USCAP Pediatrics Evening Subspecialty Conference 2015
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1 USCAP Pediatrics Evening Subspecialty Conference 2015 Sunday 22 March 2015 Alexander Lazar MD/PhD Department of Pathology S Section of Bone Soft TIssue Pathology Sarcoma Research Center
2 The Case
3 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.
4 Provided Case Images
5 Cutaneous nodule
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8 Deep popliteal nodule?biphasic
9 Phase 1
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21 Diagnosis?
22 Malignant Peripheral Nerve Sheath Tumor (MPNST) arising in association with a deep neurofibroma in a patient with Neurofibromatosis type I
23 Selected stuff of interest (hopefully) regarding MPNST
24 Nerve sheath tumours 2013 Benign Schwannoma (including variants) Melanotic schwannoma Neurofibroma (including variants) Plexiform neurofibroma Perineurioma Malignant perineurioma Granular cell tumour Dermal nerve sheath myxoma Solitary circumscribed neuroma Ectopic meningioma Nasal glial heterotopia Benign Triton tumour Hybrid nerve sheath tumours Malignant Malignant peripheral nerve sheath tumor Epithelioid malignant nerve sheath tumor Malignant Triton tumor Malignant granular cell tumor Ectomesenchymoma 24
25 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
26 Clinical Features Clinical setting 1. NF1 associated ( 50%) 2. Sporadic ( 40%) 3. Radiation associated ( 10%)
27 Clinical Features Epidemiology Gender Age Male Female Variable Usually adults Children can be affected NF1 associated MPNST patients tend to be younger at time of primary tumor diagnosis
28 Clinical presentation Anatomic location 1. Extremities 2. Trunk 3. Head & neck Signs & symptoms Clinical Features Painless/painful mass Motor/sensory deficit Radiology FDG PET/CT imaging shows increased uptake compared to neurofibromas; valuable for restaging purposes
29 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
30 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): , June DOI: /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 = ; 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 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
31 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): , June DOI: /SLA.0b013e3181a77e9a TABLE 3. Prognostic Factors for MPNST Specific Mortality in 85 Patients Who Underwent Complete Surgical Resection 2009 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
32 32 Katz D, Lazar A, Lev D, 2009.
33 Treatment Surgical resection The mainstay therapy Conventional chemotherapy and/or radiotherapy Response is generally poor Targeted therapy Potential targets include: mtor, AKT, EZH2, MET
34 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
35 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%
36 Pathology Macroscopic features Size: usually large (>5 cm) Shape: fusiform An associated neurofibroma Pseudo encapsulated tumors Infiltrative/irregular borders Hemorrhagic/necrotic
37 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
38 Histological variants Pathology 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
39 Neurofibroma
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48 The many faces of MPNST.
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70 MPNST Tibia AKA Courtesy of John Hicks Texas Children s Hospital
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81 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
82 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
83 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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85 New Molecular Features 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. SUZ12 mutations not seen in the sporadic MPNST cases. Sporadic MPSNT cases had a mutation of the EED, EPC1 and CHD4 genes all of which interact with polycomb repressor complexes (PRC)
86 Methylation of lysine 27 histone 3 Gene silencing
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89 Conclusions Histology Immunohistochemistry Clinical setting NF type 1 Sporadic Postradiation Lots of new molecular data Better diagnostics? Better treatment?
90 Thanks Wei Lien (Billy) Wang MD John Hicks MD The Cancer Genome Atlas (TCGA)
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