Enigmatic echoes: Exploring brainstem neurenteric cysts - A case series and literature review

Abstract

Introduction and importance

Neurenteric cysts (NCs) are rare congenital anomalies within the central nervous system, originating from the endodermal layer due to inappropriate embryonic notochordal plate and endoderm separation. Despite constituting a minute fraction of CNS tumors, their diverse clinical presentations and brainstem occurrence pose diagnostic challenges.

Case presentation

This study presents a series of three brainstem NCs, detailing demographics, clinical presentations, radiological features, and operative findings. Patients aged 2–40 years exhibited varied symptoms including headaches, vomiting, cranial nerve deficits, and motor/sensory deficits. Literature review of 27 cases showed a mean age of 26.8 years, predominantly in females, with diverse cystic characteristics on MRI. Surgical intervention achieved mostly complete resection, with varying outcomes including recurrence and malignant transformation.

Clinical discussion

This study sheds light on the rare entity of brainstem NCs, emphasizing their diagnostic complexity. NCs, though constituting a minute fraction of CNS tumors, present a diagnostic challenge due to their diverse clinical presentations and rarity in the brainstem.

Conclusion

This study provides insights into brainstem NCs, emphasizing diagnostic complexity and the importance of MRI in accurate diagnosis and surgical intervention. Enhanced collaboration is needed to refine management strategies for these intriguing lesions.

Highlights

• •Rare Congenital Anomalies: Neurenteric cysts (NCs) are rare congenital anomalies within the central nervous system, originating from the endodermal layer due to inappropriate separation during embryonic development.
• •Challenges in Diagnosis and Classification: While constituting only 0.01% of CNS tumours NCs, especially in the brainstem, present diagnostic challenges.
• •The study reviews three brainstem NC cases, highlighting the need for interdisciplinary collaboration and exploring the enigmatic embryonic origins.
• •Clinical Insights and Management: The study includes brainstem NC cases (age 2-40y) with varied presentations, emphasizing the importance of considering NCs in intracranial cystic lesion differentials.

1. Introduction

Neurenteric cysts (NCs) represent rare congenital, non-syndromic anomalies within the central nervous system (CNS). [1] Emerging during embryonic development due to inappropriate separation of embryonic notochordal plate and endoderm during 3rd week of development, these cystic lesions originate from the endodermal layer, sharing its unique developmental pathway with other entities such as Rathke cleft cysts and colloid cysts. [2] Previously they have also been termed as enterogenous cysts, enteric cysts, or endodermal cysts. [3] These cystic masses are covered by an epithelium that produces mucin, adopting a cuboidal or columnar structure reminiscent of the mucosa found in the gastrointestinal or respiratory tract. The contents of the cysts primarily consist of mucoid material, often accompanied by a variable protein component.

While NC can manifest in any part of the central nervous system (CNS), constituting 0.01 % of CNS tumors, they are more frequently observed in the spine (lower cervical and upper thoracic spine), comprising 0.7 % to 1.3 % of spinal tumors. Brain stem neurenteric cysts are considered extremely rare. The rarity of these cysts at this site makes it challenging to establish precise prevalence rates.

In the 1979 World Health Organization (WHO) Classification of Tumors of the CNS, described it as a cyst with epithelium resembling the gastrointestinal tract that secretes mucin. Subsequently, in the 1993 WHO Blue Book, neurenteric cysts were placed in the “cysts and tumor-like lesions” category. However, with the publication of the third edition in 2000, this category was eliminated, leading to the reclassification of neurenteric cysts, which are now no longer regarded as tumors of the central nervous system. [4,5].

The clinical presentation of NC is diverse, often dependent on their location and size. Symptoms may range from neurological deficits to non-specific complaints, adding to the diagnostic challenge. Magnetic resonance imaging (MRI) is a crucial tool for accurate diagnosis, revealing the cystic nature and providing insights into its anatomical relationships.

Management of neurenteric cysts typically involves surgical intervention, aiming for complete resection to alleviate symptoms and prevent recurrence. However, the surgical approach may be complex due to the proximity of these cysts to vital neural structures. Additionally, the rarity of neurenteric cysts contributes to limited understanding, making interdisciplinary collaboration and shared clinical experiences essential in enhancing our knowledge of these intriguing lesions.

This study explores clinicopathological features, demographics, and radiological details of 3 central nervous system NC along with a review of literature about brainstem NC.

2. Material and methods

All histologically confirmed cases of brainstem neurenteric cysts who underwent surgical excision over a period of one year from December 2022 to December 2023 were included retrospectively. The cases were operated upon by an experienced neurosurgeon with an experience of more than 10 years. The patient's age, clinical presentation, radiological features, and operative and histopathological findings were evaluated. The histopathology slides were reviewed independently by two pathologists (SA and SZ) to reduce any inter-operator variation. The data collected was analyzed by descriptive statistics. The work was reported in line with the PROCESS criteria. [6].

For a review of the literature, we did an electronic literature search of the key term “neurenteric cysts of the brain stem/ pontine/ mid-brain/ medulla” was used to search across research databases in PubMed Central (PMC), Embase, Scopus, and Google Scholar. For the PubMed Medline search a combination of Boolean operators with keywords: (neurenteric cysts AND brain stem/ pontine/ mid-brain/ medulla) was used separately. Cerebello-pontine angle cysts were excluded from the literature review.

3. Results

The present study included three cases of neurenteric cysts of the brainstem which were operated in the neurosurgery department in the last one year. Among these, one was in the region of the medulla and reaching up to the cervico-medullary region, second at the level of pons compressing the brainstem and third in the region involving the medulla. Their age ranged from 2 to 40 years. Clinical symptoms varied from headache (chronic tension-type to chronic migraine), vomiting, cranial nerve deficits, and motor and sensory deficits, and the duration of symptoms varied from 10 days to 1.5 years. The cyst lining ranged from pseudostratified ciliated cuboidal to columnar with the presence of goblet cells. [Table 1, Fig. 1, Fig. 2, Fig. 3].

Table 1.

Summary of clinicopathological and radiological details of cases.

Case	Age/Sex	Clinical presentation	Location	Clinical duration	Radiological findings	Gross and Histopathological findings	Surgical excision	Follow up
1	2/M	headache, dizziness, vomiting and quadriparesis	Brain-stem prepontine cistern and reaching upto 4th ventricle	2 months	MRI- Cystic lesion in pre-pontine cistern compressing the brainstem and 4th ventricle	Cystic structure with amorphous gray-yellow gelatinous liquid. M/E- Cyst lined by columnar epithelium with goblet cells.	Midline sub-occipital approach with complete excision of cyst	Patient doing well, and no recurrence for last 2 years
2	35/ F	Headache, Vomiting, quadriparesis and bed ridden	Brain stem medullary region reaching upto cervical region	6 months	MRI- Well-defined cystic lesion centered in the medulla.	Already cut open cystic structure. M/E- Cyst lined by pseudostratified cuboidal to columnar epithelium with goblet cells.	Midline sub-occipital approach with complete excision of cyst	Patient doing well, and no recurrence for last 1.5 years
3	40/M	Vomiting, quadriparesis and bed ridden	Brain-stem: In the region of medulla and reaching upto cervico-medullary region	8 months	T2W sagittal section – cystic lesion compressing and displacing the medulla and cervico-medullary Junction. Another cystic lesion is compressing the vermis.	Cystic structure with gelatinous liquid. M/E- Cyst lined by pseudostratified ciliated cuboidal epithelium.	Midline sub-occipital approach with complete excision of cyst	Patient doing well, and no recurrence for last 2 years

SOL: Space occupying lesion, L: Lumbar vertebra, S: Sacrum, M/E: Microscopy.

Fig. 1.

Neurenteric cyst in brainstem prepontine cistern in a 2-year-old child.

a) Magnetic resonance imaging exhibiting cystic lesion in pre-pontine cistern compressing the brainstem and 4th ventricle (shown with arrow).

b) Intraoperative image of the cystic mass (arrow).

c) Hematoxylin and eosin-stained sections exhibited cyst lined by columnar epithelium with goblet cells (arrow). [100×].

Fig. 2.

Neurenteric cyst in the brainstem medullary region in a 35-year-old female.

a) Magnetic resonance imaging exhibiting a well-defined cystic lesion centered in the medulla (shown with arrow).

b) Intraoperative image of the cystic mass centered in the medulla (arrow).

c) Hematoxylin and eosin-stained sections exhibited a cyst lined by pseudostratified cuboidal (arrow-head) to columnar epithelium with goblet cells (arrow). [100×].

Fig. 3.

Neurenteric cyst in the brainstem medullary region in a 40-year-old male.

a) Magnetic resonance imaging exhibiting a cystic lesion compressing and displacing the medulla and cervico-medullary junction (shown with arrow).

b, c) Intraoperative image of the cystic mass centred in the medulla (arrow).

d) Gross image of the excised cyst.

e-f) Hematoxylin and eosin-stained sections exhibited a cyst lined by pseudostratified ciliated cuboidal epithelium (arrow). [40×, 100×].

4. Discussion

Neurenteric cyst (NC) was first described in 1928 by Kubie and in 1934 by Puusepp. [7,8] Puusepp documented a case in a 27-year-old woman with quadriparesis in which a cyst was found at C3–C4 level, ventral to the spinal cord. Subsequently, it has been referred to by various names such as endodermal sinus cyst, intestinal cyst, enterogenic cyst, teratomatous cyst, intestinoma, and archenteric cyst. The precise cause of NC remains elusive, possibly arising due to defect or incomplete resorption of the neurenteric canal, an ad-hoc connection between amnion and yolk-sac during early embryogenesis, hence it is believed that there is persistence of the neurenteric canal leading to the formation of cyst.

Diverse terminology has been employed over time and by various observers, due to its enigmatic pathogenesis. In 1928, Kubie and Fulton named it a “teratomatous cyst,” while in 1934, Puusepp identified them as “intestinome.” Subsequently, in 1955, Knight et al. referred to them as “gastrocytoma,” and in 1963, Scoville et al. labelled them as “enterogenous cyst.” Holcomb and Matson in 1954 were the first to designate them as “neurenteric” while describing the thoracic cyst of a 4.5-year-old boy. [9] Others have also denoted them as endodermal cysts, foregut cysts, bronchogenic cysts, and respiratory cysts, given their frequent association with bronchopulmonary foregut malformations. Among these various names, neuropathologists and in literature, the term “neurenteric cyst” is commonly used.

It is an uncommon congenital cystic abnormality which develops around the third week of gestation and is believed to arise from the persistent neurenteric canal that connects the primitive gut and neural tube. Also believed is that there may be embryonal failure to separate the notochord from the foregut, resulting in the integration of primitive endodermal cells into the notochord. Further, it is believed that there might be the formation of an accessory neurenteric canal with a split notochord, or an endodermal adhesion to the notochord, and alternate adhesion between the endoderm and ectoderm. Disorder of gastrulation is also thought to be the cause of NC. Frequently, intra-abdominal or intrathoracic cysts are commonly associated with NC. [10].

The latest hypothesis proposes an abnormal migration of endodermal cells through the primitive neurenteric canal into the ectoderm, ultimately reaching more distant cranial and lateral positions. [11,12] Because of their morphological similarities, NCs, Rathke cleft cysts, and colloid cysts are thought to belong to one general group, and a common term “endodermal cysts of the central nervous system (CNS)” has been proposed.

Although there is no widely recognized and accepted classification system agreed upon. Wilkins and his team tried to categorize intraspinal neurenteric cysts (NCs) into three types taking histological characteristics into account. They classified them as type A cysts, in which the cyst walls are composed of a pseudostratified cuboidal or columnar epithelium, which is ciliated or non-ciliated, resembling respiratory or gastrointestinal epithelium Type B cysts exhibiting all the features of type A cysts and further having complex glandular structures, typically producing mucin or serous fluid, with a cyst wall which is richer in connective tissue and intermixed with smooth muscle cells and lymphoid tissue. Rarely ganglial cells are also seen and Type C cysts with type B characteristics along with the presence of glial tissue or ependymal cells. [13].

In a review of the intracranial neurenteric cyst by Gauden et al. in 2012, they reported that till then there have been 140 histopathologically confirmed cases of the neurenteric cyst, out of these there were 47 cases of posterior fossa NC, 61 cases of craniocervical NC, 19 cases of supra-tentorial NC and 12 cases in other locations. Due to the paucity of cases, assessment of the true incidence and prevalence of NC of the brainstem is very difficult. [14].

To the best of our knowledge, there has been no attempt to review cases of NC associated with the brain stem. The patient demographics and clinical features of 27 cases of brainstem neurenteric cyst in the reviewed literature is presented in Table 2.

Table 2.

Demographical and clinical features of brainstem neurenteric cyst in the reviewed literature.

	Number	Percentage
Mean age	26.8 years
Age Range	29 weeks- 75 years
Male	3	11.1 %
Female	23	85.2 %
Unspecified	1	3.7 %
Location
Pons	5	18.5 %
Mid-brain	–
Medulla	7	25.9 %
Pons+midbrain	–
Pons+ midbrain+ medulla	15	55.6 %
Others	–
Extension
4th Ventricle	4	14.8 %
Cervical region	1	3.7 %
Pre-pontine cistern	1	3.7 %
Pre-medullary cistern	3	11.1 %
Cerebello-pontine angle	3	11.1 %

Out of the 27 cases of brain stem neurenteric cysts reported in the literature, the mean age was 26.8 years. The youngest case of brain stem neurenteric cyst reported was 29 weeks old. [15] The majority of patients in previously reported literature were females (23, 85.2 %) with only 3 male patients. The most frequent location was pons and medulla followed by medulla and pons alone. However, in the present series, two out of three cases were male patients with a mean age of 25.7 years.

Headache was the most common presentation. However, other symptoms included incontinence, quadriparesis, dysphagia, dysphonia, vertigo, ataxia, worsening gait, diplopia, dysarthria, and nasal regurgitation depending on the location and extension of the cyst. [1, 3, 4, 15–31] The duration of symptoms ranged from 2 weeks to 3 years. [Table 3].

Table 3.

Clinicopathological and radiological features of previously reported cases of Neurenteric cysts of brain-stem.

Authors	Case No/ Age/ Gender	Symptoms	Duration of symptoms	Size and size of cyst	Radiological Findings	Histopathologic features	Surgical excision	Follow up
Viaene et al [16] [2019]	1/ 47/F	Incontinence and progressive quadriparesis	1 year	7 cm, posterior fossa cyst (medulla and pons)	Multiple, expanding, and recurrent neurenteric cysts in the left cerebellomedullary angle and left prepontine cistern compressing the medulla	NA		Recurrent after 3 years with hydrocephalus and again resected
Gavrjushin et al [17] [2021]	2/ 19y /F	Moderate dysphagia, dysphonia, vertigo, spontaneous nystagmus, imbalance, and numbness in the left side of the body	5 months	NA, medulla oblongata	MRI- well-defined lesion centered in the medulla. Homogeneously hypointense on T2-weighted images and heterogeneously hyperintense on T1-weighted images and demonstrated no solid enhancing components.	Gross: Cyst with amorphous gray-yellow gelatinous liquid Microscopy: ulcerated epithelium, focally showing epithelial lining	Right-sided keyhole retro-sigmoid approach craniotomy. Cyst containing pathological amorphous gray-yellow liquid was evacuated.	2 months after surgery recurrence of the cyst which was removed. MRI 2 months after 2nd surgery shows no recurrence, and all neurological symptoms gradually regressed.
Anderson et al [3] [2020]	3/ 35y /F	Headache, dizziness, memory impairment and dysphagia	1 year	3.4 × 3.3 × 3.3 cm; Left cerebello-medullary cistern extending into the premedullary cistern.	CT: mass was isodense to gray matter. CT angiogram: displacement of the prepontine vasculature. MRI with contrast: T1 and T2 hyperintense mass in the left cerebellomedullary cistern extending into the premedullary cistern	Cystic lesion lined by pseudo-stratified, ciliated epithelium with focal squamous metaplasia.	Left suboccipital craniotomy and stereotactic-guided volumetric resection.	Postoperatively, left VI cranial nerve palsy that gradually improved, as well as mild right hemibody weakness and sensory deficits that also improved over the course of the next few months. Memory improvement.
Budke et al [18] [2020]	4/ 1.5y / F	Poor gait, L arm weakness and torticollis	7 weeks	3 × 1.5 cm; prepontine space to the cervico-medullary junction on the ventral aspect of the premedullary cistern	MRI: hypointense on T1-weighted images and hyperintense on the T2-weighted and FLAIR images. No enhancement was observed after Gadolinium administration.	Cyst wall lined by non-ciliated simple columnar epithelium and composed of thin fibrovascular connective tissue	Suboccipital craniotomy and cyst resected “en bloc”	3 years post-surgery normal development with no neurological or motor deficits
Singh et al [19] [2015]	5/ 33y / F	Generalized headache, double vision, facial deviation and nasal regurgitation	2 years	In lower pons and medulla	CT and MRI: lobulated heterogeneous mass with predominant cystic component in lower pons and medulla with compression of IVth ventricle	Gross: milky white walled structure containing mucoid material. Microscopic: Cyst wall lined with columnar epithelium.	Sub-occipital craniotomy, drainage of the cyst and decompression of the lesion via transvermian approach	Discharged in satisfactory condition
Miller et al [1] [2014]	6/ 34y /F	Severe abdominal pain with nausea and vomiting.	8 months	Area postrema of medulla	Cranial MRI: cystic mass near the caudal region of the fourth ventricle, resulting in obstructive hydrocephalus and brainstem compression	Gross: NA Microscopy: cystic mass lined by mucous columnar cells, with proteinaceous material, calcifications, vascular ectasia, and embedded small glandular structures.	Suboccipital craniectomy for gross total resection	Nausea, vomiting, and abdominal pain resolved post-operatively. At 1 year follow-up no neurological concerns
Ly et al [20] [2018]	7/ 11 y / F	Intractable emesis and worsening gait. Ataxia, right-sided uvula deviation, dysmetria, and vertical nystagmus	3 weeks	Craniocervical junction connected to the brainstem through a sinus tract	MRI: extensive T2 and FLAIR hyper-intensity in the brainstem. Rim-enhancing lesion at the medulla oblongata and a non-enhancing cystic lesion at the left CCJ displacing the brainstem with an eccentric focus of calcification	Gross: thick, pale gray cyst. Microscopy: Cyst composed of fibrovascular tissue lined by columnar to pseudostratified and partially ciliated epithelium.	Suboccipital craniectomy and C1 laminectomy. Excision of the leftdorsal exophytic cystic component of the mass, including the wall	At 2-month follow-up, radiological near-complete resolution and the patient was symptom free.
Shimizu et al [21] [2019]	8/ 7y / F	Dysarthric speech, diplopia and headache	1 week	2.2 cm × 2.1 cm × 1.8 cm; pons with no connection to adjacent cisterns	MRI: Cystic mass, hypointense on the T1-weighted images, hyperintense on the T2-weighted images, and isointense on the diffusion- weighted images	Gross: cyst filled with milky white viscous fluid Microscopy: cyst wall lined by ciliated columnar epithelium along with some goblet cells.	Midline suboccipital craniotomy. Removal of cyst component by aspiration, and cyst wall and mural nodule partially removed	Asymptomatic 5 years post surgery,, and no evidence of recurrence on MRI
Preece et al [22] [2006]	9/ 46 y/F	Impaired gag reflex, decreased sensation in right VI and V3 nerves	–	1.2 × 0.8 × 0.6, pons extending to Lower Right CPA	MRI: Hyperintense on T1W1 compared to CSF and Hyperintense on T2W1 compared to brain	Pseudostratified ciliated, columnar to cuboidal, scant mucin-producing cells	–	–
	10/ 39y /F	Headache	–	0.6 × 1.4 × 1.1; Midline, pontomedullary junction	MRI: Hyperintense on T1W1 compared to CSF and Hyperintense on T2W1 compared to brain	–	–	–
	11/ 60y /F	Headache	–	1.5 × 0.8; Midline, pontomedullary junction	MRI: Hyperintense on T1W1 compared to CSF and Hyperintense on T2W1 compared to brain	Pseudostratified ciliated, columnar to cuboidal; scant mucin-producing cell	–	–
	12/ NN	–	–	1.5 × 1; Lateral pontomedullary junction	MRI: Hyperintense on T1W1 compared to CSF and Hyperintense on T2W1 compared to brain	NA	–	–
	13/ 26y /F	Headache, nausea, vomiting, fever, nuchal rigidity (2 episodes in the form of viral syndrome)	–	1.5 × 2; Midline, anterior to medulla	MRI: Hyperintense on T1W1 compared to CSF and Hyperintense on T2W1 compared to brain	Simple columnar epithelium with chronic inflammation	–	–
	14/ 21 y/ F	Persistent occipital headaches “Migraine”	–	3 × 2.5; Midline, anterior to brain stem extending into both CPA cisterns	MRI: Hyperintense on T1W1 compared to CSF and Hypointense on T2W1 compared to brain	Pseudostratified, ciliated, columnar; mucin-producing cell poor; squamous metaplasia	–	–
	15/ 13 y /M	Headache and dioplopia	4 months	Moderately sized; Superior left pre-pontine cistern	MRI: Cystic mass displacing the basilar artery and impinging III cranial nerve.	Gross: Gray capsule with fine vascular network Microscopy: Pseudostratified columnar epithelium, without goblet cells or cilia. Epithelium- PAS positive and mucicarmine negative	Endoscopic endonasal trans-sphenoidal transclavial posterial cranial base approach, piecemeal removal of cystic mass	Postoperative: doing well with no new neurological defects.
Sangrador-Deitos et al [4] [2022]	16/ 60 y/ M	Intermittent headaches, sudden decreased level of consciousness	NA	NA; Pontomedullary junction	CT scan: Right posterior fossa hypodense mass with fourth ventricle obliteration MRI: T1-weighted intra-axial, multilobulated, hypointense mass dorsal to the right pontomedullary junction. No enhancement post gadolinium administration and hypointense on FLAIR sequence	Geoss: Solid and cystic multilobulated, containing yellowish watery fluid. Microscopy: Cyst lined by single layer of pseudostratified cuboidal or columnar epithelium and intermingled goblet cells	Middle sub-occipital approach, utilizing telovelar corridor. Complete resection of mass	3 month follow-up MRI showed no residual lesion
Hingwala et al [23] [2021]	17/ 17 y/ F	Neck pain, limb weakness, numbness in L and R upper limbs and urgency of micturition	2 weeks	3 × 1.8 × 2.4 cm, Anterior and to the right of medulla extending through foramen magnum to upper cervical canal	MRI: Hyperintense on T1 and T2 weighted images with no diffusion restriction	Microscopy: Cuboidal to columnar epithelium lined cyst wall with goblet cells	Suboccipital craniectomy and total excision of the cyst by R lateral approach	Postoperatively, weakness resolved in limbs.
	18/ 28 y /F	Difficulty in holding objects with L upper limb, gait unsteadiness, dysarthria and nasal regurgitation	1 ½ year	5.4 × 4.2 × 5.3 Brainstem and distorting the 4th ventricle, in L side posterior fossa.	CT: hyperdense extraxial lesion MRI: Iso- to mildly hypointense on T2 weighted images and hyperintense on T1 weighted images	Microscopy: Pseudo-stratified ciliated columnar epithelium lining with large areas of squamous metaplasia	Midline suboccipital craniectomy with excision of cyst	NA
	19/ 7 month/F	Downgaze preference and excessive crying	1 month	7 × 5.7 × 5.8; Left side of posterior fossa compressing the brainstem and cerebellar hemisphere	MRI: CSF-intensity cystic lesion	Gross: NA Microscopy: Pseudo-stratified ciliated cuboidal to flattened epithelium lined cyst wall, wall composed of fibrocollagenous tissue with dilated vascular channels	Midline suboccipital craniotomy and decompression of cyst	NA
Ogulnick et al [24] [2021]	20/ 75 /F	Headache, progressive weakness, dizziness, and lightheadedness	4 months	Pre-medullary cistern and brainstem	CT without contrast: mildly hyperdense extra-axial mass at the upper aspect of the premedullary cistern and compressing the brainstem. MRI: T2 FLAIR showed well-circumscribed, hyperintense mass with mass effect on brainstem.	Gross: Yellowish cyst wall Microscopy: fibro-membranous cystic wall with pseudostratified, ciliated columnar epithelial lining.	L retrosigmoid craniotomy with fenestration/biopsy of cyst	Symptom-free at 5-month of follow-up
Yang et al [25] [2016]	21/ 58 y /F	Recurrent neurenteric cyst presenting with headaches and dizziness.	Previous cyst at L CP angle, 8 Y back. Duration of present illness: 5 months	Medulla oblongata	MRI: cystic mass in the left side of the foramen magnum that was located anteriolaterally to the medulla oblongata	Gross: Pseudostratified columnar and non-ciliated epithelial lining of cyst, mixed with goblet and mucin-producing cells. No malignant component	L suboccipital retrosigmoid approach with partial resection of cyst wall	23 months after the 2nd craniotomy, the patient presented with a severe headache, projectile vomiting, diplopia and limb fatigue, underwent a 3rd craniotomy for brainstem lesion and diagnosed with well-differentiated papillary adenocarcinoma.
Agresta et al [26] [2020]	22/ 18 month/ F	Recurrent neurenteric cyst presenting with dysphagia, irritability, and new onset of left torticollis and hypertonia.	3 weeks before cyst at pontomedullary junction was excised. Duration of present illness: 2 weeks	1.3 × 1.6 × 1.3 cm; Ponto-medullary junction	MRI: Showed a recurrence of the cystic lesion	Diagnosis of an NC confirmed on histopathology	Sub-occipital transvelar microscopic approach with fenestration and complete aspiration	Clinically well without any neurological deficits at the 11-month follow-up
Zalatnai et al [15] [1987]	23/ 29 weeks of gestation	Born with pallid asphyxia and died after 70 min	–	0.4 cm; Border of pons and medulla	–	Microscopic: columnar epithelium of a primitive gastrointestinal type, with abortive crypts. The nuclei were of basal location. Cells periodic acid-Schiff (PAS) positive and granular in the cytoplasm, mucicarmine and toluidine blue stains were negative	Post-mortem	–
Bechri et al [27] [2020]	24/ 28/ F	chronic headaches	6 months	At the level of brain-stem	CT: small isodense round lesion in front of the brainstem. MRI: isointense T1& hyper intense T2 extra-axial cystic lesion, with no contrast enhancement	Clinicoradiological diagnosis of neurenteric cyst	Not excised due to poor clinical presentation	–
Ko et al [28] [2008]	25/ 4y /F	Intermittent neck pain, morning headaches, and vomiting	NA	4 × 3 cm; prepontine area	MRI: low signal intensity on T1-WI and high signal intensity on T2-WI in comparison to signal of CSF Another component of the mass adjacent to the basilar artery depicted isointense signal on T1-weighted images, low signal intensity on T2-weighted images, and enhancement after gadolinium administration	Gross: Cyst containing clear fluid Microscopy: Goblet cells containing abundant mucin along the epithelium. Yellowish solid nodule yellowish solid nodule showed foamy histiocytes and chronic inflammatory cells	Right lateral suboccipital craniotomy with complete removal of cyst along with the attached yellowish solid nodule	No post-op residual tumor on MRI. Preoperative symptoms completely disappeared after tumor removal
Shin et al [29] [2002]	26/ 35/ F	Headache	3 years	Cerebellopontine angle, abutting the left side of pons	CT: hyper-attenuating mass relative to the cerebellar parenchyma MRI: well-circumscribed mass in the left cerebellopontine angle cistern and abutting pons. The mass was homogeneously hyperintense relative to CSF on T1-WI and isointense relative to CSF on T2-WI	Gross: thin translucent cyst with attached 8 mm ovoid solid nodule Microscopy: Cyst lined by ciliated columnar epithelium and focal squamous metaplasia. Solid nodule composed of foamy histiocytes, chronic inflammatory cells, multinucleated giant cells, and cholesterol clefts IHC: Positive for CK, EMA and CEA	Far-lateral sub-occipital approach with excision of mass	NA
Wang et al [30] 2009	27/ 26/ F	Pain at the left occipital region	3 months	4.0 × 2.1 cm; Cerebellopontine angle abutting the brainstem	MRI: Cystic lesion situated at the left CPA with clear confines which compressed the brainstem to the right side.	Microscopy: Cyst lined by pseudostratified ciliated columnar epithelium with scant goblet cells and simple columnar epithelium with abundant goblet cells. Malignant features including increased cellularity, anaplasia, nuclear pleomorphism, frequent mitosis, as well as features of invasion.	Total excision of the cyst	5 months latter patient presented with acute onset neck pain; along with dysphagia, hoarseness, left tinnitus, hearing hallucination and transient loss of consciousness. Lumbar puncture evaluation confirmed tumor dissemination as tumor markers were raised.

CCJ: craniocervical junction, CPA: Cerebellopontine angle, M: Male, F: Female, R: right, L: left.

Through its exceptional soft tissue contrast, MRI enables precise localization, visualization, and characterization of these cysts within the central nervous system (CNS), aiding in surgical planning. It facilitates the identification of cyst contents, ranging from proteinaceous to hemorrhagic or mucinous components, crucial for differentiation from other CNS cystic lesions. Additionally, MRI allows for a detailed assessment of the cyst wall and its relationship with adjacent neural structures, aiding in determining any compression, displacement, or infiltration of surrounding tissues. Furthermore, MRI serves to detect associated congenital anomalies such as vertebral anomalies or Chiari malformations and is invaluable for monitoring disease progression, treatment response, and post-treatment complications through follow-up scans. Overall, MRI stands as an indispensable tool in the comprehensive management of neurenteric cysts, providing essential information for guiding clinical decisions and optimizing patient outcomes.

On magnetic resonance imaging, the cysts had a varied presentation. In majority of cases, the cystic mass was hyperintense on T1WI compared to the cerebrospinal fluid and hyperintense on T2WI compared to the brain parenchyma. However, few cysts were hypointense on T1 and hyperintense on T2WI while others were isointense on both T1/ T2 or hyperintense on TI and iso to hypointense on T2WI. [3,22,24,30].

In the majority of cases, complete excision of the neurenteric cyst was achieved following decompression/aspiration of the cyst contents. However, Yang et al. reported a case where partial cyst removal was performed, and Bechri et al. chose not to excise the cyst due to a poor clinical presentation.

Gross observations varied from uniloculated to solid multiloculated cysts filled with gelatinous to watery fluid. Microscopic examination revealed a cyst lining ranging from cuboidal to pseudostratified ciliated columnar epithelium, often with goblet cells. Some cysts exhibited focal squamous metaplasia. In a specific case by Wang et al., the cyst had a lining of pseudostratified ciliated columnar epithelium with scant goblet cells and simple columnar epithelium with abundant goblet cells. Notably, this cyst displayed malignant features, including increased cellularity, anaplasia, nuclear pleomorphism, frequent mitosis, and invasion.

In cases with available postoperative follow-up, the majority experienced uneventful recovery with symptom resolution. However, two cases saw cyst recurrence, occurring 3 years and 2 months postoperatively, respectively, necessitating repeat surgery. Another case presented with severe symptoms, including headache, projectile vomiting, diplopia, and limb fatigue, leading to further investigation and the confirmation of well-differentiated papillary adenocarcinoma. Additionally, the neurenteric cyst reported by Wang et al., which displayed focal malignant features, showed evidence of tumor dissemination 5 months later, marked by acute onset neck pain, dysphagia, hoarseness, left tinnitus, hearing hallucination, and transient loss of consciousness.

This study sheds light on the rare and intriguing entity of neurenteric cysts (NCs), particularly focusing on their manifestation within the brainstem. Neurenteric cysts, though constituting a minute fraction of central nervous system tumors, present a diagnostic challenge due to their diverse clinical presentations and the rarity of their occurrence in the brainstem. The historical evolution of terminology and classification underscores the enigmatic nature of these lesions and highlights the ongoing effort to understand their embryonic origins. However, this was a retrospective study design, further prospective study could be undertaken in future.

5. Conclusion

The case series sheds light on three brainstem neurenteric cysts, highlighting varied clinical presentations and demographic aspects. It underscores the importance of considering NCs in intracranial cystic lesion diagnoses. The literature review emphasizes the rarity of NCs, challenges in determining incidence/prevalence, and proposes a classification system for differentiation. MRI remains pivotal for diagnosis, revealing cystic nature and anatomy. Surgical intervention for complete resection is primary, requiring interdisciplinary collaboration due to surgical complexity.

Ethical approval

Written informed consent was obtained from the patient for publication of this case series and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Parental Consent (For Minors): Written informed consent was obtained from the patient's parents/legal guardian for publication and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

The study was conducted in agreement with the Declaration of Helsinki.

Funding

None.

Author contribution

Sana Ahuja: Methodology, Validation, Formal analysis, Investigation, Resources, Data Curation, Writing - Original Draft, Writing - Review & Editing, Visualization.

Dipanker Singh Mankotia: Conceptualization, Methodology, Validation, Resources, Data Curation, Visualization, Supervision.

Sufian Zaheer: Methodology, Validation, Formal analysis, Investigation, Resources, Data Curation, Writing - Original Draft, Writing - Review & Editing, Visualization, Supervision.

Guarantor

Sufian Zaheer

Consent for publication

Written informed consent was obtained from the patient for publication and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Parental Consent (For Minors): Written informed consent was obtained from the patient's parents/legal guardian for publication and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Declaration of competing interest

The authors report there are no competing interests to declare.

Data availability

No additional data is available.