New Approaches to grading of IDH-mutant astrocytomas

Novel, improved grading system(s) for IDH-mutant astrocytic gliomas.

https://www.ncbi.nlm.nih.gov/pubmed/29687258

Given the list of all-star pathologists and neuro-oncologists behind this paper (including Andreas von Deimling, David Louis, Wolfgang Wick, Michael Weller, Roger Stupp, Monika Hegi, Martin van den Bent, Michael Platten, and many more), this work will very likely get translated into actual changes of the grading system for IDH-mutant astrocytomas.

"In conclusion, in all three validation sets the tested grading models performed better than the current WHO system."

"Thus a genetic approach to taxonomy would favor a term such as “high-grade A IDHmut” rather than the current term of GBM-IDHmut."      "One possible solution, which we have considered implementing in Heidelberg, would be to restrict classification to the term A[stroctyoma] IDHmut and then adapt grading according to molecular lesions, thereby omitting the term GBM-IDHmut. The term “glioblastoma” would be reserved for those histologically defined glioblastomas lacking IDH mutation or not having had adequate (not otherwise specified, NOS) or diagnostic (not elsewhere classified, NEC) work-ups"

Nice to finally see the above quotes in print, this has been my opinion for years.

This is an excellent study. My only criticism is that hypermutated tumors with very high mutational load were not evaluated as a distinct group.  This is different than the high or low copy number variant load (CNVL) considered in the paper.  Mutational load was only mentioned once, in the discussion:

"An interesting parameter emerging from our analysis was CNVL [copy number variant load]. A proportion higher than 350 Mb either lost or gained in the areas covered by the methylation arrays correlated with poorer OS. Previously, the mutational load has been shown to correlate with tumor grade in IDH-mutant glioma [9]. While our data more reflect genomic instability and those data rely on an accumulation of mutations they also support a quantitative approach to tumor grading."

A few pathology questions and suggestions for course of action on newly diagnosed AA3

My wife(45), in all other aspects healthy and fit, was diagnosed with right temporal  lobe AA3 after >90% resection mid july 2017. Early june she suffered from an epileptic seizure which was the first ever symptom of a tumour  – actually they suspected a rare venous thrombosis for three weeks and treated her as such after first CT/MRI.

Second MRI the mass was constant and they suspected a low grade glioma. MRI Radiologist described it as non- enhancement and welldefined borders 5X3X2cm.
She was transferred to The National University Hospital where we met with the neurosurgeon, who felt sure it was low grade based on the characteristics of the tumour
During surgery frozen sample couldn´t determine grade 2 or 3. Final pathology report concluded grade 3 with the following characteristics (loosely translated from Danish)

Microscopic:

Braintissue with  diffuse infiltrating nature with small microcysts. In areas the tumour has more cell density, the nucleous are light pleomorphic and hyperchromatic – there are mitosis and apoptopsies(?). There is no microvascular carprofilation or necrosis. In the most cell dense areas a moderat high proliferative activity is observed determined by KI67 colouring and up to 6 mitosis per 10/HPF are identified I PHH3 colouring

The tumour tissue is positive in immunestaining for GFA, Maj 2, P53, IDH1 mutation and ATRX mutation

Analysis of  DNA methylation: the average methylation is 33% so methylated MGMT promotor  is found in the analyzed tissue.

The analysis is conducted with pyrosequencing of 4 CpG sites in the MGMT promotor with Therascreen. Cut of value in the analysis is 10%.

MLPA analysis: IDH1 mutation ( c.395>A,p.R123H) has been found in the analyzed tissue. There is no deletion of 1p/19q in the analyzed tissue.

Macroscopic:
Leptomengial sample tissue measuring 34,25,16 mm. Central cut to freeze+ imprint. Freezediagnosis Diffuse glioma grade 2-3. Freeze sample to biobank.

Diagnosis:
Diffuce Astrocytoma and based on proliferative activity classified as Anaplastic Astrocytoma WHO gr III.

1 month after surgery she did 6 weeks of daily TMZ (125mg) and proton treatment weekdays (~59gy). She is now at home with chemo pause until nov 8^th where she will start 6-12 rounds of 300>400mg TMZ by Stupps protocol (5/28). She has no icognitive nor neurologic ssues except for a little mild vertigo at times, which NO suspect to be her Keppra medication.

Question 1:

MRIs were not made within 72 hours post op. MRIs were made on aug 1^st and sept 15^th during proton treatments, but these were merely in regards to tracking the preciseness of the proton treatment. No further feedback except that there was no change between the two scans, but also that it would be impossible to differantiate post-op scartissue, radiation effects and actual tumour at this point. Next scan is scheduled at Jan 4^th. Is that also your experience?

Question 2:

After surgery and pathology neurosurgeons and oncologist all expressed that her tumour was in the greyzone between grade 2 and 3. But as there is limited actual data e.g. “moderate high” rather than percentage of KI67 staining, further genomic data and a relatively high(?) mitosis count is most dense areas it is hard to compare to data in online datasets. Do you have an idea of what they would base their statement on? Is it the IH,MGMT,ATRX combination, the resection degree and relatively welldefined borders or something else?

Question 3:

Based on the latest NOA-9 trial would it make sense to push for a CCNU/TMZ combination instead of Stupps or are the results yet to vague and even untrialed for AA3? What would be the prime candidate for a trial in case of recurrence for a tomour with the above characteristics – Tocagen (good results – 50% or 2/4 - on high dose IDH AAs), DCVAX, MDNA-55 or something else?