Introduction

Benign pituitary cysts are a common finding in autopsy studies and can occasionally become large enough to cause symptoms by compression of the intrasellar or suprasellar structures. Although cysts in the sella and suprasellar region are a diverse group of entities, they are often indistinguishable on the basis of clinical and radiographic findings, and a diagnosis can often be made only by gross and histologic examination.

Pituitary adenoma with cystic degeneration is the most common intrasellar cyst, and it as well as other neoplastic processes in the pituitary gland and sella turcica are discussed elsewhere. Epithelial cysts', including craniopharyngioma, Rathke's cleft cysts, and epidermoid cysts, represent another group of intrasellar lesions, which differ from the first in that they can be considered primarily cystic. Although these cysts have traditionally been thought of as separate entities, there are convincing reasons for considering them as a group, and it is likely, although not proved, that they have a common ancestry. Histologically they appear to make up a spectrum ranging from craniopharyngioma, the most complex, to the single-cell-layered Rathke's cleft cyst, the simplest. The craniopharyngioma, the most common and no doubt the most often studied, is reviewed in detail elsewhere, and is considered here only as it relates to the group as a whole. Here the focus on the various epithelial cysts, and specifically the Rathke's cleft cyst.

Pathogenesis and Histology

Although the pathogenesis of these lesions is by no means clear, it is generally believed that the cells of origin are derived from or are remnants of Rathke's pouch. Rathke's pouch appears during the third or fourth week of embryonic life as an outgrowth of stomodeum and elongates dorsally to form the craniopharyngeal duct. By the 11th week, the proximal end of this duct is obliterated, while the cranial portion comes into contact with the infundibulum, a protrusion of the third ventricle. The anterior wall of the pouch proliferates to form the anterior lobe of the pituitary gland and the pars tuberalis; the posterior wall becomes the pars intermedia. The residual lumen of the pouch is reduced to a narrow cleft which generally regresses. It is the persistence and enlargement of this cleft that is said to be the cause of symptomatic Rathke's cleft cysts. Lined by a single layer of epithelium, which is frequently ciliated and often contains goblet cells, the cleft wall is histologically similar to the single-cell-layered Rathke's cleft cyst. Shanklin found such clefts in 13 of 100 human autopsy specimens; most were small, the largest measuring 2 x 3 mm. Small nests of squamous epithelium, particularly at the junction of the pars tuberalis and the stalk, which are often seen as incidental findings in human autopsies, have been widely accepted as remnants of Rathke's pouch and are thought to be the cells of origin of craniopharyngiomas and suprasellar epidermoid cysts. Other theories for the formation of Rathke's cleft cysts postulate that the cells of origin are derived from neuroepithelium or from endoderm.

Rathke's cleft cysts in their simplest form are generally composed of cuboidal or columnar epithelium on a basement membrane. These cells are frequently ciliated, and often many mucous-producing goblet cells are seen. Immunohistochemical studies of asymptomatic Rathke's cleft cysts reveal columnar or cuboidal epithelium cells that are positive for at least one of the pituitary hormones. In contrast, in symptomatic Rathke's cleft cysts, the partially stratified squamous and partially squamous epithelium contains none of the pituitary hormones. Ikeda and colleagues postulate that in symptomatic cysts, the monolayer epithelium might undergo squamous metaplasia, and the cells that are positive for pituitary hormones change into nongranulated cells. Immunohistochemistry with monoclonal and polyclonal antibodies reveals the presence of cytokeratins, vimentin, and glial fibrillary acidic protein (GFAP) in epithelial cells of Rathke's cleft cysts.

Squamous epithelial cells can be found in Rathke's cleft cysts. These can either be simple or stratified squamous components, and they may be mixed with columnar or cuboidal epithelial cells in the cyst wall. It appears that these complex Rathke's cleft cysts represent a transitional form between the simple, single-layered Rathke's cleft cyst and craniopharyngioma. Rathke's cleft cysts and craniopharyngioma may therefore be closely related and might share a common cellular origin from Rathke's pouch. Yoshida and colleagues described a complex Rathke's cleft cyst containing columnar as well as stratified squamous epithelium. In tissue culture, this tumor and a craniopharyngioma both grew prickle cells with microvilli and desmosomes; the authors suggested that both tumors had a common cell origin In contrast, Russell and Rubinstein disagree, and classify these transitional forms as true Rathke's cleft cysts with extensive squamous metaplasia.

Clinical Presentation

Rathke's cleft cysts are most often small and asymptomatic; they are found in 2.t0 26 percent of subjects in routine autopsy series. Occasionally they become large enough to cause symptoms by compression of intrasellar and suprasellar structures. At least 155 symptomatic Rathke's cleft cysts have been reported in the literature. The lesion may become symptomatic in childhood, but most reported cases have been in adults, with an even age distribution from the second to the sixth decade. Shanklin found no sex difference in his autopsy series of ciliated epithelial cysts, but others report that symptomatic Rathke's cleft cysts occur more often in female than male patients by a 2: 1 margin.

As with other tumors arising in this region, the clinical presentation of a Rathke's cleft cyst is related to the extent of compression of the pituitary gland and the surrounding structures. When symptoms occur, they cannot be distinguished from those caused by other mass lesions. The most common presenting symptoms are pituitary dysfunction (70 percent), visual field defects (55 percent), and headaches (50 percent). Hypopituitarism is the most common hormonal abnormality, and hyperprolactinemia, with or without amenorrhea and galactorrhea, is the second most common.

Mild to moderate elevations of serum prolactin levels, also seen with other non secreting tumors in this location, are presumably due to interference with prolactin-inhibiting factor at the stalk level or above. Gonadotropin failure is generally responsible for the early symptoms; failure of growth hormone secretion, thyroid and adrenal dysfunction, and diabetes insipidus generally occur later.

When the cyst expands beyond the confines of the sella, visual disturbances owing to compression of the optic chiasm and optic nerves occur. These usually include bitemporal hemianopsia and decreased visual acuity. Hydrocephalus and a resulting increase in intracranial pressure may be caused by deformation of the foramina of Monro. Aseptic meningitis, presumably caused by leakage of cyst contents into the subarachnoid space, has been reported in some cases of Rathke's cleft cyst. A case of pituitary apoplexy caused by hemorrhage into a Rathke's cleft cyst has been reported.

Differential Diagnosis

The differential diagnosis of intrasellar and suprasellar cystic lesions includes a wide variety of pathologies. Non-neoplastic intrasellar cysts include craniopharyngiomas. Rathke's cleft cysts, pars intermedia cysts, arachnoid cysts, mucoceles, cysticercosis cysts, and the "empty sella." The most common cystic lesion in the sella is a cystic pituitary adenoma, which can be formed either by necrosis or by intratumoral bleeding. Although differentiating among these various cysts can be difficult on clinical and radiographic examination, high resolution computed tomography (CT) and especially magnetic resonance imaging (MRI) make differentiation much more possible than in the past. The CT and MRI properties of Rathke's cleft cysts are quite variable, but some authors think that cystic pituitary adenomas and cystic craniopharyngiomas can be differentiated from Rathke's cleft cysts.

Pars intermedia cysts were the most common cysts in Baskin and Wilson's series of 38 non-neoplastic intrasellar cysts. These cysts all occurred in female patients who presented with menstrual irregularities and/or galactorrhea, with headaches being a less common finding. These cysts do not arise from Rathke's cleft, and the walls are made up of fibrous tissue. Pars intermedia cysts may develop when colloidal substances accumulate in a follicle or pseudofollicle in the zona intermedia and pars distalis. Degeneration and rupturing of basophiles in the adenohypophysis have been implicated in their pathogenesis. Perhaps the endocrinologic surges in the secretion of follicle-stimulating hormone, luteinizing hormone, and prolactin associated with menses and pregnancy increase the likelihood of degeneration of these cells, which then leads to cyst formation. In the experience of Baskin and Wilson, these cysts had no communication with the subarachnoid space, and after drainage did not refill.

Radiologic Features

Rathke's cleft cysts are usually located in the midline in or above the anterior portion of the sella turcica, and have well-defined margins that are round or lobular. The pituitary stalk and gland are usually displaced posteriorly. Plain x-ray films of the skull have shown the usual abnormalities associated with sellar and suprasellar lesions-ballooning of the sella and destruction of the anterior and posterior clinoid processes.

CT and MR images vary according to the morphology of the cyst wall and the contents of the cyst. A single layer of cuboidal or columnar epithelium is not clearly seen on imaging studies and will probably not enhance. However, when stratified squamous epithelium is present or if inflammation occurs in the cyst wall, CT enhancement occurs. Various kinds of cyst contents may be present, ranging from a CSF-like clear fluid to thicker, tenacious mucinous material. Cholesterol crystals have been reported in the cyst contents. Nemoto and colleagues postulated that the amount of mucopolysaccharides in the cyst will influence the imaging pattern. In some cases, the findings on CT and MRI might lead to a correct preoperative diagnosis, but in most cases the imaging features are not typical of simple cysts, and a definite preoperative diagnosis cannot be made.

CT typically shows an enlarged sella turcica containing a cystic mass, which can be either hypodense or isodense with brain. One third of the low-density cysts will show some ring enhancement. Although an exception has been reported, calcification is typically not seen in Rathke's cleft cysts.

MRI is better than CT in determining the extent of the cyst and its exact relationships to the optic nerves, optic chiasm, and hypothalamus. MRI shows a round or ovoid mass lesion in the sella, sometimes extending to the suprasellar cistern. It is sharply defined from the surrounding tissue without a remarkable mass effect or invasion. The image intensity of these cysts is quite variable, and depends on the cyst contents and the nature of the cyst wall. Thin-walled cysts filled with clear CSF-like fluid are hypointense to brain on T1-weighted images and hyperintense to brain on T2­weighted images. If the cyst is filled with creamy or mucoid material, T1-weighted images can be either iso- or hyperintense, and T2-weighted images are usually isointense. Simple Rathke's cleft cysts are usually homogenous in appearance, whereas more complex cysts have a heterogeneous internal appearance, with regions of wall thickening and contrast enhancement.

Surgical Therapy

With recent technological advancement in CT and MR imaging, increasing numbers of intrasellar cystic lesions are being diagnosed. Because most Rathke's cleft cysts are asymptomatic and because up to 20 percent of patients with no clinical manifestations of intrasellar pathology may have an area of hypodensity on CT scanning, only patients with clear neurological and endocrinologic indications should undergo exploration. In cases where endocrinologic function is normal and no compression of extrasellar structures can be demonstrated, an operation is not indicated. Symptomatic Rathke's cleft cysts should be treated by evacuation of the contents and liberal opening of the cyst wall. Biopsy of the cyst wall and histologic analysis is important in all cases to rule out other neoplastic conditions. Total removal of the cyst wall is not necessary to prevent recurrence in most cases. Extensive dissection should therefore be avoided to decrease the risk of morbidity, including partial or total pituitary insufficiency or damage to the suprasellar structures. The transsphenoidal approach is the method of choice for treatment of Rathke's cleft cysts because it involves fewer risks and complications, permits direct visualization and drainage of the cyst, and has good results. Some authors have reported good results from treating intrasellar cysts with craniotomy and cyst drainage, but this procedure should probably only be undertaken when a transsphenoidal approach is contraindicated or, occasionally, when the cyst is entirely suprasellar in location.

The recurrence rate of Rathke's cleft cysts following transsphenoidal drainage has been reported to be as low as 5 percent. Simple cyst aspiration is not recommended; two of five cysts treated in this way and reported in the literature recurred. If Rathke's cleft cyst and craniopharyngioma do represent a continuum, it seems likely that the cysts that resemble craniopharyngiomas would to some degree share a craniopharyngioma's potential for regrowth. If a complex cyst is found at operation, therefore, the patient should have careful follow-up with serial MRI studies. In cases of recurrence, a second operation with excision and drainage is recommended. Following transsphenoidal drainage of symptomatic Rathke's cleft cysts, Baskin reported that serum prolactin levels normalized in 50 percent of patients, and headaches were ameliorated in 80 percent. Among the females, menses returned in 80 percent, and galactorrhea ceased in 50 percent. Others have reported that most symptoms and signs improved or resolved after surgery, with the exception of hypopituitarism and diabetes insipidus.

Radiation therapy has no role in the treatment of these benign lesions. One patient treated initially with irradiation developed visual disturbances and hypopituitarism.