ECP, NICE, Sept 2019 Case 3cpo-media.net/ECP/2019/Congress-Presentations/1459/-Unlicensed-case...

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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

AE1/AE3

h-caldesmon

S100 protein

HMB45, Melan A

Molecular findings

FOXO1 gene rearrangement with

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

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

Botryoid Anaplastic

33% <5 years

Congenital cases

20% adults

Approximately 40-50% in head and

neck and 40-50% in GU system

Abdomen, retroperitoneum,

biliary tract

Rare in extremities

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

No consistent genetic aberrations

LOH at 11p16 locus

Whole chromosome gains or losses

Alveolar rhabdomyosarcoma

Solid variant

25% of RMS

10-25 years

Subset in adults >40 years

Extremity deep soft tissue

Head and neck

Defined by PAX3/7-FOXO1 gene

fusions

Rarely PAX3 to FOXO4, NCOA1

FOXO1-FGFR

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

‘Mixed alveolar and embryonal

RMS’

➔ lack PAX3/7-FOXO1 ➔ ERMS

‘Fusion-negative ARMS’

➔ ERMS with a primitive

phenotype

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

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

Sclerosing

rhabdomyosarcoma

Prominent hyalinization/fibrosis

Cells in cords, nests, microalveoli

Extensive matrix formation

Mentzel 2000; Folpe 2000; Nascimento

Sclerosing

rhabdomyosarcoma

Prominent hyalinization/fibrosis

Cells in cords, nests, microalveoli

Extensive matrix formation

Diffuse desmin

Focal myogenin

MyoD1 often diffuse in sclerosing

Mosquera 2013; Szuhai 2014; Kohsaka

2014; Agaram 2014; Alaggio 2016; Rekhi

2016; Watson 2018; Dashti 2018; Agaram

2019; Gui 2018

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

ARMS and ERMS

Morphologic overlap

ARMS ARMS

ARMS Typical areas of ARMS

ERMS can show prominent round cell morphology

Spindling elsewhere

Fascicular architecture

Myxoid stroma

ERMS can show prominent round cell morphology

Spindling elsewhere

Fascicular architecture

Myxoid stroma

Ewing sarcoma Solid ARMS

Ewing sarcoma

Ewing sarcoma with

pseudoalveolar pattern

Ewing sarcoma CD99 in Ewing sarcoma

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

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

Ectomesenchymoma

Multiphenotypic sarcoma

Infants and children

Mesenchymal and neuroectodermal line of differentiation

Biphasic: RMS with variable intermixed neuroectodermal/neuronal elements

Ectomesenchymoma

Pelvis, peritoneum, retroperitoneal, abdomen

Head and neck rare

Malignant Triton tumor

Heterologous component of other neoplasms

Patients with NF1

Nerve trunks

Rare in orbit

Metastatic neuroblastoma

Rare in orbit

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

ECP, NICE, Sept 2019 Case 3cpo-media.net/ECP/2019/Congress-Presentations/1459/-Unlicensed-case...

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