Section 2 -

Non-neoplastic Cysts Teresa Ribalta Hospital Clinic, University of Barcelona Barcelona, Spain

A wide variety of non-neoplastic cystic lesions occur in the central nervous system (CNS), some of which are incidental and others, symptomatic. Advances in diagnostic neuroimaging have facilitated diagnosis and surgical intervention for patients with CNS cysts. Many of these lesions are currently removed and submitted for evaluation. Only some cystic cavities are epithelium-lined, thus qualifying them as "true" cysts. An embryological origin has been proposed for most of these lesions, although controversy still exists about the precise etiology of some of them. Classifications and terminology schemes used by pathologists, neurosurgeons, and neuroradiologists have been varied and numerous, leading to some nosologic confusion, in part because cystic lesions are not always phenotypically classical; it is likely that they exist as a spectrum. The most helpful elements for the histopathological diagnosis of a non-neoplastic CNS cyst are anatomic location and type of wall lining (see Table). However, accurate histological characterization of the cyst is not infrequently limited by small specimen size or lack of adequate specimen preservation. Histochemical and immunohistochemical markers may be helpful ancillary techniques in identifying the precise nature of the cyst wall elements. Non-neoplastic cysts must be distinguished from cystic CNS neoplasms with a diminutive solid component (e.g., pilocytic astrocytoma and other cystic gliomas, hemangioblastoma, ganglioglioma, etc.), cavities arising from infarcts and other destructive processes, and cystic lesions of an infectious nature. Arachnoid Cyst Arachnoid or leptomeningeal cysts are congenital lesions that arise during development from a splitting of the arachnoid membrane. This splitting results in the formation of a cystic space containing a fluid similar to cerebrospinal fluid (CSF) that does not communicate with the ventricular system or the subarachnoid space. They may occur anywhere in the CNS where arachnoid is found, usually in association with the normal arachnoid cisterns, but most commonly in the middle cranial fossa and the suprasellar cistern. Arachnoid cysts are currently regarded as a developmental abnormality of the arachnoid and have been reported in association with various congenital abnormalities. A possible genetic origin is suspected in some cases. Arachnoid cysts are most often identified as incidental findings on imaging studies performed for other reasons, because these cysts usually do not produce symptoms even when quite large. Some cases have been diagnosed by antenatal or postnatal ultrasound examinations. Imaging studies show a smooth-bordered, non-enhancing cystic mass with signal characteristics similar to CSF. Current surgical treatment procedures for symptomatic cysts include, at most, partial resection of the cyst wall. Macroscopically, the intact cyst (as is seen only in situ in the operating room or at autopsy) typically shows a transparent, smooth wall and a cavity filled with clear colorless CSF-like fluid. The deep aspect of the cyst shows displaced, but otherwise normal, brain or spinal cord. Histological examination of intact complete specimens shows that the cyst is located within a split of the arachnoid membrane. It may be unilocular or loculated by septations. Multiple lesions are common in the spinal cord. The surgical specimen submitted for diagnosis is usually limited to a small portion of the outer leaflet of the cyst wall. The specimen consists of a delicate membrane of connective tissue, thicker than normal arachnoid but thinner than dura. No epithelial lining is observed; rather, there is usually a layer of flattened arachnoid cells or small nests of arachnoid cells present on the inner surface of the wall. As would be expected, the lining cells are immunoreactive for epithelial membrane antigen (EMA) and progesterone receptors, and negative for glial fibrillary acidic protein (GFAP), S-100 protein, transthyretin (prealbumin), and carcinoembryonic antigen (CEA). This immunophenotypic profile knowledge can be helpful in distinguishing arachnoid cysts from single ependymal and epithelial cysts in cases in which a diagnosis is difficult to make using only routine stains. There are a number of entities in the differential diagnosis of arachnoid cyst. True arachnoid cysts must be differentiated from acquired arachnoid cysts (leptomeningeal cysts) caused by arachnoid adhesions secondary to surgery, trauma, subarachnoid hemorrhage, or infection. The presence of hemosiderin-containing macrophages and other chronic inflammatory features in the cyst wall should be regarded as favoring a posthemorrhagic or postmeningitic leptomeningeal cyst. Arachnoid cysts can indent deeply into the hemisphere, simulating porencephaly. However, porencephalic cysts communicate with the ventricles, are surrounded by abnormal cortex, and follow a vascular distribution. Chronic subdural hygromas usually are located subdurally, rather than in the subarachnoid space, and often are bilateral and flat or lentiform in profile. Spinal epidural cysts, which connect with the subarachnoid space through the dura via a thin stalk, are not considered true arachnoid cysts, but rather as arachnoidal tissue herniations or diverticula. Dural cysts are cystically dilated intradural clefts that rarely cause compression of the adjacent structures. Epidermoid and Dermoid Cysts These are the two major variants of ectodermally derived CNS cysts, and both are lined by keratinizing stratified squamous epithelium. Most of these lesions are presumed to arise from ectopic ectoderm tissues, displaced into the CNS at the time of neural tube closure. These cysts may also arise, at any age, secondary to a traumatic or iatrogenic implantation that drives skin elements into the underlying CNS tissues. Complete surgical excision is curative for both lesions. Rupture of the cyst wall with leakage of the contents into the CSF produces a severe chemical meningitis. Malignant transformation to squamous cell carcinoma can occur but is exceptionally rare. Epidermoid cysts are unilocular, thin-walled cysts with a characteristic glistening pearl-like sheen ("pearly tumor"). The cyst contents consist of white, flaky material on gross examination. Like the epidermal inclusion cysts that occur at extra-CNS sites, the lining is composed of multiple layers of keratinized squamous epithelial cells supported by a delicate connective tissue capsule. A granular cell layer is invariably present, although it may be inconspicuous in areas of attenuated epithelium. The cyst cavity is filled with flattened sheets of anucleate squames. Despite their developmental origin, intracranial epidermoid cysts rarely present before the third decade of life, and most lesions are incidentally found. The cysts have a wide anatomic distribution along the neuraxis, but most develop eccentrically in the region of the cerebellopontine angle. In this location, they are often referred to as cholesteatomas; however, they are quite distinct from the acquired cholesteatomas of the middle ear, which result from local chronic infection. Other locations include the suprasellar region, the ventricles, the thalamus, the brainstem and the spinal meninges. For those epidermoid cysts arising in the suprasellar region, the differential diagnosis includes Rathke cyst with extensive squamous metaplasia, and craniopharyngioma. The advanced degree of keratinization, formation of cytoplasmic keratohyaline granules, and complete lack of mucous-secreting cells are characteristic features of the epidermoid cyst that are generally foreign to other cystic lesions. Dermoid cysts tend to present in childhood or adolescence and typically occur in the midline, in the posterior cranial fossa, or in a fontanelle. In the spinal cord, dermoid cysts predominate in the lumbosacral region and can be part of a dysraphic malformation. A sinus tract may connect a dermoid cyst to the skin. In comparison with epidermoids, dermoid cysts have a thicker wall and contain unpleasant, cheesy pilosebaceous material. By definition, the cyst wall is endowed with skin appendages, including sweat glands and pilosebaceous units. Squamous cells with keratohyaline granules are not seen in dermoid cysts. The intraluminal keratin may contain cell ghosts that are reminiscent of the "wet keratin" of adamantinomatous craniopharyngioma and are attributed to hair matrix differentiation. However, dermoid (and epidermoid) cysts have a less complex architecture than adamantinomatous craniopharyngioma and lack the peripheral palisading and internal stellate reticulum that characterize the epithelial nodules of this tumor. The presence of endodermal glandular elements, muscle, or cartilage should alert suspicion for a mature cystic teratoma, especially in the pineal and suprasellar regions. Ependymal Cysts Ependymal cysts, also named neuroepithelial or glioependymal cysts, are uncommon lesions that tend to develop in relation to the cerebral ventricles and paraventricular white matter, and only very rarely occur in the fourth ventricle or in extra-axial sites. A maldevelopmental origin is likely for all of these lesions. The cysts contain a watery fluid and are lined by a row of columnar or cuboidal, often ciliated, ependymal-like cells that rest directly on fibrillary neuroglial tissue. Pseudostratification, mucin-producing cells, and basement membrane are not features of ependymal cysts. Their neuroepithelial nature is supported by the immunoreactivity of the lining for S-100 protein and sometimes GFAP, and a lack of reactivity for EMA, CEA, and transthyretin. This immunohistochemical profile allows their distinction from colloid cysts, cysts of endodermal origin, and choroid plexus cysts. By electron microscopy, the neuroepithelial lining also exhibits typical features of ependymal epithelium, such as cytoplasmic glial filaments, intercellular junctions, apical microvilli, and often cilia, as well. Enterogenous and Bronchogenic Cysts These uncommon lesions are typically intradural and usually located anterior to the spinal cord. Enterogenous and bronchogenic cysts, also known as neurenteric and respiratory epithelial cysts, respectively, probably result from the incomplete separation of developing endodermal and notochordal tissues in early embryonic life. These endodermal lesions may be associated with vertebral anomalies, spinal dysraphism, intestinal malformations and similar cysts in the thoracic and abdominal cavities. Histologically similar intracranial lesions occasionally arising in the anterior fossa may be of ectodermal derivation. Grossly, the lesion is an opalescent, smooth-surfaced, fluid-filled cyst. Microscopically, the inner layer is a pseudostratified columnar epithelium, with or without cilia and goblet cells, which rests upon a periodic acid-Schiff (PAS)-positive basement membrane. The epithelial lining reacts with antibodies to CK, EMA and CEA, and is negative for S-100 protein and GFAP. A similar lining is seen in Rathke cysts and colloid cysts of the third ventricle. Occasional variants include seromucinous glands, smooth muscle fascicles, hyaline cartilage, and other elements of the developed digestive or respiratory tract within the cyst wall. The additional presence of glial cells or ectodermal elements should elicit a diagnosis of cystic teratoma. Colloid Cyst of the Third Ventricle The distinctive location and morphology of the colloid cyst of the third ventricle make it a clear-cut pathologic entity. Colloid cysts characteristically arise in the rostral roof of the third ventricle near the foramen of Monro and between the columns of the fornices. Symptomatic lesions, most measuring 1 cm or larger, usually present in adults with headaches and manifestations of ventricular outflow obstruction that can be intermittent, probably due to a positional "ball-valve" effect at the foramen of Monro. Surgical removal of the entire cyst is curative. Colloid cysts are grossly unilocular, thin-walled, and filled with a viscous, mucoid material. Although it would be natural to consider this lesion a variant of the ependymal cyst, morphological, immunohistochemical and ultrastructural features speak convincingly for an endodermal derivation. The cyst lining is ciliated, pseudostratified columnar epithelium with scattered goblet cells, but a simpler, low cuboidal epithelial layer may be seen as a result of intraluminal pressure. The morphological resemblance of the colloid cyst lining to respiratory epithelium is reinforced by the expression in many cases (but not invariably) of CK, EMA and CEA, and lack of reactivity for GFAP and transthyretin (prealbumin). The cyst content is PAS-positive and frequently includes characteristic filamentous, hyphae-like aggregates of degenerated nucleoproteins and phospholipids, which may be of diagnostic interest in the absence of identifiable epithelium. Adherent choroid plexus is frequently seen in the outer surface of the delicate fibrous capsule. Rupture of the cyst wall induces a florid xanthogranulomatous inflammatory reaction that in some cases largely replaces the epithelium. In the absence of an epithelial lining, distinction from other lesions with xanthomatous changes occurring in this anatomic region, such as craniopharyngioma or the so-called "xanthogranuloma of the third ventricle", may be difficult if not impossible; the nature of some of these lesions is not clear. Rathke Cleft Cyst The pars intermedia of the pituitary gland normally contain multiple small cystic remnants of the embryonic pharyngeal epithelial pouch (Rathke's pouch). These microscopic cysts rarely grow large enough to compress the pituitary and become symptomatic. The Rathke's cyst lining has a striking resemblance to that of the colloid cyst and the enterogenous cyst. Like them, Rathke's cyst may also contain squamous metaplastic elements, and in these cases, distinguishing Rathke's cyst from craniopharyngioma may be difficult. Calcification, keratin nodules, and chronic inflammation are more common in craniopharyngioma. Recently, a differential cytokeratin expression profile has been shown between Rathke cleft cysts, which express CK 8 and 20, and craniopharyngioma (all variants), which don't. This difference could be of diagnostic utility when only a small biopsy is available. Pineal gland cyst The normal pineal gland contains small fluid-filled cavities that are frequently found at postmortem examination and may be conspicuous on neuroimaging. These cavities probably result from degenerative changes in the pineal gland and rarely reach sufficient size to compress adjacent structures. On microscopic study, an adequate specimen for diagnosis should include the typical cyst wall, consisting of an inner gliotic layer with profuse numbers of Rosenthal fibers, scattered eosinophilic granular bodies, and focal hemosiderin deposition, remnants of pineal parenchyma in the middle, and an external fibrous capsule. Pineal parenchymal tumors are nearly always solid masses and are rarely cystic tumors. Choroid plexus cyst This is another typically small and asymptomatic lesion that is often discovered incidentally, most frequently in the glomus of the lateral ventricles. This cyst contains CSF, and the wall is composed of a thin fibrous membrane with an inner layer of cuboidal choroidal plexus neuroepithelial cells. The differential diagnosis of an intraventricular cyst includes ependymal cyst, colloid cyst, arachnoid cyst, Rathke's cleft cyst, and cysticercosis. Both the morphology of the inner lining and immunohistochemistry are necessary for differentiating between these types of cysts. A positive immunoreaction to transthyretin confirms the origin of an ventricular cyst as arising from choroid plexus epithelium. Table. Synonyms, Principal Locations and Diagnostic Features of Non-Neoplastic Cysts of the CNS Synonyms Anatomic Location Luminal Content Inner Wall Outer wall Useful IHC Markers Arachnoid Cyst Leptomeningeal Cyst Rostral sylvian fissure Any site where arachnoid is present CSF Arachnoid cells Thin fibrous membrane EMA, PR Epidermoid Cyst - Cerebellopontine angle Any site (eccentrical) Flaky, lamellar, "dry-keratin" Squamous epithelium only (keratohyaline granules) Thin fibrous membrane - Dermoid Cyst - Midline "Wet- keratin", greasy material with hair Squamous epithelium Thick fibrous capsule containing skin appendages - Ependymal Cyst Neuroepithelial cyst, Glioependymal cyst Cerebral ventricles IV ventricle Paraventricular white matter Clear Ependyma-like cells w/wt cilia No basement membrane Fibrillary glial tissue S-100, GFAP Enterogenous Cyst Neurenteric cyst, Bronchogenic (respiratory) cyst Rostral spinal cord Clear or mucoid Columnar epithelium w/wt cilia and goblet cells Metaplasic squamous cells Fibrous membrane CK, EMA, CEA Colloid Cyst - Anterior III ventricle Mucoid Columnar epithelium w/wt cilia and goblet cells Thin fibrous membrane CK, EMA, CEA Rathke Cleft Cyst - Sellar Suprasellar Clear Columnar epithelium w/wt cilia and goblet cells Metaplasic squamous cells Thin fibrous membrane CK, EMA, CEA Pineal Cyst - Pineal gland Clear Gliotic tissue with Rosenthal fibers Pineal remnants (middle) Fibrous tissue (external) GFAP, Synaptophysin Choroid Plexus Cyst - Lateral ventricles CSF Cuboidal choroid plexus cells Thin fibrous tissue Transthyretin Bibliography Hirano A and Hirano M. Benign cysts in the central nervous system: Neuropathological observations of the cyst walls. Neuropathology 2004;24:1-7 Coca S et al. Immunohistochemical study of intracranial cysts. Histology and Histopathology 1993;8:651-4. Ribalta T and Fuller GN. Arachnoidal cysts. In: McLendon R, Bigner DD, Rosenblum M, Bruner JM (eds): Russell and Rubinstein's Pathology of Tumors of the Nervous System, vol. 2, 7th ed. London: Edward Arnold (in press). Fuller GN and Ribalta T. Dermoid Cysts, Epidermoid Cysts, and Dermal Sinuses. In: McLendon R, Bigner DD, Rosenblum M, Bruner JM (eds): Russell and Rubinstein's Pathology of Tumors of the Nervous System, vol. 2, 7th ed. London: Edward Arnold (in press). Hitchcock MG et al. Shadow cells in an intracranial dermoid cyst. Arch Pathol Lab Med 1995;119:371-373. Ribalta T and Fuller GN. Neuroepithelial cysts of the IV ventricle. In: McLendon R, Bigner DD, Rosenblum M, Bruner JM (eds): Russell and Rubinstein's Pathology of Tumors of the Nervous System, vol. 2, 7th ed. London: Edward Arnold (in press). Goh RH and Maguire J. Neuroepithelial cyst of the posterior fossa: two case reports with radiologicpathologic correlation. Can Assoc Radiol J 1996; 47:126-31. Tsuchida T et al. Cholloid cysts of the third ventricle. Immunohistochemical evidence for nonneuroepithelial differentiation. Hum Pathol 1992;23:811-816. Lach B et al. Colloid cyst of the third ventricle. A comparative immunohistochemical study of neuraxis cysts and choroid plexus epithelium. J Neurosurg 1993;78:101-111 Ho KL and Garcia JH. Colloid cysts of the third ventricle. Ultrastructural features are compatible with endodermal derivation. Acta Neuropathol 1992;83:605-612. Xin W et al. Differential expression of cytokeratins 8 and 20 distinguishes craniopharyngioma from Rathke cleft cyst. Arch Pathol Lab Med 2002;126:1174-1178. Fain JS et al. Symptomatic glial cysts of the pineal gland. J Neurosurg 1994;80:454-460. Odake G et al. Cyst of the choroid plexus in the lateral ventricle. Case report and review of the literature. Neurosurgery 1990;27:470-476. Hambali F et al. Choroid plexus cyst and chordoid glioma: report of two cases. Neurosurg Focus 2001;10:1-6.