Detection, Prognosis and Treatment of Neurofibromas

1. Malignant Peripheral Nerve Sheath Tumors:
Devon M. Fagel, JD
Pediatrics Clerkship, YSM III
Respiratory, Oncology & Research
December 3, 2010
Detection, Prognosis and Treatment

2. Overview
• Case Presenation: 12 yo with hx of NF-1 and dx of
MPNST
• Background: Clinical features of Neurofibromatosis Type
1
• Pathogenesis: Development of Neurofibromas and
MPNST
• Prevention: Early screening, imaging and new
interventions
• Treatment: Current chemotherapy regimens/management

3. Case Presentation:
• History: 12 yo with hx of Neurofibromatosis Type 1 presented following
one year of back/abdominal pain, nausea and decreased appetite. Mother
noted 13 lb weight loss and felt a “lump” in left abdomen. MRI showed
8cm x 6cm x 14cm retroperitoneal mass, thought to be neurofibroma.
Underwent gross total resection and pathology consistent Malignant
Peripheral Nerve Sheath Tumor, histological grade 3/3. Staging CT
Chest/Abdomen/Pelvis showed two 1mm non-specific lung nodules.
Bone scan, bilateral bone marrow aspiration/biopsy were negative.
ECHO with normal EF.
• PMH: Neurofibromatosis Type 1 diagnosed at 2 months of age due to
multiple cafe-au-lait spots and bilateral Lisch nodules. Followed by
Dermatology and Ophthalmology.
• PE: Multiple cafe-au-lait spots over back, chest, arms and legs
bilaterally. Bilateral axillary freckling and Lish nodules.

4. NF-1 (von Recklinghausen’s Disease)
• 1882: German pathologist Friedrich
Daniel von Recklinghausen
describes disorder characterized by
tumors of the nervous tissue and
bone, small warty skin growths and
multiple light brown pigmented
spots.
• 1909: Joseph Merrick commonly
known as the Elephant Man is used
as an example of the disease in the
British Journal of Dermatology.
• 1986: Article in British Medical
Journal postulates that Merrick
afflicted with Proteus Syndrome.

5. Clinical Features of NF-1:
• Diagnosis
• 6 or more cafe-au-lait spots (>5mm)
• Freckling of axillary/inguinal region
• 2 or more neurofibromas of any type
• Optic glioma, 2 or more Lisch nodules
• Osseous lesions (sphenoid dysplasia)
• Genetics
• Mutation of neurofibromin gene,
negative regulator of Ras oncogene.
• Autosomonal dominant pattern of
inheritance, however 50% of cases
arise from spontaneous mutation.
• Incidence 1:3500 live births.
Ferrari et. al, Cancer 109: 1406-1412, 2007

6. Pathogenesis:
• Disorder of the neuro-
ectodermal system that may
result in tumors of skin, eyes
and nervous system (tissues
derived from neural crest i.e.
melanocytes, sensory nerves
and Schwann cells.
• Superficial (red arrow) and deep
(blue) neurofibroma of lower
extremity.
• MPNST involving sciatic nerve
and near scapula with PET
image showing avid glucose
uptake consistent with
metabolic activity.
Katz et. al, Expert Rev in Mol Med 11: 1-23, 2009

7. MPNST Diagnosis:
• Early Detection:
• Currently precluded by lack of clinical means to conclusively ascertain potential
for malignant transformation of deep neurofibromas. However given 1/3 will
undergo transformation, early detection is critical. In one study, clinical
characteristics were described which indicate higher risk for MPNST including
limb localization, larger size, depth in relation to fascia and short duration of pain
symptoms. Another study found that multiple MRIs which document rapid
growth can be prognostic. Ongoing trials using FDG-PET combined with CT in
follow-up of deep neurofibromas.
Matsumine et. al, J Cancer Res Clin Oncol 135: 891-900, 2009
• Prevention?:
• Several trials using experimental prevention treatments for
NF1including Sorafenid (inhibitor of several tyrosine protein kinases
including VEGFR and PDGFR) and Rapamycin (immunosuppressant
used to prevent rejection in organ transplantation) are currently
underway.

8. Treatment:
George et. al, Up To Date: Systemic Treatment of Metastatic Soft Tissue Sarcoma 2010
• Combination Therapy vs Single Agent Therapy : Randomized prospective
trials show combination regimens are associated with higher response rates
than single agent doxorubicin.
• Doxorubicin: Anthracycline antibiotic works by intercalating DNA, side effects include
nausea, vomiting and heart arrhythmias.
• Ifosfamide: Alkylating agent used with Mesna to prevent hemorrhagic cystitis.
Response rates are higher but have not translated into survival benefit.
• Mesna: Adjuvant therapy to neutralize metabolites and increase urinary excretion of
cysteine.
• Surgery and Radiation Therapy :
• Used in cases of discrete, localized tumors. If neurfibrosarcoma in an extremity and
well-vascularized, amputation may be necessary. Some surgeons opt for limb saving
treatment in which case radiation is used.
• Dose intensification:
• Higher doses of Doxorubicin and Ifosfamide can be administered with the
support of hematopoietic growth factors or autologous hematopoietic stem cells.

9. Future Strategies:
• Antiangiogenic Therapy:
• Sorafenib: Phase II trial of 120 patients who received Sorafenib 400mg BID, showed no
objective responses in MPNST (some positive results in other soft tissue sarcomas).
• Bevacizumab: Also targets VEGF. One trial evaluated Bevacizumab plus doxorubicin
evaluated in 17 patients with metastatic soft tissue sarcoma. Two partial responses, 11
had stable disease, however 6 patients developed grade 2 cardiac toxicity with
doxorubicin doses of 75-300 mg/m2.
Katz et. al, Expert Rev in Mol Med 11: 1-23, 2009
• Current Prognosis: 5 year survival rate of 20-50% indicate urgent need for improved
therapeutic approaches. Current research on signal transduction cascades / deregulated
tyrosine kinase receptors pose the hope for targeted therapies.