ACCME/Disclosure

Ultrastructure As An Important Component in Diagnosis
of Pediatric Round Cell & Soft Tissue Tumors: Avoiding Pitfalls
ACCME/Disclosure
John Hicks - Texas Children’s Hospital & Baylor College of Medicine
Dr. Hicks has nothing to disclosure
Differential Diagnosis of Small Round Cell
Tumors of Childhood
Differential Diagnosis of Small Round
Cell Tumors of Childhood
• Ewing Family of Tumors
– Classic, Atypical, PPNET
• Rhabdomyosarcoma
– Alveolar & Embryonal
•
•
•
•
•
•
•
•
Neuroblastoma
Lymphoma
Extramedullary ALL/AML
Wilms Tumor
Germ Cell Tumors
Neuroendocrine Tumors
Rhabdoid Tumor
Small Cell Hepatoblastoma
3
• Desmoplastic Small Round Cell
Tumor
• Clear Cell Sarcoma of Soft Tissue
• Synovial Sarcoma
• Alveolar Soft Part Sarcoma
• Medulloblastoma – CNS
• Mesenchymal Chondrosarcoma
• Pleuropulmonary Blastoma
• Small Cell Osteosarcoma
• Pancreatoblastoma
• Sialoblastoma
• Small Cell Mesothelioma
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
– Desmin, Myogenin,
MyoD1
• Epithelial
– EMA, Pancytokeratin,
CAM 5.2
• Lymphoid
– LCA, CD20, CD3, TdT,
CD61, CD31,
Myeloperoxidase,
CD30, CD43, ALK1,
CD4, CD8, CD68, CD1a
• Vascular
– CD34, CD31
• Neural
– NB84, S100, NFP,
NSE, Chromogranin
• Germ Cell
– PLAP, CD30, AFP
• Melanocytic
– HMB45, S100
Protein
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
• Ewing Sarcoma (Peripheral Primitive
Neuroectodermal Tumor) with Novel
t(20;22) EWSR1-NFAT2cTranslocation
NFATc2:
(Nuclear Factor of Activated T-Cells,
Cytoplasmic, Calcineurin-Dependent 2)
• 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 UpRegulates 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
40% - Metastatic Disease (Skin, LN, Brain)
DOD (15 of 22) At 1-24 Months
Small Round Cell Tumors in Neonates
• Congenital Ewing Sarcoma Very Rare and Not
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
6
25
7
Promiscuous Nature of EWSR1
BCOR-CCNB3
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
• No erythema, warmth, bruits or pulsations
8


Routine X-ray: large medially placed thigh mass involving
soft tissue
Femur with intact cortex and no periosteal reaction
Radiologists’ Impression


CT and MRI: large heterogenous, hypervascular mass (18 x 13 x 9
cm) with tortuous, enlarged vascular channels
(high flow lesion)
Arterial drainage into the right iliac artery and venous drainage into
the femoral vein
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:
– Desmin, Myogenin,
MSA, MyoD1
– Chromogranin, S100
Synaptophysin
– CD99
– ALK-1
– EMA, PanCytokeratin
– CD34, CD31, D2-40
– MUC4
– Collagen Type IV
• Positive Stains:
– SMA (focal expression)
– INI1 (nuclear)
– Beta-Catenin
(cytoplasmic)
– Vimentin
INI1
10
Cytogenetics & Molecular Genetics
• Karyotype: 46,XY
• Negative FISH for EWSR1, SS18, FOXO1
• RT-PCR Translocations Negative for:
– Ewing Sarcoma
– Synovial Sarcoma
– Alveolar Rhabdomyosarcoma
– Low-Grade Fibromyxoid Sarcoma
CCNB3
• Distribution of paired-end split and spanning RNA-Seq reads
joining BCOR exon 15 with CCNB3 exon 5
• Direct sequencing confirmed RNA-seq reads: BCOR–CCNB3
fusion transcript result of cryptic ‘GT’ splice donor site
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)
Embolization Prior to Resection
11
BCOR-CCNB3 Sarcoma
• 1st Described in 2012 by performing RNA-seq on
Translocation Negative Ewing-Like Sarcomas
(4% [24/594] undifferentiated sarcoma)
• RNA-Seq identified 20 distinct high-quality
paired-end fragments linking Exon 15 of BCOR
(Xp11.4) and Exon 5 of CCNB3 (Xp11.22)
• Primers for BCOR Exon 15 and CCNB3 Exon5
designed to perform RT-PCR for BCOR-CCNB3
translocation due to X-chromosome inversion
(paracentric)
46%
11%
23%
11%
4%
Immunostain Profile
• CCNB3 nuclear
• CD99 membranous
• CD99 cytoplasmic
• CD99 dot-like (Golgi)
• Desmin
• EMA
• Pancytokeratin
• S100 protein
• SMA
• CD34
• Median age:
• Gender Ratio:
• Age Groups:
13.1 yrs (range 5.9 to 25.6 yrs)
2 Male: 1 Female
1-9 years
23%
10-17 years
50%
>18 years
27%
Clinical Signs at Presentation
• Pain
• Swelling
• Limp
• Pathologic Fracture
• Fever
• Medullary Bone Compression
65%
40%
20%
15%
10%
10%
BCOR-CCNB3 Sarcoma: Differential Diagnosis
Summary of BCOR3-CCNB3:
Clinicopathologic Correlations
Original Diagnosis
• Ewing/PNET
• Small Cell Osteosarcoma
• Bone Sarcoma, NOS
• Soft Tissue Sarcoma, NOS
• MPNST
• Granulocytic Sarcoma 4%
Summary of BCOR3-CCNB3: Clinicopathologic
Correlations (n=26)
100%
16%
24%
48%
0%
0%
0%
0%
0%
0%
• Ewing Sarcoma/PNET with EWSR1-ETS
Rearrangement (EWSR1-FLI1; EWSR1-ERG;
EWSR1-ETV1; EWSRI-ETV4; EWSR1-FEV)
• Round Cell Sarcoma with EWSR1-nonETS
Rearrangement (EWSR1-NFAT2c; EWSR1-SP3;
EWSR1-PATZ1; EWSR1-SMARCA5; EWSR1POU5F1)
• Round Cell Sarcoma with non-EWSR1-ETS
Rearrangement (FUS-ERG; FUS-FEV)
• Small Cell Osteosarcoma
• Rhabdoid Tumor (INI-1 [SMARCB1] Loss or
SMARCA4 [BRG1] Loss)
12
BCOR-CCNB3 Sarcoma: Differential Diagnosis
•
•
•
•
•
•
•
•
•
Round Cell Sarcoma with CIC-DUX4 Fusion
Undifferentiated Round Cell Tumor
Mesenchymal Chondrosarcoma (HEY1-NCOA2)
Synovial Sarcoma (SS18-SSX1; SS18-SSX4)
Rhabdomyosarcoma (PAX3-FOXO1; PAX7-FOXO1;
11q15)
Desmoplastic Small Round Cell Tumor (EWSR1WT1)
Extraskeletal Myxoid Chondrosarcoma (EWSR1NR4A3; EWSR1-TAF15; TCF12-NR4A3; TFGNR4A3)
Clear Cell Sarcoma of Soft Tissue (EWSR1-ATF1)
Lymphoma/Leukemia/Granulocytic Sarcoma
BCOR Gene
• BCOR Mutations: Oculofaciocardiodental
and Lenz micro-ophthalmia syndromes;
myeloid leukemia; myelodysplastic
syndromes; medulloblastoma
• BCOR-RARA t(X;17): acute promyelocytic
leukemia
• BCOR-ZC3H7B t(X;22): Endometrial
stromal sarcoma and Ossifying fibromyxoid
tumor
• BCOR ins(4;X): Ewing-like undifferentiated
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
51
52
13
Lymph Node-Hematopathology: S/O ALCL on TP
Permanent Tissue Sections
Touch Preparations By Hematopathology
53
54
Myofilaments
55
56
14
Desmin
Myogenin
Pax7-FOXO1 RT-PCR:
Solid Variant of Alveolar RMS
Pax3-FOXO1 Pax7-FOXO1
57
58
• 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
64
16
Embryonal and Strap Cells
Spindle Cell, Botryoid & UDS
65
66
Genetics: RMS
• Alveolar RMS:
– PAX3/FOXO1 (most)
– PAX7/FOXO1
– PAX3/FOXO4,
PAX3/NCOA1,
PAX3/NCOA2
FOXO1/FGFR1
– CDK4 Amplification
– Mutations: TP53, CDKN2A,
CDKN2B, FGFR4
– ALK Copy Gain
– Tumor Suppressors: RASSF,
HIC1, CASP8
– DNA Methylation
Alveolar & Anaplastic
67
• Embryonal RMS:
– 11p15.5: IGF2, H19,
CDKN1C, HOTS
– Mutations: RB, TP53,
CDKN2A, CDKN2B, RAS,
FGFR4, PIK3CA, CTNNB1
(beta-catenin)
– NF1 Deletions
– ALK Copy Gain
– DNA Methylation
– 12q13: GLI
68
17
Paratesticular Tumor in Adolescent:
Undifferentiated Pleomorphic Sarcoma
Myofilaments
69
70
Small Cell Osteosarcoma
Thigh Mass with Bony Involvement in Adolescent Male
Alveolar RMS with Anaplasia: Paratesticular
71
72
18
Fibrosarcoma
Lower Extremity Mass in 11 Year-Old Boy
Sclerosing Rhabdomyosarcoma
73
74
Histocytosis in Lymph Node (S100, CD1a)
Embryonal Rhabdomyosarcoma, Spindle Cell
75
76
19
Rhabdomyoma-Like Rhabdomyosarcoma
Cervical Mass
77
78
79
80
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
20
Neuroblastoma Family of Tumors
NB84
• 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
Tumor of Childhood
– Lacks Histopathologic
Evidence of
Neuroblastic
Differentiation
– No Schwannian Stroma
Differentiation
– Lack Pseudorosettes
– Fine Vascular Capillary
Network
– High NC Ratio
– Lack Neuropil Processes
– May Have Fine Granular
Chromatin
– May Have Distinct
Nucleoli
– Differential Diagnosis
•
•
•
•
•
Rhabdomyosarcoma
Ewing’s Sarcoma
Blastemal Wilms Tumor
Lymphoma/Leukemia
Other SRCT with
Embryonal/Blastemal
Appearance
83
21
• Immunophenotype
–
–
–
–
–
–
–
–
NB84
• Electron Microscopy
NB84*
PGP9.5*
NSE
Chromogranin A
Synaptophysin
Tyrosine Hydroxylase*
GD2*
ALK1 in Familial Cases
– Only Necessary with
Undifferentiated Tumors
or With Aberrant &
Confusing
Immunostaining Profile
– Neurite Processes
– Dense Core
Neurosecretory Granules
– No Other Tumor Defining
Features
• Negative for:
–
–
–
–
–
VIMENTIN***
Desmin
LMW Keratins
LCA
CD99 Usually Negative,
Rare Positive Cases
85
86
Gene Mutations in Neuroblastoma
• 4 Week-Old Hispanic Male
– Red-Brown, Raised
Firm Ulcerated Skin
Lesions (multiple)
– Moderate Fever
– Recent Onset of
Diarrhea
• Differential Diagnosis
– Small Round Cell
Tumors
• Most Hereditary Neuroblastomas (AD
Inheritance) Associated with Activating
Mutations in Tyrosine Kinase Domain of
Anaplastic Lymphoma Kinase (ALK)
Oncogene (Constitutional Mutation)
• ALK Somatic Mutations in 5-15% of
Sporadic Neuroblastomas
• PHOX2B: Regulation of ANS
Development Participates in Both
Hereditary and Sporadic Neuroblastomas
– Also Neuroblastomas Associated with
Congenital Central Hypoventilation
Syndrome and Hirschsprung’s
Disease
• Leukemia
• Neuroblastoma
– Infection
87
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
Congenital Self-Healing LCH
Deep Subcutaneous Nodule:
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
107
108
27
DX: Spitz Nevus (epitheliod and spindled nevus)
3 Years Later: Needle Core Biopsy of Neck Mass
109
110
111
112
28
113
114
115
116
29
Melan-A
Example of Various Melanosome Phases
S100 Protein
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
• EWS-ATF1 Performed
on:
– Skin Biopsy: Negative
– Lung Needle Core and
Biopsy: Positive
– Lymph Node Biopsy:
Positive
– Proximal Humeral
Resection: Positive
• <1% of Soft Tissue Tumors (500 cases)
• Young to Middle Age Adults & 1.5F:1.0M Ratio
• Foot & Ankle Common (33%), Less Often Leg/Knee
(15%), Thigh (12%), Hand (18%), Elbow/Forearm
(10%), Trunk (7%), H&N (3%), Genital (2%)
• Deep Seated Tumor Arising From Tendons &
Aponeuroses
• Most <5cm
• Long Duration Prior to Diagnosis in Most
31
CCST
• EWS-ATF1 Translocation in >90%
• EWS-CREB1 Translocation in Minority
2 Month Old Male with Markedly Enlarged
Liver & Concern for Neuroblastoma (Stage IVS)
– 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 AirFilled Cysts and
Probable Pneumothorax
• CT Scan- Solid Mass
• Outside Biopsy:
Rhabdomyosarcoma
Solid Tumor Components
Myogenin
Desmin
36
Pleuropulmonary
Blastoma (PPB)
• Embryonal Malignant
Tumor Derived from
Mesenchyme of Lung and
Pleura
• Rare Tumor with 20 to 25
Cases Per Year in USA
• First Described in 1988 as
Distinct Entity
• Predominantly in Neonates,
Infants and Young Children
(single documented adult
case reported)
• Rarely Reported After 12
years of Age
• Detection May Occur During
Routine Prenatal Ultrasound
• Important to Distinguish from
Adult Pulmonary Blastoma
– Adult Pulmonary
Blastoma: Biphasic Tumor
with Both Malignant
Mesenchymal and
Epithelial (glandular)
Components
– PPB: Only Malignant
Mesenchymal Component
and No Malignant
Epithelial Component
• Equal Gender Ratio
• Laterality: Right Lung 54%;
Left Lung 37%; Bilateral 9%)
PPB & Metastatic Disease
• Brain
15-25%
– Type III PPBs
– Type II PPBs
• Bone
• Liver
•
•
•
•
•
•
•
54%
11%
6-10%
2-4%
Contralateral Lung
Ovary
Spinal Cord & Leptomeninges
Adrenal Glands
Pancreas
Choroid of Eye & Iris
Time to Metastases: 24 Months from
Diagnosis in Most
37
PPB Family Tumors and Dysplasia Syndrome
•
•
•
•
Familial Distribution in 33%
Usually Occurs in First Two Decades of
Life
Associated with Dicer 1 Mutation
Tumors/Dysplasias
– Lung Cysts (Dicer 1 Mutation)
– Cystic Nephroma (9-10%, Dicer 1
Mutation)
– Wilms Tumor (Dicer 1 Mutation)
– Dysplasias
• Intestinal Hamartomatous Polyps
(Ileal most common with
Intussusception)
• Cystic Hepatic Hamartoma
– Nasal Chondromesenchymal
Hamartoma (Dicer 1 Mutation)
– Ciliary Body Medulloepithelioma
(Dicer 1 Mutation)
– Ovarian Fibroma (Dicer 1 Mutation)
– Rhabdomyosarcoma (Dicer 1
Mutation)
•
•
•
•
•
•
•
Neuroblastoma, Medulloblastoma, &
Other CNS Tumors
Leukemias
Gonadal Tumors
– Sertoli-Leydig Cell Tumors
(Dicer 1 Mutation)
– Dysgerminoma (Dicer 1
Mutation)
– Seminoma (Dicer 1 Mutation)
– Germ Cell Tumors
Uterine/Cervival Sarcoma Botryoides
(Dicer 1 Mutation)
– Adolescent and Young Women
Thyroid
– Nodular Thyroid Hyperplasia
(Dicer 1 Mutation)
– Follicular and Papillary Thyroid
Carcinomas (Dicer 1 Mutation)
Renal Sarcoma
Other Sarcomas
PPB: Survival
Five-Year Overall Survival Rates:
– Type I PPBs:
– Type II PPBs:
– Type III PPBs:
85%
58%
42%
38
PPB Stands Out Among Other Lung Cysts
153
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
Gender Ratio 2F:1M in <30 Yr Age
Reversed Gender Ratio in >30 Yr Age
Represents 0.2-0.9% of Soft Tissue Sarcomas
Rare Before Age 5 Yrs
Most Common Sites:
– Children: Head and Neck – Tongue and Orbit
– Adults: Deep Soft Tissues of Thigh or Buttocks
• Slow Growing Painless Tumors
• Mets to Brain or Lung – 1st Presentation
Alveolar Soft Part Sarcoma
• Prognosis
• Seldom Recur Locally After Excision
• Metastases Common with Long-Term
Followup
• Survival with No Metastases at Diagnosis:
– 5 Yrs 60%, 10Yrs 38%, 20 Yrs 15%
• Prognostic Factors: Age, Size and Mets
• Metastatic Sites: Lung, Bone & Brain
• TFE Carboxy Terminal Immunoreactive: Nuclear
Pattern
– Granular Cell Tumors
• S100, Desmin (50%)
• Translocation:
–
–
–
–
der(17)(X;17)(p11;q25)
ASPL-TFE3 Fusion
RT-PCR or FISH
Transcription Factor:
Activates MET Signaling
– MET Inhibitors Target
Before ASPS Signout, Be Aware
• Renal Cell Carcinomas Account for <5% of
All Pediatric Renal Tumors
• Xp11.2 Translocation Renal Cell Carcinomas
– Account for Up to 75% of Renal Cell Carcinomas in
Pediatrics
– Tendency to Present at Advanced Stages
– Metastases Common Despite Often Small Size of Tumor
– Clinical Course Variably with Indolent Course in Most
Patients, but Rapidly Fatal In Others
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
(Rare)
• CLTC-TFE3
Yrs
(Rare)
inv(X)(p11.2;q12)
39 Yrs
t(X;17)(p11.2;q23)
14
TFE3
ASPL-TFE3
t(X;17)(p11.2;q25)
42
DICER1
• Cytoplasmic
Endoribonuclease (DOSHA)
Cleaves Precursors into
miRNA and siRNA.
• Small Silencing siRNAs
Critical in Controlling
Messenger RNA (mRNA).
• Participates in RNA-Induced
Silencing Complex (RISC),
which Degrades or Suppresses
mRNA
Novel Cancer Induction Mechanism
• Pulmonary Epithelial Cells Benign
– Segmental/Focal DICER1 Loss
• DICER1 in Malignant Mesenchymal
Cells
• Dysregulated Autocrine Signaling
From Epithelial to Mesenchymal
Cells
– Signaling Important for
Branching & Morphogenesis in
Normal Developing Lung
– Dysregulation Induces Cyst
Formation and Malignancy in
Mesenchymal Cells
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