An Official publication of The Asian Congress of Neurological Surgeons (AsianCNS)

Search Article
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Advertise Subscribe Contacts Login  Facebook Tweeter
  Users Online: 16 Home Print this page Email this page Small font sizeDefault font sizeIncrease font size  

   Table of Contents      
ORIGINAL ARTICLE
Year : 2021  |  Volume : 16  |  Issue : 1  |  Page : 72-77

The dilemma of multifocality in insular tumors: Multicentricity versus metastasis


1 Department of Neurosurgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Neurosurgery, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
3 Department of Pathology, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India

Date of Submission05-Oct-2020
Date of Decision23-Dec-2020
Date of Acceptance04-Feb-2021
Date of Web Publication20-Mar-2021

Correspondence Address:
Dr. Kuntal Kanti Das
Department of Neurosurgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ajns.AJNS_458_20

Rights and Permissions
  Abstract 

Background and Purpose: Multifocality and metastasis from insular glioma are extremely rare. Pathological insights and elaboration of the clinical course of this condition will contribute to their better understanding. Materials and Methods: Among 123 consecutively operated insular gliomas, 5 patients (4.2%) presented with a multifocal tumor. The clinico-radiological, histo-molecular, and treatment outcomes were noted and compared with the unifocal insular glioma cohort. Results: Among the five patients, all were males and involved the right insular lobe. Three patients presented with synchronous tumors, while two patients developed metachronous multifocal tumors. The histology of the insular tumor was Grade I glioma in 1, Grade II astrocytoma with p53 mutation in 2, and anaplastic astrocytoma and glioblastoma in one patient each. Histological confirmation of the second lesion was performed in two patients, showing the same histology of the insular tumor. Interconnection between the tumors was apparent through cerebrospinal fluid pathways in four patients, while no such connection could be established in one patient. Barring the patient of Grade I glioma, the rest of the patients died within months of the diagnosis. Conclusion: Multifocal insular glioma is rare and probably represents a biologically more aggressive tumor. Insular glioma that touches the ventricle appears a common denominator for multifocality. True multicentricity is rare. The prognosis in insular glioma with multifocality is poor in non-Grade I gliomas.

Keywords: Cerebrospinal fluid spread, insular glioma, multicentric, radiotherapy, surgery


How to cite this article:
Das KK, Singh A, Khatri D, Gosal JS, Bhaisora K, Mehrotra A, Gogoi S, Behari S. The dilemma of multifocality in insular tumors: Multicentricity versus metastasis. Asian J Neurosurg 2021;16:72-7

How to cite this URL:
Das KK, Singh A, Khatri D, Gosal JS, Bhaisora K, Mehrotra A, Gogoi S, Behari S. The dilemma of multifocality in insular tumors: Multicentricity versus metastasis. Asian J Neurosurg [serial online] 2021 [cited 2021 Apr 14];16:72-7. Available from: https://www.asianjns.org/text.asp?2021/16/1/72/311481


  Introduction Top


Insular gliomas are challenging tumors. Our understanding of these tumors has improved immensely, both on a conceptual and technological front.[1],[2],[3],[4] Multifocality and possible tumor metastasis from insular glioma are extremely rare and less explored.[5] Therefore, very little is known regarding the predictability of such growth patterns and their management implications. Multifocal gliomas are rare and unique entities. They constitute 8%–10% of all gliomas.[6],[7] The inherent complexity of insular gliomas gets accentuated in the setting of additional multifocality. In this article, the authors highlight multifocality in insular gliomas and share the learning points with five such cases encountered in their experience.


  Materials and Methods Top


We reviewed our experience with insular gliomas over 10 years (2010–2020) for multifocal tumors in the setting of insular gliomas. We included insular gliomas with multifocality detected at the same presentation (synchronous tumors) and those presenting subsequently after insular glioma surgery (metachronous).

The clinical, imaging, surgical, histo-molecular markers and outcome were assessed in the multifocal tumors and compared with the remaining tumor which did not have multifocality.


  Results Top


We operated on 123 cases of insular glioma over 10 years. Out of these, we found multifocality in 5 patients (4.0%). The key features of these cases are presented in [Table 1].
Table 1: Details of multifocal insular glioma in the series

Click here to view


Characteristics of the insular tumor

All five patients had right insular lobe involvement. All except one patient (patient #5) were young adults, and all were males [Table 1]. The tumor was confined to the insula in three patients [Yasargil type 3A, [Figure 1],[Figure 2],[Figure 3]], and the other two patients had insulo-opercular tumors [Yasargil type 5B, [Figure 4] and [Figure 5]] with tumor extension into the ventricle in two patients [Figure 4] and [Figure 5]. Histopathologically, we had one patient with Grade I glioma (dysembryoplastic neuroepithelial tumor [DNET]), two patients with Grade 2 astrocytoma (2 isocitrate dehydrogenase [IDH] mutant, 1 wild type), one anaplastic astrocytoma (IDH mutation could not be tested), and one glioblastoma (IDH wild type). p53 mutation was positive in both patients with both Grade II astrocytoma, absent in 1, while not performed in one patient.
Figure 1: Magnetic resonance T2 (a) and contrast-enhanced (b and c) axial images depict the right insular mass with heterogeneous enhancement, confined within the insula (Yasargil type 3A). Contrast-enhancing lesions involving the bilateral occipital horns and splenium of the corpus callosum can be appreciated (b and c)

Click here to view
Figure 2: T2 and contrast magnetic resonance axial images (a and b) show the right insular mass with no enhancement, Yasargil type 3A. Immediate postoperative computed tomography images (c) suggest a surgical cavity of anteromedial temporal resection combined with the tumor excision. Follow-up computed tomography scans done after 1 year at new-onset symptoms suggested a contralateral occipital horn hyperdense tumor mass (d and e)

Click here to view
Figure 3: T2 and contrast axial (a and b) magnetic resonance images showed an enhancing, irregularly marginated right insular mass with heterogeneous enhancement, Yasargil type 3A. Simultaneously, a single (c and d) right posterior frontal lesion (in front of the motor cortex) with heterogeneous enhancement was seen without any interconnecting tissues

Click here to view
Figure 4: Magnetic resonance T2 axial (a), coronal (b) images show a large heterointense right insular mass lesion extending into the lateral ventricle with the patchy enhancement of the ventricular part (c). The lesion corresponds to Yasargil type 5B. (d) A single left cerebellar mass lesion, it did not enhance. (e and f) The postoperative computed tomography images showing near-total excision of the insular tumor. The cerebellar tumor was observed

Click here to view
Figure 5: Preoperative magnetic resonance axial images (a and b) showing large right insular mass with patchy enhancement, Yasargil type 5B, and there was no lesion in the posterior fossa at that time. The lesion had an unusual basifrontal extension for insular glioma and extended into the ventricle (arrow). Postoperative magnetic resonance images (c and d) demonstrate a subtotal insular tumor excision with a residual tumor in the posterior insula. Magnetic resonance T2 axial (e) shows a single midline cerebellar mass after 2 years of follow-up, which was not present previously. The cerebellar lesion was subtotally resected, as shown in postoperative computed tomography (f)

Click here to view


Characteristics of the second tumor

All patients had a single second tumor. The involvement was midline (patient #3) and left paramedian (patient #2), both being around the fourth ventricle. Two patients (patient #1 and patient #4) had intraventricular tumor deposits lining the dependent parts. The patient with insular glioblastoma had an ipsilateral premotor cortex lesion (case #5).

The second lesion was synchronous in 3 patients (cases # 1, 2, and 5), while it appeared metachronously within 2 years with a new onset of symptoms in patients #3 and 4. Histopathological analysis of the second lesion was available in two cases, and it revealed the same characteristics of the primary tumor (patients #3 and 5). In patient #4, the secondary lesion showed a postcontrast enhancement indicating that the lesion was probably of a higher grade. Imaging in the rest of the cases showed characteristics precisely similar to the insular tumor.

Management and outcome

All the patients underwent surgical excision of the insular tumor. The surgical approach was either trans-sylvian (patients #1, 4, and 5) or transcortical (patients #2 and 3), as per the tumor's extension.[2],[8],[9] The extent of excision is shown in [Table 1]. In one patient (case #5), simultaneous excision (subtotal) of the second lesion was performed using the same craniotomy. In patient #3, the posterior fossa tumor was subtotally excised in a separate surgery. We pursued a policy of observation in case #2, and the lesion has remained stable during follow-up. The other two patients (#1 and #4) did not undergo surgery and died at follow-up. Patient #1 was advised chemoradiation, discharged in a stable condition, but expired from unknown cause after a month. While patient #4 presented in altered sensorium and after discussing the prognosis, they refused treatment and the patient subsequently expired within a month. Patient #2 was not advised any chemoradiation due to a Grade I tumor histology, and he is currently under follow-up. Patient #3, having undergone a subtotal excision, received radio-chemotherapy after the first surgery. He expired after 2 months of surgery for the posterior fossa tumor. Patient #5 also expired after 1 month, before adjuvant chemoradiation.

[Table 2] shows the differences between the multifocal insular gliomas and the unifocal tumors operated during the same time. Exclusive involvement of males and right insular involvement were distinctive features of multifocal insular glioma. Moreover, multifocal tumors were more common in younger patients. The frequency of p53 mutation was higher in multifocal Grade II astrocytomas.
Table 2: Basic differences between unifocal (n=118) and multifocal insular gliomas (n=5) in our series

Click here to view



  Discussion Top


In this series, we have presented five examples of insular glioma of various grades associated with a second glioma appearance at a different site. Through these examples, we want to discuss the issue of multifocality in the setting of insular involvement. We aim to discuss the possible pathogenetic mechanisms for such growth patterns.

Incidence and definitions

Multifocal gliomas constitute around 8%–10% of all gliomas.[6],[7] Their incidence with insular gliomas is probably much lower, as we saw (4%). Our previous publication on multifocal glioblastomas has pointed out the differences between the two categories and pointed out their poorer outcomes.[10] There is often a tendency to confuse them with brain metastasis from an unknown primary,[3],[11],[12] leading to underestimating these lesions' true incidence.

Historically, several authors have tried to distinguish between multifocal and multicentric gliomas.[13],[14] Multifocal gliomas are in anatomical continuity (described as collision tumors), or a connection through a known white matter path can be established between them.[15],[16],[17] On the other hand, multicentric gliomas are located at a distance geographically, and no anatomical pathway connects them (e.g., patient #5 in our series). These demarcations, however, have faded over time, and both conditions are treated identically with similar outcomes. Nevertheless, we saw both varieties in our series, and we believe that the underlying mechanisms may be different in both.

Pathology and pathogenesis

These tumors are common in the setting of a family history of malignancies or the background of some other malignancies in the patient.[18],[19],[20] P53 mutation is detected in a very high number of these patients.[6] In addition, a higher incidence of multifocal glioblastoma has been seen with carcinoma breast, indicating a possible role of the BRCA-1 gene in the pathogenesis.[21] A two-hit hypothesis has also been suggested.[6],[21] The IDH mutation status did not seem to correlate with the multifocality in our series. However, two of our patients with Grade II insular astrocytoma had p53 mutation, while one glioblastoma patient (#5) was having wild p53, and the information was not available in Grade III astrocytoma patient (patient #1). Therefore, in this series, multifocality in insular glioma resulted from all grades of gliomas, being more common in aggressive tumor types (4/5, 80%, either a high-grade glioma or p53 mutation in Grade II astrocytoma). That said, we did not find any difference in p53 mutation status with respect to the unifocal tumors. However, exclusive involvement of the right insula and the male gender were the striking findings of our study. Moreover, the involvement of younger patients was also an interesting finding.

Pathologically, the tumors may be of the same or sometimes different histology.[6],[7] In our series, we found a histological similarity in two patients where the information was available. In low-grade gliomas, it has been stated that the secondary lesion almost always spreads from the primary site.[22] In all except patient #5, the tumors could be interlinked via the ventricular cerebrospinal fluid (CSF) pathway. Insular gliomas often abut the temporal horn of the lateral ventricle, and theoretically, the tumor cells may be shed into the ventricles. Moreover, we saw that two patients (patients #2 and 3) had an intraventricular tumor extension. Therefore, it is clear that the part of the insular glioma touching/entering the ventricle or the subventricular zone enhances the risk of inherently aggressive tumor types (high grade or with an aggressive molecular profile).[23] However, patient #1 had a relatively smaller, albeit enhancing insular tumor, and the postoperative histology suggested a diagnosis of anaplastic astrocytoma. Therefore, we can assume that the tumor margins in this patient proliferated at a higher rate and must have contacted the ventricle for an intraventricular spread. In patient #4, insular glioma resection was combined with an anteromedial temporal resection. Therefore, iatrogenic temporal horn entry and subsequent tumor dissemination appeared likely in this case. In patient #2, the multifocality appeared despite a Grade I tumor histology. There are reports of Grade 1 gliomas having leptomeningeal spread and presenting multifocally.[24],[25] Patient #5 was a case of glioblastoma, and it appeared at anatomically unconnected locations. The insula and the premotor area are preferred sites of low-grade glioma due to their cytoarchitectural, functional, and molecular characteristics.[6] However, we are not aware of any previous reports to suggest a similar predilection for high-grade gliomas. Since this was an old patient with IDH wild-type glioblastoma, it cannot be ascribed to secondary anaplastic transformation of low-grade glioma. Therefore, it represented a true multicentric tumor as per the definition. A case of bilateral insular glioma was reported explaining a similar multicentricity.[5]

Apart from the CSF pathway, the Duffau group has shown that insular gliomas tend to spread through the subcortical association tracts.[26],[27],[28]

Management issues

A diagnostic dilemma is often faced in the setting of multifocal gliomas, particularly in synchronous presentations. However, younger age and a typical pattern of spread were the points against cerebral metastasis in our series. Patient #5 was an old patient presenting with two enhancing lesions, a known linkage between the two could not be established. Hence, we considered a possibility of metastasis here, and a positron emission tomogram scan was performed preoperatively in this patient which ruled out any extracranial primary. Intracranial metastasis in the insula is extremely rare, and therefore, the diagnosis of metastasis in the brain was remote in any of our patients.

A stereotactic biopsy is generally recommended in multifocal tumors, and further decisions rely on the histopathology findings.[6] If the histology is glioma, surgical excision is known to improve survival.[6],[28] On the other hand, a metastatic lesion undergoes surgery or radiosurgery depending on the histology, size, and tumor location.[10],[28] We had three patients (patients #1, 2, and 5) who presented with synchronous tumors in our series. The insular tumor was the cause of symptoms in all, and this area is not suitable for a stereotactic biopsy. Therefore, surgical excision of the insular glioma was conducted. We resected the second lesion in patient #5 due to the preoperative suspicion of a high-grade tumor or an occult primary. Therefore, if the two lesions are accessible during the same approach, it is preferable to remove both to improve the survival.

Barring the patient with insular DNET, the rest of the patients died within months of surgery. Therefore, insular multifocal glioma, like in any other site, is a fatal disease with poorer outcomes than unifocal tumors.[2] The poor prognosis has been corroborated in many previous studies.


  Conclusion Top


Insular glioma can rarely present with a multifocal disease or develop postoperative CSF dissemination. Interestingly, the condition was exclusively found in males and affected the right insula in all of them. A higher tumor grade or unfavorable mutation of the p53 gene appears to portend a higher risk; however, it is safe to say that many more intricate mechanisms probably underpin this condition. CSF pathway dissemination could be established in 80% of the cases, either by the tumor itself or by iatrogenic ventricular dissemination. True multicentric insular glioma is extremely rare. The prognosis in the face of multifocality in non-Grade I gliomas is poor.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Hervey-Jumper SL, Berger MS. Insular glioma surgery: An evolution of thought and practice. J Neurosurg 2019;130:9-16.  Back to cited text no. 1
    
2.
Khatri D, Das KK, Gosal JS, Attri G, Singh A, Bhaisora KS, et al. Surgery in high-grade insular tumors: Oncological and seizure outcomes from 41 consecutive patients. Asian J Neurosurg 2020;15:537-44.  Back to cited text no. 2
  [Full text]  
3.
Khatri D, Jaiswal A, Das KK, Pandey S, Bhaisora K, Kumar R. Health-related quality of life after surgery in supratentorial gliomas. Neurol India 2019;67:467-75.  Back to cited text no. 3
[PUBMED]  [Full text]  
4.
Singh A, Das KK, Khatri D, Singh S, Gosal JS, Jaiswal S, et al. Insular glioblastoma: Surgical challenges, survival outcomes and prognostic factors. Br J Neurosurg 2020:1-9. doi: 10.1080/02688697.2020.1859089. Epub ahead of print. PMID: 33356607.  Back to cited text no. 4
    
5.
Borkar SA, Tandon V, Kale SS, Mahapatra AK. Mirror-image insular glioma. Neurol India 2010;58:978-9.  Back to cited text no. 5
[PUBMED]  [Full text]  
6.
Giannopoulos S, Kyritsis AP. Diagnosis and management of multifocal gliomas. Oncology 2010;79:306-12.  Back to cited text no. 6
    
7.
Haque W, Thong Y, Verma V, Rostomily R, Brian Butler E, Teh BS. Patterns of management and outcomes of unifocal versus multifocal glioblastoma. J Clin Neurosci 2020;74:155-9.  Back to cited text no. 7
    
8.
Deora H, Das KK, Jaiswal A, Behari S. Letter to the Editor. Tumor extension determines approach in insular gliomas. J Neurosurg 2019;23:1-2.  Back to cited text no. 8
    
9.
Das KK, Singh S, Deora H, Khatri D, Mehrotra A, Srivastava AK, et al. Microsurgical excision of giant dominant lobe insular cavernoma presenting acutely: Sometimes you win, sometimes you learn. Interdiscip Neurosurg Adv Tech Case Manag 2019;18:100475. doi.org/10.1016/j.inat.2019.100475.  Back to cited text no. 9
    
10.
Singh G, Mehrotra A, Sardhara J, Das KK, Jamdar J, Pal L, et al. Multiple glioblastomas: Are they different from their solitary counterparts? Asian J Neurosurg 2015;10:266-71.  Back to cited text no. 10
[PUBMED]  [Full text]  
11.
Bhaskar S, Gosal JS, Garg M, Jha DK. Letter: The neurological examination. Oper Neurosurg (Hagerstown) 2020;18:E262.  Back to cited text no. 11
    
12.
Bhaskar S, Gosal JS, Garg M, Jha DK. Letter to the editor regarding “why would two patients with no disease be offered unnecessary transforaminal lumbar interbody fusions?” Surg Neurol Int 2019;10:238.  Back to cited text no. 12
    
13.
Lasocki A, Gaillard F, Tacey M, Drummond K, Stuckey S. Multifocal and multicentric glioblastoma: Improved characterisation with FLAIR imaging and prognostic implications. J Clin Neurosci 2016;31:92-8.  Back to cited text no. 13
    
14.
Shakur SF, Bit-Ivan E, Watkin WG, Merrell RT, Farhat HI. Multifocal and multicentric glioblastoma with leptomeningeal gliomatosis: A case report and review of the literature. Case Rep Med 2013;2013:132679. doi.org/10.1016/j.inat.2019.100475  Back to cited text no. 14
    
15.
Gosal JS, Shukla K, Garg M, Bhaskar S, Jha D. Collision tumors in the spinal cord: Co-existent intramedullary dermoid with spinal lipoma. Interdiscip Neurosurg Adv Tech Case Manag 2020;21:100751. doi.org/10.1016/j.inat.2019.100475  Back to cited text no. 15
    
16.
Gosal JS, Shukla K, Praneeth K, Tiwari S, Garg M, Bhaskar S, et al. Coexistent pituitary adenoma and frontal convexity meningioma with frontal sinus invasion: A rare association. Surg Neurol Int 2020;11:270.  Back to cited text no. 16
    
17.
Gosal J, Joseph J, Khatri D, Das KK, Jaiswal A, Gupta A. White epidermoid of the sylvian fissure masquerading as a dermoid cyst: An extremely rare occurrence. Asian J Neurosurg 2019;14:553-6.  Back to cited text no. 17
[PUBMED]  [Full text]  
18.
Verma PK, Nangarwal B, Verma J, Dwivedi V, Mehrotra A, Das KK, et al. A clinico-pathological and neuro-radiological study of angiomatous meningioma: Aggressive look with benign behaviour. J Clin Neurosci 2021;83:43-8. [doi: 10.1016/j.jocn. 2020.11.032].  Back to cited text no. 18
    
19.
Gosal JS, Behari S, Joseph J, Jaiswal AK, Sardhara JC, Iqbal M, et al. Surgical excision of large-to-giant petroclival meningiomas focusing on the middle fossa approaches: The lessons learnt. Neurol India 2018;66:1434-46.  Back to cited text no. 19
[PUBMED]  [Full text]  
20.
Das KK, Gosal JS, Sharma P, Mehrotra A, Bhaisora K, Sardhara J, et al. Falcine meningiomas: Analysis of the impact of radiologic tumor extensions and proposal of a modified preoperative radiologic classification scheme. World Neurosurg 2017;104:248-58.  Back to cited text no. 20
    
21.
Elmariah SB, Huse J, Mason B, Leroux P, Lustig RA. Multicentric glioblastoma multiforme in a patient with BRCA-1 invasive breast cancer. Breast J 2006;12:470-4.  Back to cited text no. 21
    
22.
Terakawa Y, Yordanova YN, Tate MC, Duffau H. Surgical management of multicentric diffuse low-grade gliomas: Functional and oncological outcomes: Clinical article. J Neurosurg 2013;118:1169-75.  Back to cited text no. 22
    
23.
Mandonnet E, Capelle L, Duffau H. Extension of paralimbic low grade gliomas: Toward an anatomical classification based on white matter invasion pattern. J Neurooncol 2006;78:179-85.  Back to cited text no. 23
    
24.
Alvarez de Eulate-Beramendi S, Rigau V, Taillandier L, Duffau H. Delayed leptomeningeal and subependymal seeding after multiple surgeries for supratentorial diffuse low-grade gliomas in adults. J Neurosurg 2014;120:833-9.  Back to cited text no. 24
    
25.
Khatri D, Bhaisora KS, Gosal JS, Das KK, Srivastava AK. Subpial cervical subependymoma: Report of an unusual tumor with review of literature. Asian J Neurosurg 2019;14:329-31.  Back to cited text no. 25
[PUBMED]  [Full text]  
26.
Duffau H, Capelle L. Preferential brain locations of low-grade gliomas. Cancer 2004;100:2622-6.  Back to cited text no. 26
    
27.
Duffau H. Surgery of insular gliomas. Prog Neurol Surg 2018;30:173-85.  Back to cited text no. 27
    
28.
Vergani F, Sanson M, Duffau H. Combined multiple surgical intervention and chemotherapy for multicentric WHO grade II glioma: A long-term follow-up study. Acta Neurochir (Wien) 2009;151:1699-704.  Back to cited text no. 28
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
 
 
  Search
 
<
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)  

 
  In this article
   Abstract
  Introduction
   Materials and Me...
  Results
  Discussion
  Conclusion
   References
   Article Figures
   Article Tables

 Article Access Statistics
    Viewed60    
    Printed0    
    Emailed0    
    PDF Downloaded18    
    Comments [Add]    

Recommend this journal