011 Blackwell Publishing Ltd, Clinical Endocrinology, 76, 151–160

19,21,22,24,26,28,39,56 Hypogonadism with amenorrhoea/impotence or

low libido and galactorrhoea because of hyperprolactinaemia (10–

46%) were the most frequent hormonal manifestations.8,10,15,18,26,28

In a recently published series of surgically-treated RCCs, gonado-

trophin deficiency was found in 60%, ACTH deficiency in 36%,

TSH deficiency in 36% and hyperprolactinaemia in 31% of the

cases.49 GH deficiency (using variable criteria) has also been

reported in 12–79% of the patients.5,6,10,26 It has been suggested

that hypopituitarism does not correlate with cyst size and is found

only in patients with high or iso-intensity cyst on T1-weighted

MRI.9 Preoperatively, the frequency of diabetes insipidus varies in

the range 0–19%7–10,18,22,26,28,49 and is also found in patients with

high or iso-intensity cysts on T1-weighted MRI.9 Inappropriate

antidiuretic hormone secretion with hyponatraemia has also been

rarely reported.4,5,9,18

Apoplexy on the background of a RCC is an uncommon form of

presentation,8,18,25,55 and intracystic haemorrhage may or may not

be detected intraoperatively.55 The clinical picture is difficult to

distinguish from that of patients with apoplexy on the background

of a pituitary adenoma, and includes sudden onset of severe head-

ache or sudden increase in headache severity accompanied by

visual disturbance, nausea and vomiting, meningismus, oculomo-

tor palsies with diplopia, impairment of pituitary function25,55 and,

occasionally, alterations in mental status.25 The duration of head-

aches varies from hours to months, with most patients describing it

for 1–2 weeks.25

Aseptic meningitis followed by visual loss has been rarely

reported in adults5,22 and children21 and is attributed to rupture of

the cystic content into the subarachnoid space or to extension of

the inflammation into surrounding structures.22 Other rarely

described presenting manifestations include sphenoid sinusitis,

syncope, seizures,5,16 ataxia,57 mood disturbance16,57 and preco-

cious puberty.

Imaging features

Currently used tools for the radiological characterization of RCCs

include CT and MRI. They usually appear as well-circumscribed,

spherical, ovoid or dumb-bell sellar lesions in the region of the pars

intermedia7,32; lobular protrusion has been seldom reported. The

maximum diameter of the cyst ranges between 5 and 50 mm (usu-

ally between 10 and 20 mm).9,10,14,18,21,32,39 The normal pituitary

gland may be displaced in any direction, and its position is usually

around or under the cyst.9,28,32 In the latter case, the sign of ‘the egg

in a cup’ is very suggestive of an RCC.58

On CT, they usually appear as low or isodensity homogeneous

lesions or with slight hyperdensity relative to the brain paren-

chyma9,10,39 with or without enhancement. The enhancement is

ring-like or capsular.9 On MRI, they usually appear as well-demar-

cated cystic lesions with homogeneous intensity signal sometimes

combined or not with thin cyst wall enhancement.8,20,54,59 The thin

peripheral rim of enhancement has been attributed to inflamma-

(iii)

(a)

(b)

(i) (ii)

(i) (ii)

Fig. 2 MRIs of Rathke’s cleft cysts: (a) coronal (i) and sagittal (ii) T1-weighted postgadolinium images showing low signal intensity and rim enhancement.

The same cyst demonstrated hyperintense signal on T2-weighted images (shown with arrow) (iii). (b) Coronal (i) and sagittal (ii) T1-weighted images show-

ing hyperintense signal.

154 R. Trifanescu et al.

� 2011 Blackwell Publishing Ltd, Clinical Endocrinology, 76, 151–160

tion or deposition of haemosiderin or cholesterol crystals or to

squamous metaplasia of the cyst wall or to a circumferential rim of

displaced pituitary gland.8,14,32,58 The signal intensity varies widely

(hypo- iso- or hyperintense)10,15,28,53,60 and depends on the cyst

content (Fig. 2a,b).60 Lesions displaying hypointensity on T1-

weighted images and hyperintensity on T2-weighted ones contain

CSF-like fluid; those with hyperintensity on T1-weighted images

and isointensity on T2-weighted ones contain mucoid material and

hyperintensity on both T1- and T2-weighted images suggest the

presence of blood. Cysts with a high protein concentration show

high T1 signal intensity and usually have a low intracystic water

content leading to T2 signal decrease.9,54 Hyperintensity on T2

images has been described in about 70% of cases; nevertheless,

homogeneous T2 hypointense signal intensity is highly suggestive

of RCC,61 and this is useful in the differential diagnosis from chor-

domas, chondroid tumours, abscesses, mucoceles and lipomas, all

showing a hyperintense T2 signal.54 Small intracystic nodules, cor-

responding to proteinaceous concentrations, may be seen in 17–

77% of RCCs and present with low signal intensity on T2-weighted

and high signal intensity on T1-weighted images compared with

that of the surrounding cyst fluid.40,53,55 The nodules do not

enhance and are virtually pathognomonic for RCCs.54 In cases of

apoplexy on the background of a RCC, mixed signal intensities

have been described.55

A combination of a number of MRI findings may be useful for

the preoperative differential diagnosis of intra- and suprasellar

masses. An ovoid shape, small tumour volume, cystic characteris-

tics and little or no cyst wall enhancement suggest an RCC. A

‘snowman’ shape, solid characteristics and homogeneous enhance-

ment of the solid portion suggest a pituitary adenoma (Fig. 3a). A

superiorly lobulated shape, third ventricle compression, mixed

solid and cystic characteristics and reticular enhancement of the

solid portion suggest a craniopharyngioma (Fig. 3b).59 Particularly

in comparison with craniopharyngiomas, RCCs are smaller and

rarely show calcification (up to 13% of cases).10 Other cystic lesions

included in the differential diagnosis are dermoid cysts (on CT,

round or lobulated, often with negative density values and foci of

calcification; no contrast enhancement or surrounding oedema; on

T1-weighted MRI, high signal, because of the lipid content), epi-

dermoid cysts (on CT, a lobulated mass with attenuation values

similar to CSF; calcification may be present; MRI signal character-

istics are usually similar to CSF; it does not enhance, but shows

(a)

(b)

(i) (ii)

(i) (ii)

Fig. 3 (a) Coronal (i) and sagittal (ii) T1-weighted

images of pituitary adenoma arising out of the pitu-

itary fossa and compressing the optic chiasm show-

ing ‘snowman’ shape and uniform signal. (b)

Coronal (i) and sagittal (ii) T1-weighted postgado-

linium images of a craniopharygioma with superi-

orly lobulated shape and mixed solid and cystic

characteristics.

Rathke’s cleft cysts 155

� 2011 Blackwell Publishing Ltd, Clinical Endocrinology, 76, 151–160

restricted diffusion on diffusion weighted images), arachnoid cysts

(cystic lesion with a clearly defined border; the density on CT and

the signal intensity on MRI are similar to that of the CSF; it does

not show calcification and does not enhance after contrast admin-

istration) and an abscess (on CT, a central area of hypodensity sur-

rounded by a ring of increased density, which shows marked

enhancement following intravenous contrast material; on MRI, the

T1-weighted images show a marked hyperintense lesion with sig-

nificant enhancement of the abscess wall after contrast administra-

tion; T2-weighted scans show hyperintensity of the abscess

contents surrounded by an area of increased signal intensity indi-

cating oedema).45

Natural history

The natural history of both symptomatic and asymptomatic RCC

is not clear. In series of nonoperated presumed RCCs, 26–94% of

them did not progress (based on imaging studies or on the

clinical picture) during follow-up periods up to 9 years.9,21,26,62

Notably, in a cohort of 29 patients with symptomatic cystic sellar

lesions and imaging characteristics consistent with RCC managed

with surveillance, spontaneous involution was described in nine

cases (31%) that had a further follow-up of 9–46 months after

the regression. Furthemore, headaches spontaneously resolved in

five of seven patients presenting with this symptom.63 Possible

mechanisms of cyst regression include absorption of cystic fluid

greater than secretion or repeated cyst ruptures and leakage.63

On the other hand, Sanno et al.62 reported that 5Æ3% of inciden-

tally found presumed RCCs increased in size during a mean

follow-up period of 38Æ9 months (range 6–93). The change in the

cyst size is probably associated with an imbalance between secre-

tion and absorption of the cyst content, intracystic haemorrhage

or infection.

Treatment

Small, asymptomatic RCC do not require surgical intervention. In

symptomatic ones, surgery is indicated aiming to drain the cyst

content and safely remove as much of the capsule as possible.26

Cyst fenestration and drainage via an endonasal/sublabial trans-

sphenoidal approach are most commonly adopted5,17,21,26,29,39

and are usually successful in achieving improvement of the pres-

sure effects. The endoscopic transsphenoidal approach has also

been used.64,65 Intraoperative alcohol cauterization has been used

with, however, no proven benefit on relapse rates.5,16 Furthermore,

significant neurological complications from the alcohol cauteriza-

tion have been described (including seizures and cranial nerve pal-

sies), and hence, this treatment approach should be avoided.66

Radiotherapy is not routinely required, but it has been used in a

small number of recurrent cysts with promising results, suggesting

that this option may be considered for particularly multiple

relapses aiming to avoid the risks of repeated surgeries.4,16

The surgical management of RCC presenting with pituitary apo-

plexy depends on the clinical picture: for those with visual deficits

or endocrine disturbance transsphenoidal surgical intervention is

recommended, whereas in cases of headaches only without cranial

nerve deficits and no evidence of haemorrhage on gradient-refo-

cused T2-weighted images, conservative management may be an

option.55 The role of conservative therapy with glucocorticoids in

the acute phase has not been clarified. Recovery of pituitary func-

tion has been described after surgery.25

Postoperative complications include a CSF leak (up to

25%),8,9,18,65 transient and/or permanent diabetes insipidus (up to

67% and up to 20%, respectively),4,9,18,21,65 anterior pituitary hor-

mone deficits, hyponatraemia,5,16 meningitis and sinusitis. Cyst

infection has been reported reaching 12% in a series of 170 cases,

with the most common isolated organisms being Staphylococcus

Table 2. Recurrence rates of Rathke’s cleft cysts following surgical intervention

Author No of patients Years covered by the cohort of patients Recurrence rate (%) Follow-up (months)

Trifanescu et al.49 32 1978–2009 22

12 at 2 years

48 at 4 years

Mean 48 (range 2–267)

Xie et al.65 23 – 8Æ7 Range 3–36 months

Wait et al.24 73 1992–2010 10Æ9 Mean 27 months (range 0–129)

Madhok et al.17 35 1998–2008 6Æ3 Mean 19 months (range 1–60)

Zada et al.21 10 1999–2007 10 Median 34 months

Koutourousiou et al.51 14 2004–2007 14Æ3 Median 29 months (range 11–48)

Nishioka et al.22 33 – 21Æ2 Mean 42 months (range: 6–112)

Aho et al.26 118 1984–1995 18 At least 60 months

Sade et al.28 10 1994–2003 0 Mean 32 months

Benveniste et al.5 62 1989–2003 16 Mean 28 months (range: 1–166)

Kim et al.8 53 1990–2000 11Æ3 Mean 31 months (range: 2–95)

Billeci et al.14 14 – 14Æ3 Range: 6 months–10 years

Kasperbauer et al.56 29 1978–1998 28 –

Isono et al.15 15 1992–1999 6Æ7 Range 1–7 years

Shin et al.10 26 1974–1998 19 Mean 35 months

Mukherjee et al.4 12 1981–1996 33 Mean 30 months (range 1–168)

156 R. Trifanescu et al.

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epidermidis and Propionibacterium acnes.67 There is no reported

perioperative mortality.5,9,10,16,18,26

Headaches5,8–10,14–17,21,22,24,26,28,39 and major visual field

defects5,8–10,14–17,22,24,26,28,39,49,56 improve or resolve in a significant

number of patients (40–100% and 33–100%, respectively), and hy-

perprolactinaemia is the most frequently resolved pituitary hor-

mone abnormality (in most series, in 100%).6–10,14,16,19,26,28,56

Partial hypopituitarism may recover postsurgery (14–

50%),9,10,16,17,21,26,39 whereas panhypopituitarism seldom

resolves.14,15,28 The poor endocrine prognosis could be due to

intense chronic inflammation of the adenohypophysis or neurohy-

pophysis.5,8,9,28,41 Notably, in one series, all patients with panhypo-

pituitarism had RCCs of high intensity on T1, contained mucous

material with high viscosity, demonstrated intense inflammation

on histology and did not improve their pituitary dysfunction after

surgery.9

New anterior pituitary hormone deficits following surgical inter-

vention have been reported in 4–30% of the cases5,7,8,10,17,19,21,26,28

and new diabetes insipidus between 2% and

67%.5,7,9,10,16,18,21,26,28,39,49,51,68 It has been proposed that aggres-

sive surgery with resection of the cyst wall is more commonly asso-

ciated with new endocrine morbidity.5,16,26 Interestingly, in a series

of 857 patients who underwent transsphenoidal microsurgery,

those with an intraoperative CSF leak, with a craniopharyngioma

or with an RCC were at higher risk for persistent diabetes insipidus

(DI).68 In this series, immediate postoperative and persistent DI

were found in 38Æ7% and 10%, respectively of the patients with

RCC.68

Data on the endocrine and visual outcome after long-term fol-

low-up are rather limited, but in a recently published series of 33

cases of RCCs with a mean follow-up of 48 months at last assess-

ment, 50% had gonadotrophin deficiency, 42% ACTH deficiency,

47% TSH deficiency, 39% required desmopressin treatment and

19% had at least quadrantinopia.49

Relapse rates and risk factors for relapse

The vast majority of the series published in the last 15 years report

recurrence rates only (and not survival data) during variable fol-

low-up periods and show wide variation (between 0% and 33%;

Table 2). Notably, the lowest relapse rates have been described in

reports with relative short mean observation periods (<3 years),

whereas in those with longer follow-up the relapse rate increases.

In a recently published series with a mean follow-up of 48 months,

one of the longest in the literature, survival analysis showed a recur-

rence rate of 48% at 4 years,49 suggesting that the previously

thought optimal course of RCCs may not reflect their true progno-

sis and long-term monitoring is needed. It should be also noted

that the different definitions of relapse (asymptomatic or symp-

tomatic, requiring or not surgical intervention) may explain the

wide variation in the relapse rates.

Relapses have been detected at intervals ranging between 4 weeks

up to 24 years4,5,8,10,14,15,56 with most of them occurring within the

first 5–6 years,8,10,14,16,18,21,26,51 suggesting that follow-up is

required for at least 5 years after surgery. It has been proposed that

there is a positive correlation between cyst size and time to recur-

rence.10 Although rare, multiple relapses have also been

described.5,14,16,18,49

Factors reported to be associated with an increased risk of recur-

rence include the presence of squamous metaplasia in the cyst

wall,5,8,16,24,26,32 cyst size,10 residual cyst demonstrated on postop-

erative MRI,8,18 enhancement of the lesion on MRI,5,8 use of

abdominal fat and/or fascial graft for closure (probably by increas-

ing the risk of loculation and reformation of the cyst),26 intraopera-

tive CSF leak16 and the presence of inflammation (probably

through promoting squamous metaplasia or encapsulation of the

cyst and facilitation of the accumulation of fluid – furthermore,

inflammation is considered to be a marker of more rapidly grow-

ing, highly secretory cysts).5,8 Suspected RCC infection is a strong

Presumed RCC on imaging

Pressure effects(headaches, visual deterioration, hypopituitarism)

No Yes

1. Yearly clinical follow-up and MRI at 1, 3 and 5 years.

1. Surgery (cyst aspiration saferemoval of cyst wall)*

2. Yearly clinical follow-up and formal visual fields assessment

3. Yearly clinical follow-up and formal visual fields assessment (imaging if indicated) for 5 years

Yes No

Increase in size

No Yes

Relapse

Clinical follow-up(duration?)

Clinical follow-up(duration?)

* In case of multiple relapses external irradiation may be considered

2. Yearly MRI for 5 years

Fig. 4 Management algorithm for Rathke’s cleft

cysts (RCCs).

Rathke’s cleft cysts 157

� 2011 Blackwell Publishing Ltd, Clinical Endocrinology, 76, 151–160

predictor of recurrence and may warrant antibiotic treatment.

With antibiotics, the recurrence rate of infected cysts (13%)

approaches that of noninfected ones (9%).67 The data on extent of

resection/aggressiveness of surgery and risk of relapse are not

consistent. A number of series suggest similar recurrence rates fol-

lowing radical (8–18%) or less radical resection (11–21%).16,26

Benveniste et al.5 showed that the relapse rate was 0% after aggres-

sive resection of the cyst wall and 18% after decompression and cyst

wall biopsy, but the difference did not reach statistical significance,

whereas Kim et al.8 showed that the extent of cyst removal was a

significant risk factor for relapse. Finally, simple cyst drainage

followed by cyst biopsy (without vigorous wall removal) and with

intraoperative alcohol cauterization showed an increased recur-

rence rate at 3 months (12Æ9%) compared with the nonalcohol

treatment group, but the difference was not significant.16

The optimal therapy of recurrent RCCs is unclear. In asymptom-

atic cases, imaging surveillance could be adopted, whereas in symp-

tomatic ones, aspiration and, where possible, removal of the cyst

wall have been used.4,49 External beam pituitary radiotherapy after

surgical intervention for a recurrent mass has also been reported,

although the role of irradiation in preventing further relapse has

not been clarified.4

Conclusions/Management algorithm

Rathke’s cleft cysts are the most common incidentally discovered

sellar lesions followed by pituitary adenomas. In routine autopsy,

they are encountered in 13–33% of normal pituitary glands and

typically lie in the pars intermedia, between the anterior and pos-

terior pituitary lobes. Small cysts are asymptomatic and their

detection is incidental. When they are large enough to cause pres-

sure effects on adjacent structures, they result in chronic clinical

manifestations, mainly headache, visual disturbance and pituitary

dysfunction. The limited number of series of asymptomatic Rath-

ke’s cleft cysts suggests that yearly clinical surveillance (with imag-

ing at 1, 3 and 5 years for the first 5 years) is a reasonable option,

but its duration, at present, is not clear. Symptomatic patients

require surgical intervention aiming to drain the cyst content and

possibly safely remove the capsule. In such cases, headaches and

visual field defects resolve/improve considerably, but the long-term

endocrine morbidity (as a result of the Rathke’s cleft cysts and/or

its treatment) is not negligible. Series with long observation peri-

ods show that the relapse rates are higher than previously thought

necessitating close follow-up with 12-monthly scans for at least

5 years after surgery. Based on the significant literature available,

our proposed management algorithm is shown in Fig. 4. Further

long-term sufficiently powered studies aiming to clarify the natural

history of asymptomatic Rathke’s cleft cysts and of those relapsing

postoperatively and to establish a clear consensus on the optimal

therapeutic approach are required.

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