CSF shunts as conduits for metastasis: is there a discrepancy between retrograde and antegrade spread?

Abstract

Background

Cerebrospinal fluid (CSF) shunting refers to the surgical drainage of excess CSF, which arises due to outflow obstruction or a reduction in absorption. Although rare, the dissemination of neoplastic cells along ventriculoperitoneal shunts is well documented, a gap in knowledge exists regarding differences in the direction of neoplastic dissemination along CSF shunts. The aim of this systematic review was to comparatively assess the nature of antegrade and retrograde metastatic spread along CSF shunts.

Methodology

A dual systematic review in six major databases was conducted for articles until June 15, 2023, without language restrictions following PRISMA 2020 guidelines and the Cochrane Handbook for Interventional Systematic Reviews. The study focused on the metastasis of both CNS malignancy to extra-neural sites and the retrograde metastasis of extra-neural tumours to the CNS along CSF shunts. Inclusion criteria were case reports with patient characteristics and clinical outcomes. Data were extracted using a standardised table and qualitatively analysed. The JBI case report critical appraisal tool assessed reporting quality. Grey literature was not included.

Results

A total of 106 reports of antegrade metastasis were identified representing 121 cases. Patients were most commonly children, with the primary tumour and shunt type being germinomas. Six reports detailing retrograde metastasis met our inclusion criteria with an overall high quality of reporting. All primary tumours were in the abdomen or pelvic cavity with treatment from metastasis depending on patient characteristics. Generally, the prognosis was poor, with one patient succumbing to peritonitis, four cases showing residual disease, and one patient receiving palliative care.

Discussion and Conclusion

This updated systematic review noted similar demographic trends regarding the metastasis of CNS malignancy to extra-neural sites through CSF shunts reported by Xu et al. (2018); yet, due to data inaccessibility, updated statistics could not be inferred. Germinomas remained the most common tumour pathology, warranting increased vigilance in patients with germinomas and a CSF shunt. Moreover, this review identified that extra-neural malignancy retrograde CSF shunt metastasis is extremely rare. This study proposes standardised nomenclature for classifying metastasis through CSF shunts for easier clinical identification.

Introduction

Cerebrospinal fluid (CSF) shunting refers to the drainage of excess CSF, where there exists an obstruction to the normal outflow or a reduction of CSF absorption [1]. A CSF shunt consists of a ventricular catheter, which is associated with a valve, and is often used for the treatment of hydrocephalus and idiopathic intracranial hypertension [2]. The distal end of the catheter can be sited in the peritoneum (ventriculoperitoneal shunt, VP); right atrium (ventriculoarterial shunt, VA); the pleura (ventriculopleural shunt) directly into the venous system (ventriculovenous shunt); i.e. into sites where the excess CSF can be deposited and absorbed [3]. VP shunts are the most common form of CSF shunt and are a highly effective [4] but are also vulnerable to a variety of complications, as observed in nearly 70% of VP shunt cases [5]. A rare complication is the extra-neural dissemination of cerebral malignancy through VP shunts, along the flow of CSF [6], as documented by Xu et al. (2018). Yet, current knowledge is limited to antegrade dissemination of malignancy along CSF shunts. Scarce literature have documented the retrograde spread from primary extra-neural tumours along CSF shunts against the current of the flow of CSF. A lack of awareness and understanding regarding this complication could have clinical implications, potentially leading to abnormal presentations, prolonged investigations, or exclusion from the clinician's differential diagnosis. Thus, the aim of this qualitative systematic review is to draw comparisons, or otherwise, between cases of antegrade and retrograde metastatic spread along CSF shunts to better characterize this rare complication of CSF shunting.

Methods

This systematic review was generated according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) Checklist 2020 [7], and the Cochrane Handbook for Systematic Reviews of Interventions [8].

PubMed, MEDLINE, Google Scholar, Science Direct, Scopus, and Semantic Scholar databases were searched for relevant articles. Combinations of the following keywords were used to develop a database-specific search strategy in combination with a series of Boolean “AND/OR” operators and asterisk wildcards, for each systematic search: “cerebrospinal fluid”; “CSF”; “ventriculoperitoneal”; “VP”; “lumboperitoneal”; “ventirculoatrial”; “VA”; “ventriculovenous”; “shunt”; “extra-neural”; “antegrade”; “retrograde”; “metastasis”; “spread”; and “dissemination”. No language restrictions were put in place. Articles concerning antegrade metastasis dissemination along CSF shunts were included in our study if published after the Xu et al. (2018) study and were conducted following the PRISMA 2020 flow diagram for updated systematic reviews which included searches of databases and registers only. No date restriction was set for articles published documenting cases of retrograde spread along CSF shunts and was conducted following PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only. The systematic searches where conducted until June 2023.

The inclusion criteria were (1) case reports or case series; (2) which clearly describe the antegrade or retrograde metastasis; (3) of a primary malignancy; (4) along a CSF shunt; and (5) which report patient characteristics and clinical details.

The database search results were exported as CSV or Bibtext format and uploaded into Rayyan reference managing software [9]. Duplicate titles were removed, and an initial screening of titles and abstracts was conducted to discard irrelevant articles. Full-text screening was then conducted. Grey literature was not searched to develop either systematic search. Data from included studies identified through the systematic review were extracted using a standardized data collection table. The extracted data were qualitatively analysed due to a lack of reported quantitative data following guidelines for qualitative systematic reviews published by Butler et al. (2016) [11].

Results

Literature search

This systematic literature review identified 14 new studies published post- Xu et al. (2018)’s systematic review, resulting in a total of 106 articles documenting 121 patients with antegrade extra-neural metastasis along CSF shunts (Fig. 1). Six articles documenting retrograde metastasis of extra-neural primary neoplasms along CSF shunts met our inclusion criteria (Fig. 2).

Fig. 1

PRISMA 2020 flow diagram representing the systematic search for articles documenting cases of antegrade metastasis [7]

Fig. 2

PRISMA 2020 flow diagram representing the systematic search for articles documenting cases of retrograde metastasis [7]

Extra-neural Antegrade metastasis of central nervous system primary tumours along CSF shunts

Of the 121 total cases of primary intracranial tumours associated with shunt placement, 66 were males, 45 were female, and 10 did not have gender reported. The gender ratio among these cases was M/F 1.47. Age at diagnosis ranged from 7 weeks old to 84 years old, with 79 cases (70.54%) being < 18 years old. The overall average and median age at diagnosis could not be determined. In nine cases, age was not reported. In 19 of 121 cases race was reported, in which 36.84% were white, 21.05% were black or African–American, 15.79% were Hispanic or Latino and 26.32% were Asian (Table 1). The most common types of tumours leading to extra-neural metastasis were germinomas (24.79%), medulloblastomas (18.18%), and glioblastoma (12.40%) (Table 2). Most cases (n = 110) involved VP shunts. Locations of metastases are summarized in Table 3. The most common location of metastasis was the peritoneum (85.95%). The leptomeningeal spread was seen in 47.93% of cases. The primary CNS tumours were treated with surgical resection in 39 cases (36.79%), using radiotherapy in some form in 89 (83.96%) cases and chemotherapy in some form was used in 37 cases (34.91%).

Table 1 Patient demographics

Table 2 Primary underlying diagnosis

Table 3 Metastasis locations

Retrograde metastasis

Five of the clinical cases described retrograde metastasis along VP shunts, while the case described by Frantzias et al. (2019) occurred along an LP shunt. Four of the six cases reported cutaneous or subcutaneous metastases along the shunt tract, while two articles reported neurological manifestations of the malignant spread. All cases indicated that the primary tumours originated from the abdomen or pelvic cavity. Two primaries were ovarian in origin, while the rest originated from the gastrointestinal tract. The patients were all adults of varying ages and sexes. The shortest interval between shunt insertion and the development of symptoms due to retrograde shunt metastasis was 1 month; attributed to an iatrogenic cause. All included cases are summarized in Table 4. The management of each of these six cases varied significantly between on another. Treatment of retrograde metastasis along CSF shunt depended on the extent of the primary tumour, patient characteristics, and whether CNS seeding occurred. The affected shunt was fully removed in two cases, while conversion to a VA shunt was done in another. Systemic therapy using chemotherapy or a combination of radiotherapy and chemotherapy was done in two cases for the treatment of metastasis. The prognosis of retrograde shunt is relatively poor; however, this was mainly attributed to the patient’s poor condition and not the retrograde metastasis itself. From the cases examined, one patient died due to peritonitis, although it was not made clear whether this was related to a treatment, the present malignancy, or a concurrent disease process. Another four cases had residual disease, with one patient receiving palliative care and the others maintaining routine lives while having routine follow-ups. The treatment offered and the corresponding outcomes can be seen summarized in Table 5.

Table 4 Summary of reported cases describing retrograde metastasis

Table 5 Treatments and outcomes of shunt metastasis

Discussion

Consideration is warranted for extra-neural metastasis originating from primary CNS tumours through CSF shunts

The antegrade metastasis of CNS malignancy to extra-neural sites through CSF shunts has been a known complication of CSF shunting since 1950s [32]. Early efforts to curb such metastatic spread included the use of filters within CSF shunts [33], however these had unacceptable high rates of obstruction [34]. Consequently, current focus has been shifted towards understanding risk factors which may increase the likelihood of extra-neural metastasis of CNS malignancy via CSF shunts [6]. Our findings reinforce conclusions drawn by Xu et al. (2018), who demonstrated that extra-neural spread via CSF shunts can occur in a wide age range of patients from a wide variety of tumours. Generalizations from this updated systematic review of a total of 121 patients demonstrated that Xu et al. (2018) insights on the conclusions of CNS malignancy metastatic spread via CSF shunts still uphold. Namely, children less than 18 years old comprise most of these cases, which echo the demographics of tumour pathologies seen in this age group which are more likely to be locate in the posterior fossa and obstruct the ventricular system. Thus, paediatric tumours are more likely to be associated with hydrocephalus development [1].

Xu et al. (2018) noted that tumour pathologies of paediatric patients also affect mean survival times, given that children often present with less aggressive tumours. However, the results provided by Xu et al. (2018) concerning patient survival by age, gender and primary underlying could not be update due to inaccessibility to the data. The distribution of tumour pathologies noted in this updated systematic review was highly similar to that reported by Xu et al. (2018), with the most common tumour types being germinomas, medulloblastomas, and glioblastomas, respectively, which may reflect the virtue of the location or origin of these tumours which may cause obstructive hydrocephalus requiring the placement of a shunt. Moreover, the degree of tumour resection and other treatment received may be another contributing factor the extra-neural spread of metastasis through CSF shunts, but case reports often did not disclose the extent of resection; hence, further studies are required to confirm any possible link (Table 6).

Table 6 Proposed frame work for classifying metastasis through cerebrospinal fluid shunts

An analysis of whether the type of shunt, tumour pathology, patient age on first presentation, and shunt placement were correlated with extra-neural metastasis through CSF shunts could not be achieved to lack of available data. Yet, this review extends Xu et al. (2018)’s assertations that patients with patients germinomas, leptomeningeal, or cerebrospinal metastasis, and a CSF shunt requires increased surveillance to detect the development of extra-neural metastasis. Cytological investigations of any ascitic which occurs subsequent to shunt placement are imperative to determine metastasis. An alternative treatment to shunt placement in patient populations who are prone to extra-neural metastasis may be endoscopic third ventriculostomy (ETV), especially for patients with germinomas [6].

Retrograde metastasis along CSF shunts is exceedingly rare

Halder et al. (2017) first introduced the term retrograde metastasis along CSF shunts, reporting a case of gastrointestinal carcinoma seeding along a VP shunt. In four of six cases in this review, cutaneous lesions along the shunt tract indicated metastatic deposits, deviating from expected radiographical findings. Lesions tended to overlay the VP shunt tract, originating from neoplastic cells migrating retrogradely along the shunt. Eralp et al. (2008) suggested leptomeningeal involvement of ovarian cancer via the VP shunt, while Frantzias et al. (2019) proposed three routes of spread: intraoperative, via the shunt track, or from within the catheter lumen. Takatu et al. (2018) and Kataoka et al. (2021) emphasized careful intraoperative manipulation and post-operative follow-ups to reduce metastases.

Two cases involved retrograde metastasis to the CNS: one spreading to the brain via the VP shunt and the other to the conus medullaris via an LP shunt. Both cases presented with neurological symptoms. Takatu et al. (2018) suggested free neoplastic cells in peritoneal fluid as the source, migrating via the catheter lumen or subcutaneous tunnel. Upon suspected retrograde metastases, further investigation is crucial, potentially altering the original malignancy treatment. Biopsy for histology and immunoexpression confirmation of the primary tumour are recommended.

MRI can assess the shunt track and skin lesions, aiding in mass characterization. Radionuclide imaging identifies shunt obstruction and metastasis, albeit with the drawbacks of cost and ionizing radiation. Computed tomography complements the evaluation of the original tumour. Detection of retrograde metastases prompts essential interventions for patient management.

Current nomenclature of metastasis through CSF shunts is ambiguous

The lack of a standardized framework for describing the phenomenon of metastasis along the CSF shunts poses an issue in nomenclature. Although the term "retrograde metastasis" is utilized, it might not comprehensively capture the complexity and diverse routes of spread, as indicated by various authors. It is noted in the text that Halder et al. (2017) initially employed this term when describing a case involving subcutaneous gastrointestinal carcinoma seeding along a ventriculoperitoneal (VP) shunt. Subsequent authors, such as Frantzias et al. (2019), have suggested alternative routes, including intraoperative dissemination, spread via the shunt track, and migration from within the catheter lumen via the CSF. This variability in terminology reflects the evolving understanding of the mechanisms underlying the retrograde spread of malignancies along CSF shunts. Similarly, no criteria exist to aid clinicians identify antegrade metastasis of primary CNS malignancy to extra-neural sites. Standardizing the nomenclature could enhance clarity and facilitate communication among researchers and clinicians investigating this rare phenomenon.

Strengths and limitations

To the best of the authors' knowledge, this represents the first systematic review to comprehensively examine the attributes, treatment modalities, and prognostic factors associated with retrograde CSF shunt metastasis beyond the confines of the neural system. Furthermore, this study built upon the investigation conducted by Xu et al. (2018), thereby presenting an updated systematic review focusing on the metastatic spread of CNS malignancies via CSF shunts to extra-neural locations. The reporting of results and discussion mirrored closely that presented by Xu et al. (2018) to reflect their study and extend their findings with congruency.

It is imperative to acknowledge the constraints inherent in this review. The primary constraint pertains to the unavailability of the dataset compiled by Xu et al. (2018), impeding the provision of aggregated descriptive statistics for the entire cohort of 121 cases, as well as the derivation and application of inferential statistical analyses. Moreover, another inherent limitation arises from the paucity of documented instances, leading to challenges in drawing generalizable conclusions. Additionally, a subset of the case reports detailing retrograde metastasis along CSF shunts lacked histological validation for the metastatic occurrences. Despite this, an analysis of the six scrutinized case reports facilitated the identification of clinically significant findings.

It is noteworthy that the ambit of this review is constrained by the available corpus of data, given the rare incidence of metastatic events along CSF shunts. Consequently, the reliance predominantly rests upon case reports and case series as the principal sources of information. One must acknowledge the plausible presence of inherent bias within the accessible literature due to the inherent nature of case reports, with retrospective data retrieval further encumbered by variable levels of data availability and precision. Despite these acknowledged limitations, the extant data continue to hold intrinsic value in affording insights into potential clinical nuances and delineating avenues that warrant prospective research endeavours.

Conclusions and recommendations

This systematic review updates Xu et al.'s (2018) findings on extra-neural metastasis through CSF shunts and while providing new insight regarding retrograde metastasis. Risk factors and demographics mirror previous research, emphasizing the need for increased surveillance, especially for paediatric patients with certain tumour types. Collaborative data sharing and prospective studies are recommended for better statistical analysis and comprehensive insights. Histological validation of retrograde metastasis cases is crucial. Clinical awareness, timely investigations, and consideration of treatment modifications upon detection are essential. Educating healthcare providers about these possibilities can improve patient care. This review underscores the rarity of these events, highlighting the importance of careful management and preventive measures.