Malignant Peripheral Nerve Sheath Tumors:

Devon M. Fagel, JDPediatrics Clerkship, YSM III

Respiratory, Oncology & ResearchDecember 3, 2010

Detection, Prognosis and Treatment

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

• Conclusion: Future strategies for improved prognosis

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.

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.

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

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

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.

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.

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.