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Small round cell tumors of bone and soft
tissue, part 2 (non-Ewing group)
David Parham, MD
Chief of Anatomic Pathology
Children’s Hospital Los Angeles
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Where in the world is Carmen Sandiego (or the
diagnosis!)
2
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Other small round cell tumors to consider
• Undifferentiated neuroblastoma
– Retroperitoneal, paraspinal location
• NUT translocation carcinoma
– Midline head, neck, and upper thorax location
• Extrarenal rhabdoid tumor
– Any location, favors “paraxial” sites
– Age important
– History of previous rhabdoid tumors
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Other round cell sarcomas of bone
• Mesenchymal chondrosarcoma
– Mostly Paraxial
• Small cell osteosarcoma
– Mostly Extremities
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Undifferentiated neuroblastoma
• Defined in the International Neuroblastoma Classification as:
– Diagnosed only by supplementary techniques
– Patients may have elevated serum catecholamine levels.
– Contain undifferentiated cells with indiscernible-to-thin cytoplasm
– Contain no neuropil.
– Cells contain nuclei with salt-and-pepper chromatin.
– The majority contain prominent nucleoli, a marker of bad prognosis
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Undifferentiated Neuroblastoma
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Undifferentiated Neuroblastoma
Gross and Microscopic Features
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Poorly differentiated Neuroblastoma
Neuropil
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Undifferentiated Neuroblastoma
Prognosis and Clinical Outcome: Classification
• Good prognosis
• Poorly differentiated neuroblastomas with low or intermediate
MKI,** <1.5 years of age
• Poor prognosis
• Poorly differentiated neuroblastomas with high MKI, <1.5 years of
age
• Poorly differentiated neuroblastomas, age 1.5–5 years, any MKI
• Neuroblastoma, any type, age >5 years
• Undifferentiated neuroblastoma
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Undifferentiated Neuroblastoma
Ancillary Diagnostic Techniques
• Tyrosine Hydroxylase
• N-myc IHC
• C-myc IHC
• PHOX2B: a novel marker
• Neural markers (often non-specific)
• N-myc FISH (does not exclude alveolar rhabdomyosarcoma
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Undifferentiated Neuroblastoma
PHOX2B
• PHOX2B: a transcription factor for peripheral autonomic nervous
system.
• Mutated in Ondine’s curse
– neuroblastoma, sleep apnea, and Hirschsprung’s disease
• Expressed by neuroblastoma, paraganglioma, and
pheochromocytoma.
• Universally expressed in small series of undifferentiated
neuroblastomas in one study (6/6) and in no “neuroblastoma-like
undifferentiated sarcoma”
• Negative in panel of 109 other tumors (8 diagnoses).
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Ondine, a water
nymph with an
unfaithful mortal
lover
“Every waking breath
will be a testiment to
my love”
The curse: stop
breathing when
asleep.
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Undifferentiated NBL
• Nucleolar type, associated findings:
– N-myc expression – associated with MYCN amplication
– C-myc expression – associated with lack of amplification
– May not show MYCN amplification
– Outcome not affected by other factors (MKI, age, ploidy, etc),
[caveat: usually high stage lesions]
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BRD4-NUT carcinoma
• Predominately affects young patients, but wide age range
• Usually involves midline structures: upper respiratory tract,
mediastinum
• Characterized by t(15;19)(q13;p13.1) translocation
• Almost invariably fatal course
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BRD4-NUT carcinoma
• Resembles small cell carcinoma.
• May not show obvious epithelial differentiation on H and E stain,
but should be cytokeratin-positive (as are 15% of Ewing sarcoma).
• Squamous differentiation is often abrupt.
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Undifferentiated BRD4-NUT carcinoma
Courtesy of Sara Vargas, MD, Boston Children’s Hospital
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Differentiating BRD4-NUT carcinoma
Courtesy of Sara Vargas, MD, Boston Children’s Hospital
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BRD4-NUT carcinoma: cytokeratin
Courtesy of Sara Vargas, MD, Boston Children’s Hospital
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BRD4-NUT carcinoma NUT stain
Courtesy of Sara Vargas, MD, Boston Children’s Hospital
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Pediatric epithelial/epitheliod malignancies to
also consider:
• EBV-associated carcinoma (nasopharyngeal carcinoma)
• Mucoepidermoid carcinoma
• Keratin-positive sarcomas, such as rhabdoid tumor and epithelioid
sarcoma
• Poorly differentiated germ cell tumor, e.g embryonal carcinoma,
yolk sac tumors
• Location, location, location!
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Extrarenal rhabdoid tumor
• Wide variety of primary sites, including soft tissue and skin
• Primarily affects infacts and younger children, with overlap with
epithelioid sarcoma in older ones
• Diverse histologies, including “lymphomatoid” pattern described
by Weeks and Beckwith.
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Rhabdoid tumor – typical histology
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Rhabdoid tumor, lymphomatoid
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INI1 stain: lack of expression
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Tumors lacking INI1 expression
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• Rhabdoid tumor
• Epithelioid sarcoma
• Renal medullary carcinoma
• Extraskeletal myxoid
chondrosarcoma
• Epithelioid MPNST
• Myoepithelial carcinoma
• Small cell hepatoblastoma
• Poorly differentiated
chordoma
• Synovial sarcomas
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Other Ewing-like tumors of bone
• Mesenchymal chondrosarcoma
• Small cell osteosarcoma
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Vesalius
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Mesenchymal chondrosarcoma: clinical
• Most common form of chondrosarcoma in children
• Occurs in unusual locations:
– Craniofacial bones, chest wall, spine, sacrum
• Extraosseous locations:
– Meninges included
• Highly malignant
– Prolonged course with late metastases (survival 21-67%)
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Mesenchymal chondrosarcoma: pathology
• Biphasic appearance
– Undifferentiated small blue cells or spindle cells
– Well-differentiated cartilage
• Other features:
– Hemangiopericytoma appearance
– Foci of chondroid ossification
– Myxoid zones
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Mesenchymal chondrosarcoma: small cell component
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Mesenchymal chondrosarcoma:
spindle cell component
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Mesenchymal chondrosarcoma: HPC pattern
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Mesenchymal chondrosarcoma:
cartilage with ossification
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Mesenchymal chondrosarcoma: myxoid focus
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Mesenchymal chondrosarcoma: IHC
• Sox9: positive in round cells and chondrocytes
• β-catenin: negative in round cells, positive at cartilage interface
• Osteocalcin: negative in round cells, positive in bony matrix
• S100: positive in only occasional cases in round cells; usually
positive in cartilage
• EMA (30%) and desmin (50%) can be positive
• FLI1 negative; CD99 can be positive
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Sox9 (Nine Socks): the product of the SRY gene
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SRY gene: androgen insensitivity
36
http://en.wikipedia.org/wiki/File:Orchids01.JPG
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Mesenchymal chondrosarcoma genetics
• HEY1-NCOA2 fusion gene
• Identified by genome wide screen using known cancer genes
• Results from submicroscopic 10 Mb interstitial deletion between
8q13 and 8q21.
• Detected in 15 of 16 cases by fusion FISH (not break-apart FISH).
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Hay (Hey1) and Non Commissioned Officer (NCOA2)
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1 bale of “hey” NCO[A2]
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Small cell osteosarcoma
• A rare form of osteosarcoma (<2%)
• Small blue cell tumors with osteoid production
• Usually in long bones, second decade
• May have worse prognosis than other osteosarcomas,
– But too few cases to be sure.
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Small cell osteosarcoma: imaging
• Intramedullary, permeative lesion
• Ill-defined margins
• Cortical destruction
• Aggressive periosteal reaction
• Soft tissue mass
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Small cell osteosarcoma: histology
• Small blue cells with hyperchromatic nuclei
• Similar to Ewing sarcoma
• At least focal osteoid production
• Osteoid must be separated from non-osteoidal matrix
• Tumor spindling may be present (also seen in some Ewings)
• CD99 MAY be negative (but also positive)
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Osteoid: think of bubble gum
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The problem
• Minimal amounts of osteoid
• Overlap with sclerosing Ewing sarcoma (atypical Ewing).
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Sclerosing Ewing sarcoma
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Synovial sarcoma: a mimicker of Ewing sarcoma
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Synovial sarcoma
• Peak incidence in young adults, but most common non-rhabdo
sarcoma of soft tissue.
• Mainly in extremities, but has propensity to occur in odd locations
(including nerve).
• Ranges from intermediate to high grade (mitoses, necrosis are key
factors).
• Monophasic variants often confused with Ewing sarcoma.
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Monophasic variant of synovial sarcoma
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Synovial sarcoma IHC
• Epithelial markers (cytokeratin, EMA): usually but not always
positive
• CD99: usually positive, furthering confusion
• BCL2: sensitive but non-specific
• TLE1: a “surrogate” fusion marker: typically positive
– Specificity has been questioned.
• Reduced INI1 expression (not mutation)
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Genetics of synovial sarcoma: SSX-SS18 fusion
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t(X;18): Freshman co-ed
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SSX genes
• SSX1
• SSX2
• SSX4
• Not predictive of outcome
• Have been linked to histology
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Colorado Street Bridge, Pasadena, CA
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SSX-SS18 fusion protein: a molecular bridge to
badness
• SS18-SSX serves as a bridge between activating transcription factor
2 (ATF2) and transducin-like enhancer of split 1 (TLE1)
• TLE1 attaches to histone deacetylase complex (HDAC), resulting in
altered epigenetics.
• Results in repression of ATF2 target genes.
• HDAC inhibitors rescues target gene expression, leading to growth
sup
• Cancer Cell, Volume 21, Issue 3, 2012, 333 - 347
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Le Su , Arthur V. Sampaio , Kevin B. Jones , Marina Pacheco , Angela Goytain , Shujun Lin , Neal Poulin , Lin Yi...
Deconstruction of the SS18-SSX Fusion Oncoprotein Complex: Insights into Disease Etiology and Therapeutics
Cancer Cell, Volume 21, Issue 3, 2012, 333 - 347
http://dx.doi.org/10.1016/j.ccr.2012.01.010
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An Illustrative case of Synovial sarcoma treachery Courtesy of Zhongxin Yu, MD
University of Oklahoma
• 14 years old with left hip
pathological fracture
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CD99: negative
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INI-1: negative (occasional positive)
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Vimentin: negative
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Other IHC
• Lymphoma markers: negative
– (CD3, CD5, CD20, CD43, CD79a, PAX5, TdT, CD117, CD34)
• Myeloperoxidase: weakly positive, focal
• Myogenin and desmin: negative
• S-100: negative
• NSE and synaptophysin: negative
• CD68, CD163: negative
• EMA and pan-cytokeratin: negative
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Preliminary Diagnosis
• Small round blue cell tumor of the bone
– ? Ewing’s sarcoma
• Pending EWS FISH result
– ? Ewing’s – like small cell osteosarcoma
• Pending FISH to rule out Ewing’s sarcoma
• ?rebiopsy to get more tissue with osteoid
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Final diagnosis
• FISH is negative for EWSR1 rearrangement
• FISH is positive for SYT(SS18) rearrangement
• Final diagnosis—Synovial sarcoma
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Post-therapy
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