Atypical "DIPGs" Not all Gliomas

This Japanese article electronically published in Childs Nervous System makes the case that although MRIs have been the basis for diagnosis for DIPGs since the 1990s,  "the accuracy of MR imaging baded diagnosis has not been fully confirmed".  This article goes on to say that there have been several reports indicating that some of these diffuse intrinsic brainstem lesions have been found to be other tumors rather than gliomas.  These have included  PNETs, ependymomas, gagliogliomas, rhabdoid tumors and pilocytic astroctyomas.   These other pathologies have been particularly found in those tumors that have an atypical appearance.

The authors decided to perform biopsy for pediatric intrinsic pontine lesions with atypical for DIPG findings on MRI.   Atypical MRI findings were defined as:
a) extended beyond the pons
b) had a well-defined, localized enhancing part with in a high intensity lesion on T2-weighted images.

Seven patients underwent open biopsy because of diffuse lesions in the pons that were not typical for DIPG. Four patients had a focal enhancing lesion, five had extension beyond the pons and two had both.  
The biopsy revealed:
5- diffuse brainstem glioma
1- PNET
1-pilocytic astrocytoma

There were no biopsy related deaths or intra-operative complications.  One child has transient worsening of hemiparesis.

The 12 year-old child harboring a PNET presented with double vision, unsteady gait and a facial palsy.  His tumor had focal enhancement but no extension beyond the pons.  The child received craniospinal radiation with tumor boost and chemotherapy as would be done for a supratentorial PNET with marked shrinkage.  At 13 months the tumor recurred near the genu of the corpus collosum.  This lesion had radiosurgery.

The 7 year old female with a pilocytic astrocytoma presented with difficulty speaking.   Her tumor did not enhance but extended beyond the pons into the right cerebellar peduncle and pons.  She did not have radiation but rather carboplatin and vincristine.   At the time of article submission the tumor had been stable for 9 month.

So, of the 5 children found to have high grade gliomas three of these had areas of focal enhancement and four had extension outside the pons.   The presenting symptoms included only right hemiparesis in one, only a facial palsy in one and lethargy in one.   Only two children had 2 symptoms of the typical triad.  One child had gait disturbance and facial palsy and the other had gait disturbance and hemiparesis.  Of these 5 high-grade glioma children, four of the tumors regrew within 7months( range 3-7 months).  Two of these children had died at the time of publication.

From this very small sample it seems there is no way to predict by MRI pathology without biopsy in atypical diffuse pontine tumors.   The article concluded that "an open biopsy of intrinsic brainstem lesions is considered safe and effective for selecting appropriate course of therapy".

References:
The efficacy of biopsy of intrinsic brainstem lesions for decision making of treatment.Childs Nerv Syst. 2013 Feb 3. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/23377758

Biopsy Consensus Statements on DIPGs

Over the last few years there have been rapid change in treating and understanding pediatric brain tumors.   Per this recently electronically published article in Neuro Oncology these include :
1) Brainstem tumors are now considered to be safe targets for either stereotactic or open biopsy;
2) Age is a major factor interacting with tumor behavior (progression risk);
3) Recent research identifying new biologic markers of tumor classification and new druggable targets for trials has provided and opportunity to explore novel approaches to therapy.

In  February 2011, the second Consensus Conference on Pediatric Neurosurgery (CPN 2011) was held in Paris, France with the objective to establish a new consensus on surgical approaches to pediatric gliomas.   Statements on high grade gliomas, hypothalamic chiasmatic gliomas and diffuse intrinsic pontine gliomas were developed.  Statements  were disseminated to the 92 participants for a vote.  A statement was accepted if there was more than 70% of votes in favor of the statement.

Here are the final statements regarding DIPGs.
Typical DIPG
Biopsy of  a typical DIPG (defined by a short history and typical imaging findings) is justified when the patient is part of an ethically approved clinical study in which the tissue obtained will be used to investigate or inform the role of biological markers after treatment selection or molecular tumor grading.

Atypical Pontine Region Tumors
(A) Biopsy by an experienced pediatric neurosurgeon is indicated to confirm the diagnosis and guide therapy,
(B) An atypical pontine region tumor would be considered separately from classic DIPG for therapy or research purposes.

Authors of the final consensus paper included:
* David A Walker- Nottingham, United Kingdom
* JoFen Liu- Boston, USA
* Mark Kieran- Boston,  USA
* Nada Jabado- Quebec, Canada
* Susan Picton- Leeds, United Kingdom
* Roger Packer- Washington, USA
* Christian St. Rose - Paris, France

References:
A multi-disciplinary consensus statement concerning surgical approaches to low grade, high grade astrocytomas and diffuse intrinsic pontine gliomas (CPN Paris 2011) using the Delphi method.
Neuro Oncol 2013 March 15 [epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/23502427

Typical Versus Atypical- What does that mean?

At one time all gliomas of the brainstem were thought to have an equally poor outcome.   Over the years (especially with better imaging), we have come to find not all brainstem gliomas are the same.—  and actually some brainstem gliomas (tectal gliomas, cervicomedullary gliomas, focal gliomas) were found to have a favorable prognosis.  However, the vast majority of brainstem gliomas- perhaps 85%- were diffuse and intrinsic and pontine.   These DIPGs, diffuse intrinsic pontine gliomas were all though to the same terrible life expectancy.

Now it has been found that not all DIPGs are the same.   Some children initially diagnosed with diffuse intrinsic pontine gliomas unexpectedly had prolonged survival.   There seems to be increasing understanding that some of these tumors are typical with the predicted short survival; then there are others that are atypical and might have longer time.

So what makes a DIPG atypical versus typical?  

 Well, there have been developing imaging appearance and clinical presentation criteria that may put a child on one side or the other. 

Typical Imaging-

1)   The tumor is diffuse without exophytic components or focality,   The tumor is mixed in through normal tissue like “sand in grass” or “pepper in jello”.

2)   The epicenter is located in the pons.  

3)   A majority of the base of the pons is affected.    Some trials require 50% while others require infiltration of 2/3 of the basis pons.

Typical Clinical Features-

1)   Age- So far seems to be written as more than 3 years of age to 18 or 21.  Younger and older patients with diffuse intrinsic pontine tumors are more likely to have prolonged survival.

2)   Clinical Symptoms Triad- Children at the time of presentation tend to have 2 out of 3 typical symptoms.   The typical triad includes a) ataxia/unbalanced gait, b) cranial nerve signs, and c) “long tract signs”- often weakness on one side.

3)   Symptom progression-Symptoms progress rapidly within one to two months from onset to diagnosis.

So, what difference does typical versus atypical make?   

Those with atypical radiographic appearance or clinical  features a may have increased survival.   This may be because these tumors are not high grade gliomas.  Thus, many DIPG trials are requiring biopsy for those children that are atypical.  If one is atypical a difference treatment course might be recommended.

It is likely better to know if a child is atypical before choosing a treatment course.   To get another opinion one can contact the DIPG Registry (http://dipgregistry.org/patients-families/second-opinion/)
or potentially contact a primary investigator of a DIPG trial (www.clinicaltrials.gov).

Note:  As we gain more understanding of diffuse intrinsic pontine tumors the categorization and definitions will probably change just as we have seen over the last couple decades.

DIPG Foundation Spotlight- Team Julian Foundation

DIPG Foundation Spotlight is a new series of posts intended to highlight the work of so many parent lead foundations that are creating awareness, supportting other families, funding research as well as other developing other endeavors to better the lives of other kids and their families.

Team Julian Foundation- In Support of a Little Super Hero
The exceptional, imaginative, dark-haired 4-year-old sounded like every parent's dream.   He was a soccer player, a lover of books and music, a social little being that could make people laugh, and a fighter of bad guys.  On November 29, 2010, this family's world was turned upside down when that Monday morning he woke up disoriented.  In a Detroit ER, Julian was diagnosed with a brain tumor that was later classified an atypical brainstem glioma.  He was eventually airlifted to St Jude and began radiation on December 23,  2010.

Unfortunately his post radiation scans in February 2011 showed spread through the brain and lower spine.   Julian endured more radiation and returned to Michigan for chemotherapy.  The tumor was relentless.  Only seven months after diagnosis the little superhero died.

His family and friends were inspired by Julian's charm and courage.    They became "fiercely determined to keep his spirit alive by helping other kids and their families get a fighting chance against this devastating disease."Team Julian Foundation came into being.

As always pictures are worth a thousand words.  Here is an eight minute video about Julian and the foundation......

In two years they have raised 200K which has gone to support DIPG research as well as other things.   There has been 130K to research at St Jude Research Hospital, Keller Lab at OHSU(primary coordinator for the DIPG Preclinical Consortium) and the DIPG Collaborative.   They have also supported Make A Wish and the distribution of the ACCO book on Understanding the DIPG Journey.

At the very end of the video, there was  a hint of what will come in 2013.   It looks like the foundation will become Julian B Bovins Courage for Cures Foundation.    Looking forward to finding out more about the developments with this organization.


Team Julian Foundation-
http://www.teamjulianfoundation.com/