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.
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.
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 8th
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 1st and sept
15th 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 4th. 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?
This page might help with question number 2.
ReplyDeletehttp://www.pathologyoutlines.com/topic/cnstumorwhograding.html
It's most likely that in your wife's case the grade 3 designation comes from the presence of mitoses. More than 1 mitosis would indicate a grade 3 rather than a grade 2. Also "Ki-67 proliferation index aids in the separation of grade II from grade III tumors".
As for question 3, in my opinion it makes perfect sense to combine CCNU and TMZ, given the MGMT methylated status of her tumor, although you would likely meet with resistance from her medical team as this is not even yet established for GBM let alone lower grades.
As for trials for recurrence, in a better case scenario she will hopefully not need a trial for another 5 years or more, and at that time there will be a different set of trials recruiting and several more years worth of scientific data to aid in the decision. Currently the Tocagen therapy looks like one of the best options esp. for IDH1-mutants, with "All 4 IDH1 mt patients treated at 1st recurrence had CRs [complete responses]"
http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.e13504
It's very unclear whether IDH1-mutant gliomas would be as responsive to vaccines, due to the immunosuppressive microenvironment caused by the high concentrations of 2-hydroxyglutarate around these tumors. Perhaps by that time they'll be testing combinations of mutant IDH1 inhibiting drugs with vaccines.
I had 1st post-op MRI in that 72 hour window. But I'm fairly certain that is just to objectively assess extent of resection. I read a few articles which state that it is not uncommon that surgeons overestimate extent of resection, so MRI is done to confirm it.
ReplyDeleteI remember seeing that first post-op MRI and I'm not really sure how they see anything from those pictures, because everything is really swollen. For example my resection cavity is around 10 ccm, but on that MRI there was only a "hole" around 0,5 ccm big. My second MRI was done 3 months after surgery, which is now a baseline.
In regards to question 2, the pathology grading is done mostly on microscope work, proliferation rates/mitotic figures, then genetics that identify the type (such as ATRX and P53 differentiating astro from oligo) and to a lesser extent or not at all the subcategories like mgmt methylated.
ReplyDeleteBut I suspect you are asking where in the spectrum of prognosis does the pathology report place her. With the combination of a low grade 3 pathology, idh1 mut and mgmt meth, a successful near total resection, and overall good health, then I think it is safe to say you could use survival curves that are more in the grade 2 category. So good news!
For Q3, if the NO is against TMZ/CCNU combo they might be more ok with doing TMZ for a while and then finishing with 2-3 rounds of CCNU. That may also help protect against the hypermutation risks of TMZ
I think we're in agreement here on question 2, but just to make sure it is crystal clear to everyone, markers such as IDH1, ATRX, p53, 1p/19q, do not determine grade. The link I provided in my comment above gives a concise summary of how grading is done for diffuse (grade 2-4) astrocytic tumors.
DeleteIDH1 status is necessary for diagnosis of tumor subcategory (IDH mutant versus wild type), and 1p/19q codeletion versus loss/mutation of ATRX aids in the diagnosis of oligodendroglioma versus astrocytoma. MGMT status is a predictive marker for response to chemotherapy and does not designate a tumor type - MGMT status can be methylated or unmethylated in any of the various tumor types, although it is most commonly methylated in IDH1-mutant types.
Any of these genetic markers can be found in any grade of diffuse glioma (grades 2-4). Grading is indeed based on microscope work - looking at nuclear atypia (deformities in the cell nucleus), mitoses (cells undergoing mitosis), microvascular proliferation and necrosis.
Thank you all for your very helpful answers.
ReplyDeleteI am aware of the grade designation but the grading designation does not tell you much about where on the spectrum you are. e.g. where is "up to 6/10 HPF mitosis" and "moderate high Ki67" on a scale. It´s a very on/off or gated way of describing a tumor. Seems like IDH, PH53, ATRX, MGMT, co-deletion, resection degree etc are better in describing the statistical spectrum of a tumor than the grading system itself.
@Matjaz: Seems like the same input we got - except the first MRI is not until January. But I guess they would have reacted on the ones for "internal use" from august 1st and sept 15th if they saw something unexepected.
@bs1966: Good tip on the CCNU finalization rounds - will take that up with the NO on Wednesday when the TMZ cycles start.
I believe that if there is a single mitosis in a large area of tumor, that could still be considered a grade 2, but more than one mitosis per high powered field would usually qualify as a grade 3.
DeleteIDH1 status is more important than grade in determining prognosis. Grade 2 astrocytomas without IDH mutation and alterations more typical of GBM do not generally do as well as say a grade 3 astrocytoma with IDH1 mutation. Also on the whole, as Bryan mentioned, overall outcomes are not greatly different between grade 2 and 3 astroctyomas with IDH1 mutation. Outcome is likely more determined by how quickly (if and when) these progress to grade 4, which can be unpredictable. A grade 3 that recurs as a grade 3 may do better than a grade 2 that recurs as a grade 4.
Note that Astro more typically has randomly scattered cancerous cells and Olig is very prone to clustering. So # of mitoses per HPF is a good bit more variable in Oligo. Also mitotic figures show up in a smaller window of time than ki-67 staining. So #/HPF is more prone to sampling error.
DeleteBut in your case it looks like they may have done one of the newer 'automated' mitotic figure counting using PHH3 staining. That likely would give a higher count than the 'classic' method of a pathologist looking under the microscope and physically counting the # of cells in the middle of dividing.
The range of #/hpf and Ki-67 % is fairly wide and overlapping between grades 2/3. So it seems likely she is on the border between grades and the pathologist had to use the grading guidelines to decide where it should fall.
Regardless, grading/prognosis/statistics are useful to guide decisions about risks (ie doing standard treatment, or jump in a phase 1 trial, or extra aggressive surgery,etc), BUT she is not statistic! The point of this board is to find ways to be the 1% !! Be the anomaly!
Clarification -- the clustering comment applies to lower grades where there is a lack of major vasculature changes. In higher grades there certainly are clusters around regions of higher vascularity.
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