This study provides additional data on the signalment, neuroanatomical location, histopathological subtype and long-term outcome following the surgical resection of intracranial meningiomas. Although this data is available for cats following the recent publication of a large multicentre study [9], there remains limited information available for dogs. The results of this study illustrate the variability and differing combinations of adjunctive treatment protocols currently utilised in dogs following the surgical resection of an intracranial meningioma. Whilst there was no significant difference in survival time with the addition of any specific adjunctive therapy, it highlights that surgery for meningioma resection offers an excellent prognosis for hospital discharge and a median long-term survival of 386 days.
In human medicine, intracranial meningiomas are most commonly treated via their primary excision, which is also true of cats in veterinary medicine [10]. In cats, we often think of the surgical excision of an intracranial meningioma as curative, with a reported median survival time of 37 months and the majority of cats eventually dying of causes unrelated to the meningioma [9]. Unlike dogs, meningiomas in cats are often better defined and less invasive [8, 9, 11], and hence further adjunctive therapy following their excision is not typically necessary. However dogs have a larger percentage of higher grade meningiomas (atypical grade II) when compared to cats and humans [11]. This higher incidence of atypical (grade II) meningiomas in dogs and their more invasive nature might account for their poorer therapeutic response when compared to humans and cats [11]. Because of this, additional adjunctive therapies are often used following the surgical excision of meningiomas in dogs in order to try and augment their survival time.
The MST for dogs that had standard cytoreductive surgery alone without the addition of any of the adjunctive therapies was 353 days compared to dogs that had one or more of any form of adjunctive therapy utilised having a median survival time of 403 days, with no significant difference in survival between these two groups. Whilst hugely variable, the average MST for dogs that had standard cytoreductive surgery in previous studies was approximately 10 months (range 7 months − 16.5 months) [1, 4, 12].
An ultrasonic aspirator was the most common adjunctive therapy utilised with more than 50% of all dogs in this study having it used. For those dogs where an ultrasonic aspirator was used during surgery without the addition of any other adjunctive treatments (n = 18), the MST was 421 days and not statistically different to those that had surgery alone. Ultrasonic aspirators are widely used in human neurosurgery for the resection of meningiomas and allow preferential ablation of tissue with a higher water content such as neoplastic tissue [2, 13]. Previous studies examining the use of aspirators for meningioma resection in dogs reported a MST of 1274 days [2, 14, 15]. However, this MST was based on the analysis of approximately three surviving dogs only [2, 16]. Another study used an aspirator in 23 dogs for the excision of intracranial meningiomas with 16 of these dogs surviving for more than 2 years following surgery [17]. However, an intraoperative MRI was also used in this study which might also have contributed to the extended survival times reported [17].
Hydroxyurea is an antimetabolite that specifically affects the S stage of the cell cycle and has been suggested as a chemotherapeutic agent for the management of meningiomas [3]. The administration of hydroxyurea was the second most commonly used adjunctive therapy with 41% (41/101) of dogs being administered it. For those dogs that had hydroxyurea administered without the addition of any other adjunctive treatments (n = 6), the MST was 626 days and not statistically different to those that had surgery alone. To date, there have been a few reports of the use of hydroxyurea in dogs following meningioma resection and whilst many dogs in this study received hydroxyurea, very few had it as the sole adjunctive therapy making any meaningful comparisons difficult [5,6,7]. It is worth noting that the dose, frequency of administration and treatment length of hydroxyurea varied widely between dogs making it difficult to allow accurate comparisons. In humans, hydroxyurea has been shown to increase progression-free survival following incomplete resection of meningiomas and hence this treatment is potentially worth investigating further in the future [18, 19].
Eleven dogs were administered post-operative radiotherapy with only 4 dogs receiving it as the sole adjunctive therapy. Two of these are still alive at the time of writing and two didn’t complete the full radiotherapy course as they were euthanised before completion. It is interesting that this was the least utilised of the four adjunctive therapies particularly given it is the one with the strongest evidence base compared to other types of adjunctive therapy [4, 20, 21]. Reasons for this might include the cost, perceived invasiveness of multiple general anaesthetics, prolonged periods of time away from home and the fact that it was not available at any of the treatment centres that performed the surgery. The MST in this study is far below that which has been previously reported in the literature which ranges from 16 to 30 months for dogs having had surgical resection and post-operative radiotherapy [4, 20, 21]. Given the small number of dogs in this group, the variation in radiotherapy protocols received and the fact that two didn’t complete their course and two are still alive, the MST reported in this study is likely not reflective of the true benefit of post-operative radiotherapy. In humans, radiotherapy as a sole treatment or following incomplete surgical resection of meningiomas has been shown to be beneficial with 5-year progression-free survival rates of 80–100% for both benign and atypical tumours [22, 23].
One centre used intraoperative topical chemotherapy as a clinical trial up until 2015 in the form of methotrexate and cytosine arabinoside following the removal of the meningioma. It was never used as the sole adjunctive therapy and was always in combination with one of those previously discussed. The MST of all dogs that received topical chemotherapy (in combination with other adjunctive therapies) was 166 days whilst the median survival time of dogs receiving any of the other adjunctive therapies (apart from topical chemotherapy) was 454 days (95% CI 258.7–649.3), which was significantly different (p < 0.05). There is a report of the use of this combination of topical chemotherapy in the veterinary literature with one previous paper reporting its use following the excision of an intracranial inflammatory fibrosarcoma [24]. The reduced survival time for those dogs that received this topical chemotherapy in this study could be due to the direct action of these agents themselves or potentially for different reasons but based on these results, it cannot be recommended as an adjunctive treatment following the surgical excision of an intracranial meningioma.
The most common breeds in this study included Labradors, German Shepherds and Boxers with no sex predilection identified, which is consistent with previous studies [2, 4, 11, 25]. The most common presenting clinical complaint was seizure activity with over 90% of dogs having had documented seizures at the time of presentation. This is different to cats where seizures are less common as a presenting sign seen only in approximately 14–25% of cats [26,27,28]. Over 92% of the meningiomas resected were in the forebrain with almost 70% of the meningiomas being associated with either the olfactory lobe or frontal lobe, consistent with previous reports [11, 29]. This might be reflective of our inclusion criteria as it is possible our study selected for cases that had meningiomas in locations thought to be more surgically accessible such as those in the frontal and olfactory lobes. Fifty percent of dogs in this study had extracranial imaging performed as part of staging and none had evidence of extra-cranial meningioma metastases, possibly suggesting that extracranial imaging might not be worthwhile in intracranial meningioma cases. However this also might be reflective of our inclusion criteria as it is possible our study selected for cases that had no evidence of extra-cranial metastases before intracranial surgery was performed. Hence, thoracic and abdominal imaging could still be considered in such cases before performing often expensive and invasive intracranial surgery, since 27% of meningioma patients were found to have an unrelated but potentially clinically relevant form of neoplasia in a post-mortem examination study [29]. Of those in our study that had extracranial imaging performed, 12% had clinically unrelated abnormalities identified with only one confirmed to be neoplastic in nature.
Meningiomas are particularly interesting tumours due to the number of histological subtypes that exist. The meningotheliomatous (28/101) and transitional (23/101) histological subtypes were the most commonly identified in this study, together accounting for greater than 50% of the total number of meningiomas. This is similar to other studies that have also shown these two subtypes to be the most commonly identified in dogs [11, 30, 31]. In cats, the most frequent subtypes identified tend to be the psammomatous and transitional meningiomas with anaplastic meningiomas being very rare [9, 32, 33]. In humans, the anaplastic variant of meningioma is also rare accounting for 1–3% of all meningiomas in people with the most common morphological subtypes in humans being meningothelial, fibroblastic, transitional and psammomatous [34,35,36]. We found no significant association between long-term survival and histopathological tumour type using the domestic animal WHO tumour classification system [8]. However, a future study using the WHO international histological classification of human meningiomas into grades I, II or III or the molecular subtyping of meningiomas could be interesting in order to ascertain if there is an association between tumour grade or the molecular characterisation and long-term prognosis [37, 38].
Whilst the removal of a brain tumour can be a daunting prospect for both the clinician and owner, this study shows that the survival to hospital discharge following such a procedure is relatively high at almost 95%. Sixteen percent of dogs developed a post-operative complication whilst hospitalised, with the most common being aspiration pneumonia seen in 6% of dogs, which is consistent with previous studies examining intracranial surgery in dogs [39, 40].
Interestingly, those dogs that had a transfrontal surgical approach in this study had a significantly reduced survival time compared to those that had a rostrotentorial approach. Given the many differences already identified in how these patients are treated and hence the possibility of many confounding factors within these two groups, it could be a type 1 error and hence we are cautious as to how much significance to place on this finding. However potential reasons for this difference might include that the rostrotentorial approach affords better access to allow a more complete surgical excision or that the transfrontal approach results in more frequent long term post-operative complications that are life limiting or a possible increased risk of post-operative seizures. Further work is needed to confirm this difference and to ascertain the potential underlying reasons for it.
The limitations of this study are reflective of its retrospective nature with a very heterogenous sample, neurosurgeons of differing experience and a nearly universal lack of quantifiable assessment of the extent of surgical resection (be it surgeon or imaging based). Long term follow up of such cases can be challenging for many reasons and the cause of death with these dogs should be treated with caution as to differentiate the cause of death as neurological due to regrowth or non-neurological in nature is difficult particularly in a mainly geriatric population.
The aim of this study was to detail what is currently being done in the surgical removal of meningiomas in dogs. It encompasses four large referral centres in the UK and due to its sample size, gives a fairly accurate estimation of the long-term survival of dogs following intracranial meningioma resection. This study suggests that whilst adjunctive therapy for such cases is often utilised, there is no clear consensus on which of those described is the most appropriate and reflects the current lack of evidence-based treatment. The results of this study fail to identify the superiority of one type of adjunctive therapy but further work is needed to allow for more meaningful comparisons in the form of prospective studies, which will hopefully allow for superior treatment of this condition in the future.
