ACCME/Disclosure of Pediatric Round Cell & Soft Tissue Tumors: Avoiding Pitfalls John Hicks - Texas Children’S Hospital & Baylor College of Medicine Dr

Ultrastructure As An Important Component in Diagnosis ACCME/Disclosure of Pediatric Round Cell & Soft Tissue Tumors: Avoiding Pitfalls John Hicks - Texas Children’s Hospital & Baylor College of Medicine Dr. Hicks has nothing to disclosure

Differential Diagnosis of Small Round Differential Diagnosis of Small Round Cell Cell Tumors of Childhood Tumors of Childhood • Ewing Family of Tumors • Desmoplastic Small Round Cell – Classic, Atypical, PPNET Tumor • Rhabdomyosarcoma • Clear Cell Sarcoma of Soft Tissue – Alveolar & Embryonal • Synovial Sarcoma • Neuroblastoma • Alveolar Soft Part Sarcoma • Lymphoma • Medulloblastoma – CNS • Extramedullary ALL/AML • Mesenchymal Chondrosarcoma • Wilms Tumor • Pleuropulmonary Blastoma • Germ Cell Tumors • Small Cell Osteosarcoma • Neuroendocrine Tumors • Pancreatoblastoma • Rhabdoid Tumor • Sialoblastoma • Small Cell Hepatoblastoma • Small Cell Mesothelioma 3 4

1 Case History

• 37 Week Gestation Male Neonate Delivered Vaginally • At Delivery, Purple-Blue 8 cm Mass Protruded from Left Facial/Ear Region • Mass Not Present on Ultrasound at 20 Weeks Gestation • Diagnostic Imaging and Clinical Impression: Congenital/Infantile Hemangioma (Vascular Tumor) • Prednisone and Beta-Blocker Therapy Initiated • Tumor Rapidly Increased in Size & Ulcerated • Resection Performed on 8th Day of Life

2 Flow Cytometry Results • CD56 (NCAM) • CD38 Positivity • Interpretation: – Not Compatible with Hematopoietic/Lymphoid Neoplasm

FISH for MYC-N • No Evidence of Amplification

Routine Cytogenetics Pending

3 Immunohistochemistry: Negative

• Myogenic • Vascular – Desmin, Myogenin, – CD34, CD31 MyoD1 • Neural • Epithelial – NB84, S100, NFP, – EMA, Pancytokeratin, NSE, Chromogranin CAM 5.2 • Germ Cell • Lymphoid – PLAP, CD30, AFP – LCA, CD20, CD3, TdT, • Melanocytic CD61, CD31, – HMB45, S100 Myeloperoxidase, Protein CD30, CD43, ALK1, CD4, CD8, CD68, CD1a

4 Cytogenetics FISH Breakapart Rearrangement of EWSR1 • Splitting and Rearrangement of 5’ EWSR1 to 20q11.2 (FISH requested after EM Findings) Conventional Cytogenetics • 50,XY,+6,+12,+15,+17,t(20;22)(q11.2;q12) • 51,idem,+der(22)(t20;22)(q11.2;q12)

Diagnosis NFATc2: (Nuclear Factor of Activated T-Cells, • Ewing Sarcoma (Peripheral Primitive Cytoplasmic, Calcineurin-Dependent 2) Neuroectodermal Tumor) with Novel t(20;22) EWSR1-NFAT2cTranslocation • Implicated in Breast Cancer & In Cell Motility as Basis for Metastasis • NFATc2: Pro-Invasive and Pro-Migratory in Breast Cancer • To Increase Cell Motility NFATc2 Up- Regulates Lipocalin 2 Expression and Modulatse TWEAKR/TWEAK • NFATc2 Interacts with MEF2D, EP200, IRG48, Protein Kinase M

5 • ES/pPNET: 15% Before Age 5 Yrs • 22 Congenital Ewing Sarcoma Cases Small Round Cell Tumors in Neonates • 40% - Metastatic Disease (Skin, LN, Brain) • Congenital Ewing Sarcoma Very Rare and Not • DOD (15 of 22) At 1-24 Months Usually in Differential Diagnosis • Ewing Sarcoma Rare Diagnosis in Neonates and May be Misdiagnosed as Another Small Round Cell Tumor Due to Variable Degrees of Neuroectodermal Differentiation • Median Age for Ewing Sarcoma: – 15 Yrs of Age – 70% Presenting Before 20 Yrs of Age • Only 15% of Ewing Sarcomas Diagnosed Before 5 Yrs of Age

Small Round Cell Tumors in Neonates • Differential Diagnosis for Congenital Tumors include: – Teratoma, Rhabdomyosarcoma – Neuroblastoma – Hemangioma, Other Vascular Tumors – Leukemia, Lymphoma – Langerhans Cell Histiocytosis – Lymphatic Malformations • Congenital Malignant Tumors Account For Less than 2% of All Childhood Malignancies • Typical Small Round Cell Tumors Identified During Neonatal Period: Leukemias and Neuroblastomas Most Common (LCH benign) 24

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7 Promiscuous Nature of EWSR1 Clinical History

• 7 year-old healthy boy with painless, nontender swelling of his right upper thigh noticed 2 months prior to presentation • Mass recently increased markedly and affected gait - walks with a limp, pain on running and tires easily • Normal sensation and range of motion • Physical Examination: Swollen firm right thigh with increased superficial vascularity BCOR-CCNB3 • No erythema, warmth, bruits or pulsations

8  Routine X-ray: large medially placed thigh mass involving  CT and MRI: large heterogenous, hypervascular mass (18 x 13 x 9 soft tissue cm) with tortuous, enlarged vascular channels (high flow lesion)  Femur with intact cortex and no periosteal reaction  Arterial drainage into the right iliac artery and venous drainage into the femoral vein

Radiologists’ Impression Needle Core Biopsy

• Mixed Vascular Lesion with Large AVM Component with Intralesional Hemorrhage

• Prior to Embolization of This Possible Hypervascular Lesion with an AVM Component, Biopsy was Performed.

9 Immunostains • Negative Stains: • Positive Stains: – Desmin, Myogenin, – SMA (focal expression) MSA, MyoD1 – INI1 (nuclear) – Chromogranin, S100 – Beta-Catenin Synaptophysin (cytoplasmic) –CD99 – Vimentin –ALK-1 – EMA, PanCytokeratin – CD34, CD31, D2-40 –MUC4 – Collagen Type IV

INI1

10 Cytogenetics & Molecular Genetics

• Karyotype: 46,XY • Negative FISH for EWSR1, SS18, FOXO1

• RT-PCR Translocations Negative for: – Ewing Sarcoma • Distribution of paired-end split and spanning RNA-Seq reads – Synovial Sarcoma joining BCOR exon 15 with CCNB3 exon 5 • Direct sequencing confirmed RNA-seq reads: BCOR–CCNB3 – Alveolar Rhabdomyosarcoma fusion transcript result of cryptic ‘GT’ splice donor site – Low-Grade Fibromyxoid Sarcoma activation in BCOR exon 15 leading to skipping of ‘TGA’ termination. • RT-PCR with fusion-specific primers - expression of 171-bp band only in the tumors (current patient T107)

CCNB3 Embolization Prior to Resection

11 BCOR-CCNB3 Sarcoma Summary of BCOR3-CCNB3: Clinicopathologic • 1st Described in 2012 by performing RNA-seq on Correlations (n=26) Translocation Negative Ewing-Like Sarcomas • Median age: 13.1 yrs (range 5.9 to 25.6 yrs) • Gender Ratio: 2 Male: 1 Female (4% [24/594] undifferentiated sarcoma) • Age Groups: 1-9 years 23% • RNA-Seq identified 20 distinct high-quality 10-17 years 50% paired-end fragments linking Exon 15 of BCOR >18 years 27% (Xp11.4) and Exon 5 of CCNB3 (Xp11.22) Clinical Signs at Presentation • Pain 65% • Primers for BCOR Exon 15 and CCNB3 Exon5 • Swelling 40% designed to perform RT-PCR for BCOR-CCNB3 • Limp 20% translocation due to X-chromosome inversion • Pathologic Fracture 15% • Fever 10% (paracentric) • Medullary Bone Compression 10%

BCOR-CCNB3 Sarcoma: Differential Diagnosis Summary of BCOR3-CCNB3: Clinicopathologic Correlations • Ewing Sarcoma/PNET with EWSR1-ETS Original Diagnosis Immunostain Profile Rearrangement (EWSR1-FLI1; EWSR1-ERG; • Ewing/PNET 46% • CCNB3 nuclear 100% EWSR1-ETV1; EWSRI-ETV4; EWSR1-FEV) • Small Cell Osteosarcoma 11% • CD99 membranous 16% • Round Cell Sarcoma with EWSR1-nonETS • Bone Sarcoma, NOS 23% • CD99 cytoplasmic 24% Rearrangement (EWSR1-NFAT2c; EWSR1-SP3; • Soft Tissue Sarcoma, NOS 11% • CD99 dot-like (Golgi) 48% EWSR1-PATZ1; EWSR1-SMARCA5; EWSR1- • MPNST 4% • Desmin 0% POU5F1) • Granulocytic Sarcoma 4% •EMA 0% • Pancytokeratin 0% • Round Cell Sarcoma with non-EWSR1-ETS • S100 protein 0% Rearrangement (FUS-ERG; FUS-FEV) •SMA 0% • Small Cell Osteosarcoma •CD34 0% • Rhabdoid Tumor (INI-1 [SMARCB1] Loss or SMARCA4 [BRG1] Loss)

12 BCOR-CCNB3 Sarcoma: Differential Diagnosis BCOR Gene • Round Cell Sarcoma with CIC-DUX4 Fusion • BCOR Mutations: Oculofaciocardiodental • Undifferentiated Round Cell Tumor and Lenz micro-ophthalmia syndromes; • Mesenchymal Chondrosarcoma (HEY1-NCOA2) myeloid leukemia; myelodysplastic • Synovial Sarcoma (SS18-SSX1; SS18-SSX4) syndromes; medulloblastoma • Rhabdomyosarcoma (PAX3-FOXO1; PAX7-FOXO1; 11q15) • BCOR-RARA t(X;17): acute promyelocytic • Desmoplastic Small Round Cell Tumor (EWSR1- leukemia WT1) • BCOR-ZC3H7B t(X;22): Endometrial • Extraskeletal Myxoid Chondrosarcoma (EWSR1- NR4A3; EWSR1-TAF15; TCF12-NR4A3; TFG- stromal sarcoma and Ossifying fibromyxoid NR4A3) tumor • Clear Cell Sarcoma of Soft Tissue (EWSR1-ATF1) • BCOR ins(4;X): Ewing-like undifferentiated • Lymphoma/Leukemia/Granulocytic Sarcoma round cell sarcoma

Case History • 8 Yr-Old Hispanic Female with Right Cheek Swelling Noticed by Parents 1 Month Ago While Visiting Mexico • Went to Dentist in Matamoros: Not A Tooth Problem • PCP in Matamoros: Acyclovir With No Resolution • PCP in Brownsville: – Antibiotics No improvement • Dentist in Brownsville: Problem Due to Chewing on Teeth. Removed Primary Molars & Incisor – No Change in Swelling • “Pain Spasms" for 3-4 Hours Night without Relief. • Valley Baptist Hospital: CT with Angle of Jaw Lymph Node Enlargement – Concern for Malignancy • Transferred To TCH-Houston

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13 Lymph Node-Hematopathology: S/O ALCL on TP Permanent Tissue Sections Touch Preparations By Hematopathology

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Myofilaments

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14 Desmin Myogenin Pax7-FOXO1 RT-PCR: Solid Variant of Alveolar RMS

Pax3-FOXO1 Pax7-FOXO1

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• 7 Year-Old Male with Recent Onset of Swallowing Problems • Notice Rapid Increase in Tongue Size a Few Weeks Ago with Increased Drooling

15 Desmin Myogenin Rhabdomyosarcoma

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16 Embryonal and Strap Cells Spindle Cell, Botryoid & UDS

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Genetics: RMS • Alveolar RMS: • Embryonal RMS: – PAX3/FOXO1 (most) – 11p15.5: IGF2, H19, – PAX7/FOXO1 CDKN1C, HOTS – PAX3/FOXO4, – Mutations: RB, TP53, PAX3/NCOA1, CDKN2A, CDKN2B, RAS, PAX3/NCOA2 FGFR4, PIK3CA, CTNNB1 Alveolar & Anaplastic FOXO1/FGFR1 (beta-catenin) – CDK4 Amplification – NF1 Deletions – Mutations: TP53, CDKN2A, – ALK Copy Gain CDKN2B, FGFR4 – DNA Methylation – ALK Copy Gain – 12q13: GLI – Tumor Suppressors: RASSF, HIC1, CASP8 – DNA Methylation

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17 Paratesticular Tumor in Adolescent: Undifferentiated Pleomorphic Sarcoma

Myofilaments

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Small Cell Osteosarcoma

Thigh Mass with Bony Involvement in Adolescent Male

71 72 Alveolar RMS with Anaplasia: Paratesticular

18 Fibrosarcoma

Sclerosing Rhabdomyosarcoma Lower Extremity Mass in 11 Year-Old Boy

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Histocytosis in Lymph Node (S100, CD1a)

Embryonal Rhabdomyosarcoma, Spindle Cell

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19 Rhabdomyoma-Like Rhabdomyosarcoma Cervical Mass

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Case History • 18 Month Old Male with Anemia, Fever, Weight Loss, Diarrhea, Hypertension • Recent Submandibular Lymph Node Enlargement • Suspected Lymphoblastic Lymphoma/Leukemia • Underwent Lymph Node Biopsy

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20 NB84 Neuroblastoma Family of Tumors • Three Major Classes of Neuroblastic Tumors Based on Degree of Differentiation of Neuroblastic and Schwannian Stroma Cells – Schwannian Stroma Poor (0 to <50%): Undifferentiated, Poorly Differentiated and Differentiating Neuroblastomas – Schwannian Stroma-Rich (>50%): Ganglioneuroblastoma: Intermixed or Nodular Types – Schwannian Stroma Dominant (nearly 100%): Ganglioneuroma: Maturing and Mature 82

• Undifferentiated NB • Undifferentiated NB – Small Round Cell – High NC Ratio Tumor of Childhood – Lack Neuropil Processes – Lacks Histopathologic – May Have Fine Granular Evidence of Chromatin Neuroblastic – May Have Distinct Differentiation Nucleoli – No Schwannian Stroma – Differential Diagnosis Differentiation • Rhabdomyosarcoma • Ewing’s Sarcoma – Lack Pseudorosettes • Blastemal Wilms Tumor – Fine Vascular Capillary • Lymphoma/Leukemia Network • Other SRCT with Embryonal/Blastemal Appearance

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21 • Immunophenotype NB84 – NB84* • Electron Microscopy – PGP9.5* – Only Necessary with –NSE Undifferentiated Tumors – Chromogranin A or With Aberrant & – Synaptophysin Confusing – Tyrosine Hydroxylase* – GD2* Immunostaining Profile – ALK1 in Familial Cases – Neurite Processes • Negative for: –Dense Core – VIMENTIN*** Neurosecretory Granules – Desmin – No Other Tumor Defining – LMW Keratins Features –LCA – CD99 Usually Negative, Rare Positive Cases

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Gene Mutations in Neuroblastoma • 4 Week-Old Hispanic Male • Most Hereditary Neuroblastomas (AD Inheritance) Associated with Activating – Red-Brown, Raised Mutations in Tyrosine Kinase Domain of Firm Ulcerated Skin Anaplastic Lymphoma Kinase (ALK) Lesions (multiple) Oncogene (Constitutional Mutation) – Moderate Fever • ALK Somatic Mutations in 5-15% of – Recent Onset of Sporadic Neuroblastomas Diarrhea • PHOX2B: Regulation of ANS Development Participates in Both • Differential Diagnosis Hereditary and Sporadic Neuroblastomas – Small Round Cell – Also Neuroblastomas Associated with Tumors Congenital Central Hypoventilation • Leukemia Syndrome and Hirschsprung’s • Neuroblastoma Disease – Infection

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22 CD207 (Langerin)

23 Langerhans Cell Histiocytosis – Predominantly Disease of Infancy and Early Childhood (peaks at 3 years of age) – Unifocal; Multifocal & Unisystem; and Multifocal & Multisystem Disease Patterns – 5 Distinct LCH Clinical Entities • Eosinophilic Granuloma • Hand-Schuller-Christian Disease • Letterer-Siwe disease • Congenital Self-Healing LCH • Pulmonary LCH

Deep Subcutaneous Nodule: Congenital Self-Healing LCH 6 Month Old Hispanic Girl

• Described 4 Decades Ago – Hashimoto-Pritzker Histiocytosis – Congenital Self-Healing Reticulohistiocytosis • Represent 10% of Pediatric LCH Cases • Clinical Suspicion for Leukemia, Neuroblastoma, Small Round Cell Tumors, Infection, JXG & LCH • Indistinguishable from LCH on LM and IHC • Laminated and Non-Laminated Dense Bodies • Pentalaminar Bodies (<30% of LC histiocytes) • Clinical Course: 98% Involute with No Treatment

24 Cytogenetics 56,X,?r(X)(p22q28),add(1)(p36),+i(1)(q10),+4, +add(6)(q12),+7,add(7)(p11.2)x2,+8,add(12)(q21), +15,+20,+21,+21,+22[16]/46,XX,inv(9)(p11q13)[4] Flow Cytometry Results Interpretation: Not Compatible with Hematopoietic/Lymphoid Neoplasm

25 26 • 8 year-old with right shoulder mass and prior history of melanocytic nevus

Died of Disease-50%

(J Am Acad Dermatol 2002;47:77-90.) 106

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27 3 Years Later: Needle Core Biopsy of Neck Mass DX: Spitz Nevus (epitheliod and spindled nevus)

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29 Melan-A S100 Protein

Example of Various Melanosome Phases HMB45 118

30 Cytogenetics • 46,XX,add(12)(q24.3),t(?20;22) (?p11.2;q12) in Only 2 Cells – Probably Balanced Translocation • Abnormal Chromosomal & FISH (89.5% of Cells) Analysis with EWSR1 Gene Rearrangement • 21 and 26 Day Primary Cultures

CCSST RT-PCR • <1% of Soft Tissue Tumors (500 cases) • EWS-ATF1 Performed • Young to Middle Age Adults & 1.5F:1.0M Ratio on: • Foot & Ankle Common (33%), Less Often Leg/Knee – Skin Biopsy: Negative (15%), Thigh (12%), Hand (18%), Elbow/Forearm (10%), Trunk (7%), H&N (3%), Genital (2%) – Lung Needle Core and • Deep Seated Tumor Arising From Tendons & Biopsy: Positive Aponeuroses – Lymph Node Biopsy: •Most <5cm Positive • Long Duration Prior to Diagnosis in Most – Proximal Humeral Resection: Positive

31 CCST 2 Month Old Male with Markedly Enlarged • EWS-ATF1 Translocation in >90% Liver & Concern for Neuroblastoma (Stage IVS) • EWS-CREB1 Translocation in Minority – More Common in GI Clear Cell Sarcoma • ATF1 Member of CREB Family • CREB and ATF1 in Combination with SOX10 – Crucial in Driving Expression of MITF (regulator of melanocyte differentiation) in normal melanocytes • Gene Expression Profiles – CCSST Clusters with Melanoma – Expression of Melanocytic Differentiation Genes (MITF, SOX10, ERBB3, FGFR1

Urinary Catecholamines: Negative Transferred To Pediatric Hospital

32 Congenital Acute Megakaryoblastic Leukemia

• Rare Form of Acute Myeloid Leukemia (1%) • Median Age 4 months (range neonate to 3 yrs) • Mimics Stage IVS Undifferentiated Neuroblastoma – Hepatomegaly, Anemia, Thrombocytopenia • Liver Biopsy: Displacement of Hepatocytes • Immunoreactivity with – NB84, NSE, PGP 9.5 – CD41, CD61, CD42, CD12, CD33 • Translocation Detection RMB15-MKL1 (OTT-MAL) – t(1;22)(p13;q13)

6 Year-Old Male with Enlarged Cervical Lymph Nodes

33 • Transferred To Pediatric Hospital • Urinary Catecholamines: Positive • Cytogenetics: MYC-N Amplified, Loss of 1p36 • Negative for ALCL Translocation

Nature 2008;455:967

Human Pathol 2009;40:1638

34 Paraspinal Mass in 7 year-old boy

35 Case History • 33 Month-Old Male with Decreased Heart Tones Shifted to Left & Decreased Breath Sounds on Right • Moderate Respiratory Distress • Chest X-Ray with Air- Filled Cysts and Probable Pneumothorax • CT Scan- Solid Mass • Outside Biopsy: Rhabdomyosarcoma

Solid Tumor Components

Myogenin

Desmin

36 Pleuropulmonary • Detection May Occur During Routine Prenatal Ultrasound PPB & Metastatic Disease Blastoma (PPB) • Important to Distinguish from • Brain 15-25% Adult Pulmonary Blastoma – Type III PPBs 54% • Embryonal Malignant – Adult Pulmonary – Type II PPBs 11% Blastoma: Biphasic Tumor Tumor Derived from • Bone 6-10% Mesenchyme of Lung and with Both Malignant Pleura Mesenchymal and • Liver 2-4% Epithelial (glandular) • Rare Tumor with 20 to 25 Components Cases Per Year in USA • Contralateral Lung – PPB: Only Malignant •Ovary • First Described in 1988 as Mesenchymal Component Distinct Entity and No Malignant • Spinal Cord & Leptomeninges • Predominantly in Neonates, Epithelial Component • Adrenal Glands Infants and Young Children • Equal Gender Ratio • Pancreas (single documented adult • Laterality: Right Lung 54%; • Choroid of Eye & Iris case reported) Left Lung 37%; Bilateral 9%) • Time to Metastases: 24 Months from • Rarely Reported After 12 Diagnosis in Most years of Age

37 PPB Family Tumors and Dysplasia Syndrome • Familial Distribution in 33% • Neuroblastoma, Medulloblastoma, & • Usually Occurs in First Two Decades of Other CNS Tumors Life • Leukemias • Associated with Dicer 1 Mutation • Gonadal Tumors • Tumors/Dysplasias – Sertoli-Leydig Cell Tumors – Lung Cysts (Dicer 1 Mutation) (Dicer 1 Mutation) – Cystic Nephroma (9-10%, Dicer 1 – Dysgerminoma (Dicer 1 Mutation) Mutation) – Wilms Tumor (Dicer 1 Mutation) – Seminoma (Dicer 1 Mutation) –Dysplasias – Germ Cell Tumors • Intestinal Hamartomatous Polyps • Uterine/Cervival Sarcoma Botryoides (Ileal most common with (Dicer 1 Mutation) Intussusception) – Adolescent and Young Women • Cystic Hepatic Hamartoma •Thyroid – Nasal Chondromesenchymal – Nodular Thyroid Hyperplasia Hamartoma (Dicer 1 Mutation) (Dicer 1 Mutation) – Ciliary Body Medulloepithelioma – Follicular and Papillary Thyroid (Dicer 1 Mutation) Carcinomas (Dicer 1 Mutation) – Ovarian Fibroma (Dicer 1 Mutation) • Renal Sarcoma – Rhabdomyosarcoma (Dicer 1 • Other Sarcomas Mutation)

PPB: Survival Five-Year Overall Survival Rates: – Type I PPBs: 85% – Type II PPBs: 58% – Type III PPBs: 42%

38 PPB Stands Out Among Other Lung Cysts

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Case History: • 12 year-old female with slowly enlarging tongue mass • Recently mass has increased rapidly in size • Hypervascular mass with prominent draining veins on angiography & CT

39 Translocation: der(17)(X;17)(p11;q25) ASPL-TFE3 Fusion

40 Alveolar Soft Part Sarcoma Alveolar Soft Part Sarcoma • Most Common Between Ages 5-35 yrs • TFE Carboxy Terminal Immunoreactive: Nuclear • Gender Ratio 2F:1M in <30 Yr Age Pattern • Reversed Gender Ratio in >30 Yr Age – Granular Cell Tumors • Represents 0.2-0.9% of Soft Tissue Sarcomas • S100, Desmin (50%) • Rare Before Age 5 Yrs • Most Common Sites: • Translocation: – Children: Head and Neck – Tongue and Orbit – der(17)(X;17)(p11;q25) – Adults: Deep Soft Tissues of Thigh or Buttocks – ASPL-TFE3 Fusion • Slow Growing Painless Tumors – RT-PCR or FISH • Mets to Brain or Lung – 1st Presentation – Transcription Factor: Activates MET Signaling – MET Inhibitors Target

Alveolar Soft Part Sarcoma Before ASPS Signout, Be Aware

• Prognosis • Renal Cell Carcinomas Account for <5% of • Seldom Recur Locally After Excision All Pediatric Renal Tumors • Xp11.2 Translocation Renal Cell Carcinomas • Metastases Common with Long-Term – Account for Up to 75% of Renal Cell Carcinomas in Followup Pediatrics • Survival with No Metastases at Diagnosis: – Tendency to Present at Advanced Stages – 5 Yrs 60%, 10Yrs 38%, 20 Yrs 15% – Metastases Common Despite Often Small Size of Tumor – Clinical Course Variably with Indolent Course in Most • Prognostic Factors: Age, Size and Mets Patients, but Rapidly Fatal In Others • Metastatic Sites: Lung, Bone & Brain

41 Xp11.2 Renal Cell Carcinoma TFE3 Located at Xp11.2 Has Several Fusion Partners That Lead To Renal Cell Carcinoma • ASPL-TFE3 t(X;17)(p11.2;q25) 2 to 68 Yrs

• PRCC-TFE3 t(X;1)(p11.2;q21) 2 to 70 Yrs

• PSF-TFE3 t(X;1)(p11.2;p34) 3 to 68 Yrs

• NonO-TFE3 inv(X)(p11.2;q12) 39 Yrs (Rare) • CLTC-TFE3 t(X;17)(p11.2;q23) 14 Yrs (Rare)

TFE3

ASPL-TFE3 t(X;17)(p11.2;q25)

42 DICER1 Novel Cancer Induction Mechanism • Cytoplasmic • Pulmonary Epithelial Cells Benign Endoribonuclease (DOSHA) – Segmental/Focal DICER1 Loss Cleaves Precursors into • DICER1 in Malignant Mesenchymal miRNA and siRNA. Cells • Small Silencing siRNAs Critical in Controlling • Dysregulated Autocrine Signaling Messenger RNA (mRNA). From Epithelial to Mesenchymal • Participates in RNA-Induced Cells Silencing Complex (RISC), – Signaling Important for which Degrades or Suppresses Branching & Morphogenesis in mRNA Normal Developing Lung – Dysregulation Induces Cyst Formation and Malignancy in Mesenchymal Cells

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