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The Royal Marsden
ECP, NICE, Sept 2019
Case 3
Khin ThwayMD, FRCPath
Consultant Pathologist, Sarcoma Unit, The Royal Marsden
Hospital, London, UK
Reader in Translational Pathology, Molecular Pathology, The
Institute of Cancer Research, London, UK
Case 2
16 year old female
Proptosis
Rapidly enlarging orbital mass
Cellular infiltrative tumor
Markedly infiltrative
Irregular nests
Rounded cells
Immunohistochemistry
Desmin Desmin
Immunohistochemistry
Myogenin Myogenin
Immunohistochemical findings
Positive Negative
Desmin
Myogenin
MyoD1
CD99
AE1/AE3
SMA
h-caldesmon
CD34
SOX10
S100 protein
HMB45, Melan A
Molecular findings
FOXO1 gene rearrangement with
FISH
PAX3-FOXO1 fusion transcripts
with RT-PCR
Diagnosis
Alveolar
rhabdomyosarcoma
Solid variant
PAX3-FOXO1 gene fusion
Primary orbital
rhabdomyosarcoma
Rhabdomyosarcoma
Sarcomas with variable
differentiation towards skeletal
muscle
Birth – 8th decade
7% of pediatric cancers
Commonest childhood soft tissue
sarcoma
Etiology
From skeletal muscle precursors that fail to undergo appropriate terminal differentiation?
Many RMS in anatomic sites lacking skeletal muscle, e.g. genitourinary and biliary tracts
Multipotent mesenchymal stem cells (which are mesodermal in origin but are not committed to the myogenic lineage)
Rhabdomyosarcoma
Most common soft tissue sarcoma
of the head and neck
10% of all cases occur in the orbit
Image per kind courtesy of Prof L-G
Kindblom/Dr VP Sumathi, ROH
Orbital rhabdomyosarcoma
Presentation and behavior Rapid proptosis
Globe displacement (2/3
superonasal)
Most orbital RMS present with
localized disease
Metastasis unusual: lung, bone,
marrow (hematogenous spread, as
orbital lymphatics scarce)
Invade orbital bones
Intracranial
Rhabdomyosarcoma
Survival for localized embryonal
>95%
Outcome for metastatic RMS <30%
Orbital rhabdomyosarcoma
5-year survival 84%
Orbit: 80-90% DFS
cf parameningeal 40-50%
Favorable factors:
<10 years
Female sex
Embryonal histology
Rhabdomyosarcoma
RhabdomyosarcomaHistory and Classification
Weber and Wilks
‘rhabdomyosarcoma’ in 1850s
Stafford 1839
Guersant 1854
Tumor in tongue of 21M: ‘muscle cells in all stages of differentiation from adult to embryonal forms’
Rhabdomyosarcoma
Montpellier 1929: ‘Sarcoma alveolaire,’ composed of ‘small neoplastic myocytes in arranged pattern’
Rhabdomyosarcoma
Horn and Enterline, 1958:
subclassified into 4 categories:
pleomorphic, alveolar, embryonal
and botryoid
First ultrastructural study in 1963
(Chaoman et al.)
Even early on, it was postulated
that most RMS arose from
undifferentiated mesoderm,
rather than from myotome-
derived skeletal muscle
RhabdomyosarcomaClassification
Embryonal
rhabdomyosarcoma
Alveolar
rhabdomyosarcoma
RhabdomyosarcomaClassification
Spindle cell/sclerosing
rhabdomyosarcoma
Pleomorphic
rhabdomyosarcoma
Embryonal rhabdomyosarcoma
Embryonal rhabdomyosarcoma
Embryonal rhabdomyosarcoma
Botryoid Anaplastic
Embryonal rhabdomyosarcoma
33% <5 years
Congenital cases
20% adults
Embryonal rhabdomyosarcoma
Approximately 40-50% in head and
neck and 40-50% in GU system
Abdomen, retroperitoneum,
biliary tract
Rare in extremities
Embryonal rhabdomyosarcoma
Associated with several syndromes
involving alterations of RAS
pathway
e.g. Costello syndrome, NF1,
Noonan syndrome
>30% of ERMS: mutation of RAS
isoform
>50% of ERMS: mutation of RAS
pathway member
Embryonal rhabdomyosarcoma
No consistent genetic aberrations
LOH at 11p16 locus
Whole chromosome gains or losses
Alveolar rhabdomyosarcoma
Alveolar rhabdomyosarcoma
Solid variant
Alveolar rhabdomyosarcoma
25% of RMS
10-25 years
Subset in adults >40 years
Extremity deep soft tissue
Head and neck
Trunk
Alveolar rhabdomyosarcoma
Defined by PAX3/7-FOXO1 gene
fusions
Rarely PAX3 to FOXO4, NCOA1
FOXO1-FGFR
Alveolar rhabdomyosarcoma
PAX3-FOXO1 gene fusions not
specific for ARMS
Present in a subset of
biphenotypic sinonasal sarcoma
Wong et al., 2015; Andreaasen et al.,
2018; Le Loarer et al., 2019
Alveolar rhabdomyosarcoma
‘Mixed alveolar and embryonal
RMS’
➔ lack PAX3/7-FOXO1 ➔ ERMS
‘Fusion-negative ARMS’
➔ ERMS with a primitive
phenotype
Alveolar rhabdomyosarcoma
Myogenin Diffuse strong myogenin
Often only focal MyoD1
Spindle cell/sclerosing rhabdomyosarcoma
Evolving subtype
Infants, children, adults
Head and neck
Extremities
Peds- paratesticular, head and
neck
Uterus, prostate,
retroperitoneum, bone
Spindle cell rhabdomyosarcoma
Cellular fascicles of spindle cells
Resemble leiomyosarcoma or
fibrosarcoma
Atypia, hyperchromasia, mitotic
figures
Primitive undifferentiated areas
Strap cells
Spindle cell rhabdomyosarcoma
Spindle cell/sclerosing rhabdomyosarcoma
Sclerosing
rhabdomyosarcoma
Prominent hyalinization/fibrosis
Cells in cords, nests, microalveoli
Extensive matrix formation
Mentzel 2000; Folpe 2000; Nascimento
2005
Spindle cell/sclerosing rhabdomyosarcoma
Sclerosing
rhabdomyosarcoma
Prominent hyalinization/fibrosis
Cells in cords, nests, microalveoli
Extensive matrix formation
Spindle cell/sclerosing rhabdomyosarcoma
Diffuse desmin
Focal myogenin
MyoD1 often diffuse in sclerosing
RMS
Mosquera 2013; Szuhai 2014; Kohsaka
2014; Agaram 2014; Alaggio 2016; Rekhi
2016; Watson 2018; Dashti 2018; Agaram
2019; Gui 2018
Spindle cell/sclerosing rhabdomyosarcoma
1) Congenital:
VGLL2/NCOA2/CITED
rearrangements
2) Adolescents/young adults:
MyoD1 mutant spindle
cell/sclerosing RMS
3) Intraosseous spindle cell RMS:
TFCP2/NCOA2 rearrangements (to
EWSR1 or FUS)
4) No recurrent gene alterations
Pleomorphic rhabdomyosarcoma
6-7th decades
Deep soft tissue of extremities
Trunk, head and neck
Exceptionally rare in orbit
Furlong 2001; Chaves 1967
Pleomorphic rhabdomyosarcoma
Complex karyotypes
Numerical and structural
alterations
Genetic profiles indistinguishable
from undifferentiated
pleomorphic sarcoma
Differential diagnosis
Differential diagnosis
ARMS and ERMS
Morphologic overlap
Differential diagnosis
ARMS ARMS
Differential diagnosis
ARMS Typical areas of ARMS
Differential diagnosis
ERMS can show prominent round cell morphology
Spindling elsewhere
Fascicular architecture
Myxoid stroma
Differential diagnosis
ERMS can show prominent round cell morphology
Spindling elsewhere
Fascicular architecture
Myxoid stroma
Differential diagnosis
Ewing sarcoma Solid ARMS
Differential diagnosis
Ewing sarcoma
Ewing sarcoma with
pseudoalveolar pattern
Differential diagnosis
Ewing sarcoma CD99 in Ewing sarcoma
Differential diagnosis
Rhabdomyoma
Most adult and fetal arise in head and neck
(postauricular; salivary glands, parapharyngeal space, larynx, soft tissue of neck, mouth)
Rhabdomyoma of orbit very rare
Fetal RM- basal cell nevus syndrome, loss of function of PTCH1
Fetal rhabdomyoma
Differential diagnosis
Rhabdomyoma
Circumscribed, sessile or pedunculated
Adult: large polygonal cells
Spider cells, mitoses rare
Fetal: bundles of immature cells, skeletal muscle fibers, myxoid stroma
No atypia, infiltrative margin, necrosis or atypical mitotic figures
Adult rhabdomyoma
Differential diagnosis
Ectomesenchymoma
Multiphenotypic sarcoma
Infants and children
Mesenchymal and neuroectodermal line of differentiation
Biphasic: RMS with variable intermixed neuroectodermal/neuronal elements
Differential diagnosis
Ectomesenchymoma
Pelvis, peritoneum, retroperitoneal, abdomen
Head and neck rare
Differential diagnosis
Malignant Triton tumor
Heterologous component of other neoplasms
Patients with NF1
Nerve trunks
Rare in orbit
Differential diagnosis
Metastatic neuroblastoma
Rare in orbit
Differential diagnosis
Metastatic neuroblastoma
Neurofibrillary stroma
Conclusions Orbital rhabdomyosarcoma
Embryonal > alveolar
Embryonal favorable behavior
Distinct genetic backgrounds
Potential therapeutic strategies in
future
Conclusions Orbital rhabdomyosarcoma
Diagnostic awareness ERMS heterogeneous morphology
ARMS can be solid
ARMS- myogenin diffuse
Spindle cell RMS- evolving subtype
that may be further characterized
in the orbit
The Royal Marsden
Thank you
Dr Ann Sandison
Prof Phil Luthert
Dr Caroline Thaung
Prof Cyril Fisher
Dr VP Sumathi
Prof LG Kindblom
Dr Magnus Hallin