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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 8-11

Implementation of molecular markers in glioma histology reporting: A survey


Department of Neurosurgery, Apollo Hospital; Founder-Director, Exsegen Research Private Limited, Hyderabad, Telangana, India

Date of Submission29-Apr-2020
Date of Acceptance04-Jun-2020
Date of Web Publication2-Jul-2020

Correspondence Address:
Dr. Amitava Ray
Department of Neurosurgery, Apollo Hospital, Jubilee Hills, Hyderabad - 500 033, Telangana; Exsegen Research Private Limited, Jubilee Hills, Hyderabad - 500 033, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJNO.IJNO_8_20

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  Abstract 


Purpose: The purpose of this study is to judge the extent of implementation of the Indian Society of Neuro-Oncology (ISNO) guidelines for the incorporation of molecular markers in glioma histopathological reporting.
Materials and Methods: This study was conducted electronically. A form was created on Google Forms and the link was shared on E-mail and WhatsApp to members of the Neurological Society of India and ISNO.
Results: One hundred doctors replied to the questionnaire, and the majority worked in large tertiary care hospitals in big cities. However, practitioners from smaller tier 2 and tier 3 cities also participated. Sixty-eight percent of those who responded were neurosurgeons and more than two-thirds of all respondents had a specific interest in neuro-oncology. More than 90% thought that molecular markers added value to histopathology alone, but a much smaller number (12%) had the infrastructure to test all the markers. Only 10% relied on histopathology exclusively, without performing any molecular tests. Lack of adequate infrastructure and the additional cost that was usually borne by the patient were the two largest roadblocks in its wider acceptance. There was also an overwhelming majority of clinicians who thought that the current pathology reports should change and indicate not only the tumor type but include active pathways and suggest the best options for treatment.
Conclusion: In spite of the roadblocks, there has been a fair amount of success in clinicians successfully testing for molecular markers in gliomas. As testing becomes more specific and sensitive and treatment becomes targets to specific molecular pathways, analysis of molecular pathways will become integral to glioma histopathology.

Keywords: Glioma, molecular markers, survey


How to cite this article:
Ray A. Implementation of molecular markers in glioma histology reporting: A survey. Int J Neurooncol 2020;3:8-11

How to cite this URL:
Ray A. Implementation of molecular markers in glioma histology reporting: A survey. Int J Neurooncol [serial online] 2020 [cited 2020 Dec 3];3:8-11. Available from: https://www.Internationaljneurooncology.com/text.asp?2020/3/1/8/288795




  Introduction Top


Ever since the publication of the first article on IDH mutant gliomas in 2009[1] in the New England Journal of Medicine and the subsequent WHO 2016 and cIMPACT-NOW guidelines,[2] there has been a slow but definite shift in the way that brain tumors are classified. Initially limited to histopathology alone, molecular biology is now an integral part of the decision-making process. Molecular markers are not limited to one specific genetic change but involve the whole gamut of possibilities – mutations, deletions, splice variants, promoter methylations, loss of heterozygosity, and so on. This change in methodology has required medical professionals to be acquainted with ordering and interpreting these tests, but also knowing the number of ways the same test can be performed and the relative merits and de-merits of each test- starting with immunohistochemistry, but including polymerase chain reactions and its variants DDPCR and BEAM,[3] fluorescent in situ hybridization,[4] microarrays, and now, next-generation sequencing.[5] Genome-wide sequencing, once a preserve of research, is now on the threshold of being used in day-to-day clinical practice. All these have also meant additional investment infrastructure capabilities at hospitals and diagnostic laboratories which have translated into additional costs for patients. Realizing the need for clarity, in 2019, the Indian Society of Neuro-Oncology (ISNO) issued guidelines that were based on the WHO 2016 recommendations to guide clinicians on the best practice in India, keeping in mind the socioeconomic background and the variation of availability of tertiary services across the country.[6] This study was conducted electronically, from June to August, and the preliminary results were collated in September 2019. This study surveys clinicians across India who are at the front line of treating brain tumors and tries to assess the adoption of molecular tests in glioma diagnosis and management in the country.


  Materials and Methods Top


This questionnaire consisted of 10 questions that were created on Google Forms. The link, which is https://forms.gle/AybjkZF6TLjbTjM97, was circulated electronically by E-mail to all the members of the Neurological Society of India and the ISNO. It was also posted on WhatsApp on specific neurosurgery and neuro-oncology groups. In addition, E-mails were sent separately to 60 experts in the field across India. Only one filled form from each ID was allowed. Questions were divided into three distinct parts: the first two questions enquired about the person filling the form and the level of interest in neuro-oncology, the next four about the current state of molecular diagnostics in brain tumors, and the last four on future technologies and “wish lists” that would make adoption of such molecular tests easier in India. The questions were formatted in two separate ways: in seven out of ten questions only one out of the four answers could be chosen, while in three, one or more answers could apply.


  Results Top


About 300 doctors involved in the care of brain tumor patients were contacted. One hundred and two responded to the E-mail questionnaire. Two were incomplete and so were discarded. These are the results of 100 doctors who were surveyed.

Demographics

Of the 100 doctors that were surveyed, 68 were neurosurgeons, 20 oncologists, 8 neurologists, and 4 pathologists. Sixty-four of the respondents had a particular interest in neuro-oncology, whereas four said that their practice was limited to neuro-oncology alone. Twenty-nine had a general interest in neuro-oncology. Three respondents did not treat patients but were the neuropathologists who answered the survey. Confirmation of filling in the form of a message was received in 73 cases, though it was not mandatory. The decision to make contact sharing optional was done to ensure participation as a larger number of clinicians, some of whom are unwilling to share their contact. We also believed that not sharing contact details would encourage more honest opinions. When these 73 responses were analyzed for demographics, it indicated that doctors who had filled the form were usually practicing in the metros, though 21% (16/73) were in smaller tier 2 towns such as Karimnagar, Vijayawada, Dibrugarh, Burdwan, Panipat, and so on. There was a preponderance of doctors practicing in the private sector in large multispecialty hospitals (50/73), but there were representations from large government and trust hospitals and from smaller individual practitioners both in the metros and in tier 2 cities. Clinicians practicing in 17 Indian states were represented in the study.

Survey of current status

When asked specifically about the value of including molecular tests as a part of routine histopathological studies, all except two agreed that it did add value, although they differed in the quantum of difference made by these tests. Almost half of all respondents (48/100) thought that it is a matter of time before molecular markers became a critical component in all clinical decision making, 34 said that genotyping is of value in specific tumor types, but the role will increase in the future, whereas 16 saw minimal use of molecular subtyping at present. What was very encouraging was that more than 80% of clinicians had the ability to test some of the markers, in keeping with the ISNO guidelines.[6] While in September 2019, only 12% had the ability to test comprehensively, but the number is significantly higher now, thanks to the investments made by the hospitals and the large number of testing “packages” that are offered by the diagnostic laboratories. Although all respondents could not be contacted at the time of writing the paper, this number is probably in excess of 50% now. Only 10% of practicing clinicians relied on histopathology alone. Interestingly, approximately 15% of clinicians would order a more extensive genetic testing panel for treating such patients (Foundation 1 test, Foundation Medicine Inc., California, USA) which are far beyond the ISNO recommendations for more than 50% of their patients. However, about 30% of clinicians would use the prescribed tests alone, without ordering extra tests.

Doctors were specifically also asked about the possible bottlenecks in more widespread adoption. One of the main challenges highlighted were that of added cost to the patient (59/100 respondents). This was due to the fact that a lot of hospitals (48/100) did not have the comprehensive testing capabilities which made the expense “out of pocket” as it had to be sent outside and so was not covered by insurance. The fact that the treatment did not change radically as a result of molecular testing also served as a significant disincentive for a few clinicians (12/100). Almost half (44/100) of the surveyed clinicians said that the molecular tests were confusing and difficult to interpret. There often was a lack of consensus on the best modality for each test, and the same test done in different modalities generated different results. This was compounded by the fact that the same marker could be one of the both good and poor prognoses, depending on other molecular markers of the specific tumor type and histological grade. New biomarkers and testing modalities are constantly being added to the diagnostic armamentarium. This has made it almost impossible for the busy practicing clinician with a general oncology or neurosurgical practice to keep track of the constant updates and changes in the field [Table 1].
Table 1: Bottlenecks in adoption of molecular markers

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Attitudes to adopting future changes

Almost 90% of all surveyed doctors also felt that the current traditional pathology reports will need to change and keep pace with the rapid developments in the field and that interpretation of the molecular tests will have to be a routine part of reporting. 41/100 respondents felt that active tumor pathways detected as a result of mutational analysis must be highlighted along with all the possible drugs that can be used, whereas almost two-thirds (62/100) were of the opinion that the best possible treatment for the particular patient must also be highlighted, as directed by best clinical practice. Thirty-one percent also thought that a list of possible clinical trials will also be useful for clinicians, especially for patients who are not responding to conventional treatment protocols. When asked about the use of newer technologies, 90% thought that it was a good idea if it is used judiciously in selective patients who would benefit. When asked specifically about liquid biopsies in diagnosis and treatment, up to 90% were willing to use it in some form and thought that it would be useful targeting specific molecular pathways, when applicable, and in patients where a physical biopsy was either to dangerous or too difficult [Table 2].
Table 2: Molecular reporting wishlist

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  Discussion Top


This study hopes to present a snapshot of the adoption of molecular markers across India and presents a glimpse of the current adoption rate of molecular markers in glioma diagnosis. This study is by no means exhaustive. However, spread across the length and breadth of India made the study relevant to most of the clinicians, though pockets of excellence and those with a complete lack of facilities could not be ruled out. The greater number of surgeons in the study is a bias, as there are a larger number of oncologists more than neurosurgeons in practice. This bias is probably influenced by the profession of the author, who is a practicing neurosurgeon.

Surgical training till very recently has been more about learning the skill of operating centered around the exhaustive study of anatomy. It is still considered to be based primarily on learning by observing and then being taken through operations by seniors. The extensive study of molecular biology has never been an essential for surgical training. Moreover, even if it were available, the rapid pace of change would have certainly made any knowledge of techniques learned decades ago completely obsolete by now. Clinicians acquainted with the first sequencing of the human genome, also known as the human genome project, would realize that what had initially taken 15 years and billions of dollars to execute could now be done in a machine the size of a small fridge in 44 h for a few hundred dollars at most. And not for one genome but 48 done simultaneously! There has also been a similar explosion in data handling and processing capabilities and in the number of technologies that can test different components of the molecular pathway and achieve the same end result, i.e., IDH mutations can be detected by immunohistochemistry, Sanger sequencing of the specific gene or as a part of a large panel of genes on the next-generation sequencing machines, by total RNA-seq or even proteomic analyses on a mass spectrophotometer.

As each of these tests comes with its own strengths and weaknesses and specificity/sensitivity issues, it is almost impossible for the general neurosurgeon or oncologist to keep abreast of developments. While the obvious answer I smaller nations would be to have more specialized and larger centers for brain tumor management across the country, the size of the country and its population of India coupled with the chronic shortage of medical practitioners make such solutions impractical. In an effective work-around, there is now an effort to pool knowledge and resources to provide the best care. To this end, a number of neuro-oncology tumor boards have come up in hospitals all around the country where a multidisciplinary team of doctors treats patients. These setups are not confined to the four hospital walls and are now available to a lot of clinicians working either alone or in very small groups in the local community or in adjacent in tier 2 and tier 3 cities. As these newer methods of working become commonplace, these virtual tumor boards will become more and more popular, providing care to patients around the country, where an acute shortage of trained health-care professionals still exists.

What we are witnessing today is probably the start of a fundamental change in glioma care and management, where molecular data are at least as important as the histopathological grade, as demonstrated already in the diagnosis of oligodendroglioma. Few targeted therapies that are based on single-gene mutations have already become common, and a number of others are now in late-stage clinical trials, which will mean that molecular testing will be integral to treatment.[7] However, the burden of proof now rests with us clinicians to conduct clinical studies that not only prove safety and its true efficacy but also analyze cost–benefit ratios for the implementation of such tests and the relevance of such treatment for developing economies. Claims that this lethal disease can be cured have been made several times in the past but have only resulted in minimal improvements in survival-measured in days and weeks. Such braggadocio is no longer acceptable. As technology advances, and testing gets more sensitive and specific and more accessible, it is imperative that relevant tests and modalities are identified and standardized for global use. Tests performed must translate into a definite improvement in patient outcome. Only then can we expect molecular testing to be fully integrated in clinical neuro-oncology practice.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009;360:765-73.  Back to cited text no. 1
    
2.
Louis DN, Aldape K, Brat DJ, Capper D, Ellison DW, Hawkins C, et al. Announcing cIMPACT-NOW: The consortium to inform molecular and practical approaches to CNS tumor taxonomy. Acta Neuropathol 2017;133:1-3.  Back to cited text no. 2
    
3.
Diehl F, Li M, He Y, Kinzler KW, Vogelstein B, Dressman D. BEAMing: Single-molecule PCR on microparticles in water-in-oil emulsions. Nat Methods 2006;3:551-9.  Back to cited text no. 3
    
4.
Leeper HE, Caron AA, Decker PA, Jenkins RB, Lachance DH, Giannini C. IDH mutation, 1p19q codeletion and ATRX loss in WHO grade II gliomas. Oncotarget 2015;6:30295-305.  Back to cited text no. 4
    
5.
Parilla M, Kadri S, Patil SA, Fitzpatrick C, Ritterhouse L, Segal J, et al. Integrating a large next-generation sequencing panel into the clinical diagnosis of gliomas provides a comprehensive platform for classification from FFPE tissue or smear preparations. J Neuropathol Exp Neurol 2019;78:257-67.  Back to cited text no. 5
    
6.
Santosh V, Sravya P, Gupta T, Muzumdar D, Chacko G, Suri V, et al. ISNO consensus guidelines for practical adaptation of the WHO 2016 classification of adult diffuse gliomas. Neurol India 2019;67:173-82.  Back to cited text no. 6
[PUBMED]  [Full text]  
7.
Olson JJ, Nayak L, Ormond DR, Wen PY, Kalkanis SN, Ryken TC, et al. The role of targeted therapies in the management of progressive glioblastoma: A systematic review and evidence-based clinical practice guideline. J Neurooncol 2014;118:557-99.  Back to cited text no. 7
    



 
 
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  [Table 1], [Table 2]



 

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