Abstract
Neurenteric cyst (NEC) is a rare benign condition resulting from a failure of the separation of the primitive endoderm and ectoderm. This cystic lesion grows in the central nervous system and compresses surrounding neurological structures. It can also arise with other dysraphisms. Patients experience various neurological symptoms depending on the location of the lesion. The cystic mass can be identified with MRI. As the epithelial morphology of NEC share similarities with other intracranial and intraspinal cystic growths, the definitive diagnosis of NEC can be made after a histochemical analysis with endodermal markers. The surgical removal is the current management of choice. A dramatic symptomatic improvement is prevalent when the mass effect is reduced. The complete resection is associated with the lowest disease recurrence rate.
Introduction
Neurenteric cyst is an infrequent condition, which lacks the consensus of management approach. Various manifestations and different phenotypical associations of NEC render each case report and case series unique. This comprehensive review has a goal to examine the general anatomy, the embryology, the histology and the current surgical management of NEC to better understand the disease condition and its histopathological characteristics.
Anatomy
Derived from abnormal embryological primitive cells separation, neurenteric cyst is a rare condition that can arise in the intracranial and intraspinal region. Its intraspinal occurrence is reportedly 0.7% – 1.3% of “all spinal tumors” and tends to affect more males than females [1,2]. The population affected is between neonate to early seventies with a higher incidence in children and young adults [3,4]. Depending on the location of the lesion, spinal neurenteric cysts can be described as intra- or extradural and intra- or extramedullary. The most common type being intradural, extramedullary lesions, accounts between 78% to 90% of the reported spinal neurenteric cysts while intramedullary and extradural lesions account for the rest of the minorities [5,6]. Spinal neurenteric cysts are predominantly found in the ventral to ventro-lateral aspect of the spinal cord. The cervical vertebrae are the most common level of its occurrence, followed by the thoracic and lumbosacral spine [2,7,8]. This predilection tendency may vary depending on the location of neurenteric cyst in relation to the spinal cord as isolated intramedullary subsets of this benign tumor were more frequent in the thoracic level without any gender preference [9].
The cystic growth can interfere with the local anatomy of the central nervous system. Patients experience a spectrum of symptoms from focal neurological deficits such as pain, paresthesia, motor deficit, progressive weakness, hyperreflexia, urinary incontinence, and tethered cord syndrome to more generalized symptoms like paraplegia and quadriplegia [4-6,10,11]. The clinical presentations are related to the level of the lesion as the cystic mass can compress, flatten and widen the affected level of the spinal cord [4,10]. Spinal neurenteric cysts are also reported with the presence of other diverse anatomical deformities, including vertebral deformities or cutaneous anomalies. Reported bony deformities include the malformation of vertebra, hemivertebra, scoliosis, single or multiple spina bifida, spinal dysraphism and Klippel-Feil [1,4,6,11]. Rauzzino et al. have pointed the presence of cutaneous manifestations, which are traditionally rather known as more prevalent features of occult spinal dysrphism, in their patients with spinal neurenteric cysts. These include hairy patch, pedunculated mass, capillary hemangioma, and subcutaneous mass [6]. However, a clear pattern of the association between a specific vertebral or cutaneous deformity and NEC has not been identified.
Embryology
The anatomical presentation and the histopathological illustration are closely related to the embryogenic defect of the condition. During the third week of the gestation, the gastrulation takes place and embryonic trilaminar germ layers are formed. Cell proliferations followed by proper migrations of different cell lineages determine the morphology and the primitive axis of the body. Mesodermal cells migrate to give a rise to the notochord around which paraxial mesoderm aggregates. The amniotic sac and yolk sac cavities are temporarily connected via neurenteral canal, which later obliterates upon the development of the notochord. The ectoderm developing from epiblast, later gives a rise to various parts of the nervous system. As for the endoderm, which is destined to line the gastrointestinal system and some part of respiratory tract, replaces the hypoblast.
Under a rare condition, primitive endodermal cells may fail to separate from ectodermal counterparts resulting in a condition known as neurenteric cysts. These abnormal lesions are characterized by cystic growths in the central nervous system [6]. The cystic wall is lined by well differentiated cells of endodermal origin. The exact mechanism of pathogenesis behind this defect is not fully understood. Several postulates exist, and they can be grouped into the following 5 different mechanisms: 1) the split of notochord by endodermal tissue or diverticulum [11, 12], 2) the adhesion between the notochord and the endodermal tissue, 3) a failure of the obliteration of neurenteric canal, 4) the “incomplete excalation” of the notochord [13] and 5) abnormal notochord development secondary to an incomplete ectoderm-endoderm separation [14]. Depending on the location, size, and rate of the growth of the defect, the degree of anatomical abnormality and the clinical manifestation vary.
Histology
Neurenteric cyst is lined by cuboidal to columnar cells. The epithelial layer exhibits features of the gastrointestinal or respiratory lining with or without cilia, mucous glands, and/or goblet cells [3,4,6,9,10,16]. This benign cyst can also be associated with the presence of other connective tissue components. Based on the epithelial integration to the basement membrane and/or the presence of other complex cellular types, Wilkins and Odum have proposed three different histopathological categories of neurenteric cysts. Type A exhibits the simplest organization with a single layer of cuboidal to columnar cells that is associated with the basement membrane. These cells may or may not present with apical cilia. Type B has the feature of type A in the presence of other connective tissue components such as glandular, cartilagenous or lymphatic cellular histology. Type C is characterized by the cyst lined by the cellular component of type A in the presence of glial and ependymal cells [15]. It is not clear under what circumstance the development of one cyst type is preferred over another. However, increasing the histopathological complexity of neurenteric cyst may be associated with the additional presence of dysraphism in patients [6].
The best diagnostic imaging tool of neurenteric cyst is MRI. However, a series of microscopic cellular analysis is required to differentiate NEC from other differential diagnoses of intraspinal cystic mass such as ependymal, epidermoid, or dermoid cysts. Differentiating neurenteric cysts solely on the light microscopy from other intramedullary or intradural growths is also challenging [17, 18]. For instance, intradural ependymal cysts exhibit similar cellular morphology with ciliated simple cuboidal to columnar epithelium. However, these types of lesions are reactive with glial fibrillary acidic protein (GFAP) and S-100 protein along with other specific immunochemical markers for neuroglial cells [18,19]. Although the neurenteric cyst conventionally is known to stain negative with GFAP, which is a neuroectodermal marker [1,20], in some minority of cases, focal positive reactivities were unusually observed. [17].
Neurenteric cyst, with the abundance of goblet cells and mucin secreting cells, stains positive with periodic acidic Schiff and mucicarmin [3,20]. It is also known to be reactive with Carcinoembryogenic antigen (CEA), Epithelial Membrane Antigen (EMA), cytokeratin 7 and 20 [17,20]. Cytokeratin 7 (CK7) is abundantly present on the lining of pancreaticobiliary tree and the foregut structure. Cytokeratin 20 (CK20) is widely expressed by the epithelial lining of small intestine and of the colon. [21] These markers immunohistologically confirm the possible primitive endodermal origin of neurenteric cysts [17,20,25].
This cystic growth can also be associated with dystrophic calcification [9,17]. An intracranial and an isolated intramedullary neurenteric cyst case report suggested that NEC can be considered as a differential diagnosis in the pathologies leading to intramedullary calcification. [9] The inner aspect of the neurenteric cystic cavity is filled with fluid. The physical appearance and the viscosity of these liquids varied: milky appearance [4], yellow or brown colored fluid [22] with watery-like [10,11], mucous [18], “jelly-like” [3] or viscous consistencies were reported [11]. Molecular analysis of the the fluid revealed a high protein concentration of variable degree with lipid substances. Brown color was observed as a result of possible hemorrhage [22,23]. These compositions of cyst influenced the imaging studies. MRI is the imaging modality to visualize spinal neurenteric cysts, while CT can be employed to depict any presence of associated dysraphisms. Due to the variations of the cystic content, the imaging intensity pattern on MRI study may be inconsistent. While the majority of the reported cases exhibit isointensity to hyperintensity signaling relative to the cerebrospinal fluid, on T1 and T2-weighted images, all spectrums of variations were reported [4,11,16]. The use of Fluid Attenuated Inversion Recovery (FLAIR) sequence MRI revealed mostly hyperintensity patterns [4,16]. Pattern of “rim enhancement” was detected in patients as a sign of chronic inflammation [4,23]. A recent study also had reported the presence of a solid nodular mass with melanin deposition [23].
Surgery
Neurenteric cyst are removed surgically. Total removal, subtotal resection, fenestration of cyst, and simple aspiration are the surgical options [4,10]. While the total removal is the optimal treatment approach for its lowest recurrence rate, the ventral predilection site of the lesions or their close adherence to the spinal cord may not permit the complete excision [3]. Under these circumstances, incomplete micro-dissection, instead, is offered. However, this treatment option is associated with a higher recurrence rate, necessitating for a further management [10,11]. Cystic fluid, if leaked into the intramedullary cavity, may cause meningeal irritation, and this is more prevalent in newborn and infants [11]. Aspiration is used in combination with resection to remove the cystic content prior to the excision of the wall and to relieve the local mass effect temporarily [4]. Aspiration monotherapy, however, is not practiced as it does not offer a long-term therapeutic effect [10]. Fenestration, which consists of establishing a communication between the cystic lumen and the subarachnoid space, is another proposed method to manage NEC. The shunting mechanism alleviates the growth of the non-communicating cystic mass. [21] This method is also offered in conjunction to a subtotal excision of a cyst to prevent the return of clinical manifestations. [24] A failure of the shunt function therefore, can lead to the recurrence of the neurenteric cyst and its symptoms [8].
Neurenteric cysts are approached mainly by two different surgical planes. More feasible methods are chosen to achieve a complete excision with a minimal risk. The anterior approach offers a better visual field for lesions located anterior to the spinal cord. This method is less favored over the posterior approach due to the technical difficulty and the involved anatomy. The neurovascular damage and vertebral malfusion risk is also higher. This surgical methodology is offered when a benefit is concomitant. A recurring neurenteric cyst on a patient who previously had a placement of the fenestration shunt via the posterior approach, was excised by an anterior approach for complete removal and to avoid previous surgical adhesion [8].
The posterior approach, with fewer complications, is more widely used and offered via posterior laminectomy, laminotomy [1], or laminoplasty [11]. A standard surgical recommendation does not exist. Regardless of the planes of surgical approach and irrespective of a complete or an incomplete resection, upon the removal of the cystic mass, most patients experienced a dramatic improvement from neurological deficits [3,4,6,8,10,11,21]. Structural abnormalities such as scoliosis though persisted [4].
Conclusion
Intraspinal cystic growth can be identified with MRI. The use of electron microscopy, histological markers, special stains, and immunochemistry are tools to confirm the diagnosis of neurenteric cyst. The majority of NECs are located anterior to the spinal cord. Proposed pathogenesis do not clearly explain the mechanism of the occurrence of this benign growth in both the anterior and posterior aspect of spinal cord. Spinal NEC tends to be associated more often with additional dysraphism than intracranial counterparts. Yet, clear genetic association or molecular backgrounds are to be identified. Currently, there is not enough data to establish a definitive approach to treatment. The complete resection of the cyst remains the best surgical management with the lowest incidence of recurrence. Once recurred, the cyst has a tendency to exhibit the same histopathology of the original cyst. Given risk associated with the damage of the surrounding neurovasculature, the complete excision may not always be possible. Under such circumstance, incomplete resection can be offered while considering the potential risks and benefits for individual patients.