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USCAP – Pediatrics Evening Subspecialty Conference 2015
Sunday 22 March 2015Alexander Lazar MD/PhDDepartment of Pathology SSection of Bone Soft TIssue PathologySarcoma Research Center
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The Case
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Patient History
• 16 year old female with a history of multiple light brown macules since age 3 and several nodules including one with recent growth in the left popliteal fossa.
• MRI reveals an enlarging 6 cm mass which is PET avid. Surgery resection reveals an "encapsulated appearing mass" as well as a smaller (2.5 cm) distal mass.
• Subcutaneous nodules were also noted.
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Provided Case Images
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Cutaneous nodule
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Deep popliteal nodule –?Biphasic
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Phase 1
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Phase 2
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Diagnosis?
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Malignant Peripheral Nerve Sheath Tumor (MPNST) arising in association with a deep neurofibroma in a patient
with Neurofibromatosis type I
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Selected stuff of interest (hopefully) regarding MPNST……
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Nerve sheath tumours
2013BenignSchwannoma (including variants)Melanotic schwannomaNeurofibroma (including variants)Plexiform neurofibromaPerineuriomaMalignant perineuriomaGranular cell tumourDermal nerve sheath myxomaSolitary circumscribed neuromaEctopic meningioma
Nasal glial heterotopiaBenign Triton tumourHybrid nerve sheath tumours
MalignantMalignant peripheral nerve sheath tumorEpithelioid malignant nerve sheath tumorMalignant Triton tumorMalignant granular cell tumorEctomesenchymoma
24
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Introduction
• MPNSTs are malignant mesenchymal tumors that arise from major peripheral nerves or pre‐existing benign nerve sheath tumors
• They manifest Schwann cell‐type differentiation under immunohistochemical and/or ultrastructural examination
• They comprise 3‐10% of soft tissue sarcomas• Synonyms: malignant schwannoma, neurogenic sarcoma, neurofibrosarcoma, neurosarcoma
• Precursors: neurofibromas (deep>>>cutaneous), schwannomas, perineuriomas
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Clinical Features
• Clinical setting1. NF1‐associated (≈50%)2. Sporadic (≈40%)3. Radiation‐associated (≈10%)
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Clinical Features
• Epidemiology– Gender
• Male ≈ Female
– Age • Variable• Usually adults• Children can be affected• NF1‐associated MPNST patients tend to be younger at time of primary tumor diagnosis
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Clinical Features• Clinical presentation
– Anatomic location1. Extremities2. Trunk3. Head & neck
– Signs & symptoms• Painless/painful mass• Motor/sensory deficit
– Radiology• FDG‐PET/CT imaging shows increased uptake compared to neurofibromas; valuable for restaging purposes
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Clinical Features
• Prognosis – Generally aggressive– Recurrence in 38‐45%– Metastasis in 40‐80%– Poor prognostic factors
• Clinical: Location; Size ≥ 10 cm; Metastasis; NF1 status• Pathological: Rhabdomyoblastic component• Molecular: TP53 mutation
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© 2009 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
FIGURE 1.Clinical, Pathological, and Molecular Variables Predictive of Malignant Peripheral Nerve Sheath Tumor Outcome.Zou, Changye; Smith, Kerrington; Liu, Jun; Lahat, Guy; Myers, Sarah; Wang, Wei‐Lien; Zhang, Wei; McCutcheon, Ian; Slopis, John; Lazar, Alexander; MD, PhD; Pollock, Raphael; MD, PhD; Lev, Dina
Annals of Surgery. 249(6):1014‐1022, June 2009.DOI: 10.1097/SLA.0b013e3181a77e9a
FIGURE 1. Clinical factors affecting DSS in all MPNST patients. Univariable analysis demonstrated that patients presenting with metastasis harbor the most dismal prognosis (P = 0.0025; A); no difference in outcome was observed when comparing primary to recurrent lesions (P = 0.92) or neurofibromatosis‐1 status (NF1+ versus NF1‐; P = 0.39; B). Kaplan Meier curves are depicted.
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© 2009 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
TABLE 3.Clinical, Pathological, and Molecular Variables Predictive of Malignant Peripheral Nerve Sheath Tumor Outcome.Zou, Changye; Smith, Kerrington; Liu, Jun; Lahat, Guy; Myers, Sarah; Wang, Wei‐Lien; Zhang, Wei; McCutcheon, Ian; Slopis, John; Lazar, Alexander; MD, PhD; Pollock, Raphael; MD, PhD; Lev, Dina
Annals of Surgery. 249(6):1014‐1022, June 2009.DOI: 10.1097/SLA.0b013e3181a77e9a
TABLE 3. Prognostic Factors for MPNST‐Specific Mortality in 85 Patients Who Underwent Complete Surgical Resection
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Katz D, Lazar A, Lev D, 2009.32
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Treatment
• Surgical resection– The mainstay therapy
• Conventional chemotherapy and/or radiotherapy– Response is generally poor
• Targeted therapy– Potential targets include: mTOR, AKT, EZH2, MET
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MPNST in Children I• Rare but one of the most common non‐round blue cell malignant
tumors• 10‐20% of MPNSTs affect patients ≤20 years• Mostly affect adolescents over the age of 10 years • Slight male predilection • Significantly higher proportion of black and Hispanic cases than
seen among adults• Trunk most common location, followed by extremities and head &
neck• Prognostic factors
– Sex: females were reported to have larger tumors and worse survival outcome
– Race: non‐Hispanic black pediatric patients have significantly lower survival– Treatment protocol: lack of post‐operative radiotherapy was reported to be
associated with better survival
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MPNST in Children II• MDACC experience
– No age is immune– Age range is <1‐80 years– 17% of all MPNST patients are ≤20 years of age– Extremely rare below the age of 5 years (2/50 cases)– Over 60% are known to have NF type 1– Slight male predilection
• 44% female• 46% male
– Anatomic location• Extremities=44%• Trunk=36%• Head & neck=20%
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Pathology
• Macroscopic features– Size: usually large (>5 cm)– Shape: fusiform– An associated neurofibroma– Pseudo‐encapsulated tumors– Infiltrative/irregular borders– Hemorrhagic/necrotic
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Pathology
• Microscopic features– High grade sarcoma is the hallmark– Fascicular/storiform pattern, geographic necrosis– Cells: spindle, epithelioid, pleomorphism, frequent mitoses
– Heterologous elements: osteoid, chondroid, myogenic, others
– Standardized grading system is not available– Low grade MPNST vs atypical neurofibroma
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Pathology– Histological variants
• Glandular MPNST (NF1)• Epithelioid MPNST (sporadic, pre‐existing schwannoma)• Malignant Triton tumor
– Differential diagnosis• Atypical neurofibroma• Cellular schwannoma• UPS• Fibrosarcoma• Synovial sarcoma• Melanoma• Dedifferentiated liposarcoma
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Neurofibroma
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The many faces of MPNST…….
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MPNST – Tibia AKA
Courtesy of John HicksTexas Children’s Hospital
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Pathology Immunoprofile
• Immunohistochemical profile– S100 protein, GFAP, SOX10, PGP9.5, Leu‐7, p53 – Keratin (epithelioid and glandular)– EMA (rare, perineurial differentiation)– Loss of p16 and p27
• Ultrastructure – Schwann cell and perineurial cell differentiation
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Molecular Pathology
• Cytogenetic and molecular features–Complex karyotype–Germline NF1 gene (17q11.2) alteration–NF1 gene somatic mutations–Multiple genomic losses and gains
• NF1 LOH• CDKN2A• TP53
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What is New & Cool?
• Ongoing studies to better understand the molecular basis of MPNSTs – Recent papers– TCGA– Mouse models
• Continuous attempts to understand the genetic and molecular alterations that drive the progression of precursor benign lesions to MPNSTs
• Investigations of potential molecular therapeutic targets
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84
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• Median of over 60 somatic nonsynonymous point mutations or small insertion‐deletions
• Inactivating mutations of SUZ12 occurred in MPNST, confirmed by direct sequencing.
• The SUZ12 gene encodes zeste homolog 12 (Drosophila), a chromatin‐modifying protein.
• SUZ12mutations not seen in the sporadic MPNST cases.
• Sporadic MPSNT cases had a mutation of the EED , EPC1and CHD4 genes all of which interact with polycombrepressor complexes (PRC)
New Molecular Features
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Methylation of lysine 27 histone 3
Gene silencing
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Conclusions• Histology• Immunohistochemistry• Clinical setting
– NF type 1– Sporadic– Postradiation
• Lots of new molecular data– Better diagnostics?– Better treatment?
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Thanks
• Wei‐Lien (Billy) Wang MD• John Hicks MD
• The Cancer Genome Atlas (TCGA)