Friday, May 9, 2014

Somebody just needed to tell me! GIST, not everything is in the BAG (or known!) if you get my drift...!

THE CLINICAL CASE :
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A 50 year old Hispanic woman with history of Neurofibromatosis came to me in March  2014, she had an episode of hematemesis .  She was found to have a large mass in the body of the stomach.  The mass was a GIST (gastrointestinal stromal tumor).  She reportedly was seen by a surgeon who in consult with the internist and before Oncology was involved decided a neoadjuvant approached.  The patient was on Gleevec before my consultation.   The patient had skin lesions of Neurofibromatosis and could not raise her arms because of extensive shoulder arthritis.  We decided to continue her her Gleevec at 400 mg daily.
Now 3 months later, her ANA is positive 1:1280,  and her mass in the stomach has grown from 11 cm to 15 cm, marking a resistance disease.   A surgeon will see her today for an eventual resection of  "resistance disease" and Sutent has been initiated!

SHOULD WE HAVE SUSPECTED THIS?  HERE IS THE LITERATURE!
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Yang et al:"Further, genetic or pharmacologic attenuation of c-kit signaling in Nf1+/- hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation."

Ingram et al:"Neurofibromin, the protein encoded by NF1, functions as a tumor suppressor protein by negatively regulating Ras activity in mammalian cells."
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 "FROM THE INTERNATIONAL GIST SUPPORT GROUP!

Pathology and Prognostic Findings

The GISTs in NF1 patients are usually multiple and usually found on the small intestine, though a few have been found on the stomach. Areas of hyperplasia of ICCs between GISTs in NF1 may be precursor lesions (Andersson et al, 2005). NF1 GISTs do generally stain positive for KIT protein (CD117), like most other GISTs. Compared to sporadic GISTs, NF1 GISTs are more likely to show S-100 reactivity (a marker of neural differentiation), entrapped myenteric nerves within the tumor, and skeinoid fibers within the tumor (Takazawa et al, 2005).
Yamamoto et al (2008) found that all GISTs from five NF1 patients did stain positive for PKC theta.
Although they may fall into any GIST risk category, NF1 GISTs usually show low cell proliferation (growth) indicators such as mitotic count or Ki-67 index (Andersson et al, 2005; Miettinen et al, 2006). NF1 GISTs rarely metastasize (Levy et al, 2004). Andersson et al (2005) reported follow-up for 9 NF1 patients who had surgery for GIST; none of the patients died of GIST, and 6 of 9 were well up to 32 years later. Miettinen et al (2006) described follow-up for 35 NF1 GIST patients, of whom only 5 died of metastatic disease.  Mussi et al (2008) reported follow-up for 28 NF1 GIST patients, of whom 7 (25%) developed metastases.  In both of the preceding two series of NF1 GIST patients, none of those with multiple GISTs developed metastatic disease."

"
There are no reports yet of the use of mTOR inhibitors or MAPK inhibitors on NF1 GIST cells or in NF1 patients with GIST.  Johannssen et al (2008) found that MPNST cell lines from NF1 do show growth arrest (but not cell death) when exposed to rapamycin (an mTOR inhibitor).  The rationale for use of mTOR and MAPK inhibitors in NF1 is clear.

Response of NF1 GIST to Imatinib and Sunitinib

There are only a few published papers about response of NF1 GISTs to tyrosine kinase inhibitor drugs:
  • Lee et al (2006) reported a case of NF1 GIST that did respond to imatinib (Gleevec). 
  • Kalender et al (2007) reported  a patient with initial response to imatinib (Gleevec) who subsequently became resistant and experienced progression.  However, the metastatic lesions in liver and omentum did decrease in size during the first four cycles of sunitinib (Sutent).  Results of longer follow-up were not provided in the paper.
  • Mussi et al (2008) described imatinib treatment results for eight NF1 patients.  Four patients who received adjuvant imatinib after complete resection did not experience recurrence.  Four additional patients with metastases received imatinib, and three of them demonstrated primary resistance (rapid progression), while one patient with a PDGFRA mutation had stable disease temporarily."
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THIS IS NOT YOU STANDARD GIST
MAY BE AN MTOR INHIBITOR WORKING DOWNSTREAM SHOULD BE MORE EFFECTIVE
OR MAY BE SOMETHING UPSTREAM
IT IS A MAST CELL ISSUE
AND MAY BE THAT'S WHY THE SKIN LESION HAPPENS IN NF1 PATIENTS
COULD AN ANTI-MEK OR IBRUTINIB DO A BETTER JOB?
OR JUST DIRECTLY AN ANTI-RAS?

WE WILL ARGUE FOR MTOR INHIBITOR SINCE THIS IS NOT A GIST WITH STANDARD DRIVE OR INTENTIONS?  YOU TELL ME!  WILL UPDATE THIS CASE AS IT UNFOLDS!

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