Small Round Cell Sarcomas Notes

Small Round Cell Sarcomas

  • Heterogeneous group of high-grade malignancies in bone and soft tissue.

  • Ewing sarcoma is the prototype.

  • WHO 2020 classification:

    • Ewing Sarcoma (EWSR1/FUS-ETS fusions)

    • CIC-rearranged sarcomas

    • BCOR-altered sarcomas

    • EWSR1::non-ETS sarcomas

  • Increasing role of molecular genetics in tumor classification.

FISH

  • FISH for EWSR1 or FUS can be utilized if undifferentiated small round cell sarcoma is suspected.

  • Small round cell morphology, bland:

    • CD99: +++

    • NKX2.2: +++

    • ERG: +/-

    • FLI1: +/-

    • Keratin: +/-

    • p40: +/-

    • NGS: EWSR1/FUS:: FLI1/ERG/ETV4/FEV1

    • Diagnosis: Ewing Sarcoma

  • Spindle to round cell, myxoid stroma, prominent capillary network:

    • CD99: +/-++

    • WT1: +++

    • SATB2: +/++

    • ERG: +/++

    • NGS: CIC::DUX4/DUX4L/FOX04

    • Diagnosis: CIC-rearranged sarcoma

  • Fibrohyaline stroma

    • CD99: -/+

    • Desmin: +/++

    • S100: +/++

    • GFAP: ++/+++

    • Keratin: +/++

    • NGS: EWSR1::PATZ1

    • Diagnosis: EWSR1::PATZ1-rearranged sarcoma

  • Small round cell morphology, pleomorphic:

    • CD99: -/+

    • NKX2.2: ++

    • Keratin: +/++ (dot-like)

    • NGS: EWSR1/FUS::NFATc2

    • Diagnosis: EWSR1/FUS::NFATc2-rearranged sarcoma

  • Spindle and round cell, microcystic, hyalinized vessel:

    • CD99: +/++

    • BCOR: +++

    • Cyclin D1: +++

    • SATB2: +++

    • NGS: BCOR::CCNB3*, BCOR ITD

    • Diagnosis: BCOR-rearranged sarcoma

Ewing Sarcoma

  • Clinical Features:

    • Most common in children and adolescents.

    • Primary sites: diaphysis of long bones, pelvis, ribs.

    • Symptoms: localized pain, swelling, sometimes systemic signs (fever, anemia).

    • Can mimic osteomyelitis, delaying diagnosis.

    • Slight male predominance.

    • 10-20% occur in soft tissue.

    • Highly aggressive; metastases in ~25% at presentation.

  • Radiographic and Macroscopic Features:

    • Bone tumors: poorly marginated permeative intramedullary lesions.

    • Periosteal reaction: “onion-skin” or “sunburst" patterns.

    • Soft tissue extension often extensive.

    • Extraskeletal tumors: cortical bone erosion ("saucerization").

    • Gross: soft, fleshy, white tumor with frequent necrosis.

  • Microscopic Features:

    • Sheets of small round blue cells.

    • Round nuclei with fine chromatin, scant cytoplasm.

    • Common necrosis, mitotic figures not always prominent.

    • Highly discohesive tumor cells.

Differential Diagnosis of Ewing Sarcoma

  • Primary bone lymphoma: CD45+, CD20/CD3+

  • Small cell osteosarcoma: matrix production

  • Mesenchymal chondrosarcoma

  • Metastatic neuroblastoma (children <2 years), neuroendocrine carcinoma

CIC-Rearranged Sarcoma

  • Clinical Characteristics

    • Aggressive tumor affecting mostly young adults, but can occur at any age.

    • Common sites: deep soft tissues of head/neck, retroperitoneum, pelvis.

    • Rare in viscera or bone.

    • Poor prognosis: ~50% 5-year survival; high rate of metastasis at diagnosis (~40%).

    • No specific treatment protocol; limited response to standard chemotherapy.

  • Primary Tumor Sites

    • Soft tissues (~ 87%):

      • trunk

      • limbs

      • head and neck

    • Viscera (~ 10%):

      • brain

    • Bone (~ 3%):

      • axial skeleton

  • Morphological Features

    • Pleomorphism

    • High mitotic count

    • Variable CD99

    • Reactivity for: DUX4, ETV4, ETV5, WT1, CCND2, MUC5AC

  • Prognosis

    • 5-years overall survival: ~ 50%

    • Metastasis at diagnosis: ~ 40%

    • Metastatic disease sites: lung, liver, lymph nodes, brain, bone

  • Genetic Features

    • Fusion transcripts:

      • CIC-DUX4

      • CIC-FOX04

      • CIC-NUTM1

      • NUTM2A-CIC

      • CIC-LEUTX

    • Trisomy of chr 8: c-myc amplification

  • Histology

    • Infiltrative growth; geographic necrosis alternating with viable tumor

    • Diffuse sheets or lobulated growth within fibrotic stroma

    • Slight nuclear pleomorphism, vesicular chromatin, prominent nucleoli

    • Myxoid stroma common (reticular patterns)

    • Stronger cytoplasmic cohesion than in Ewing sarcoma

    • Other features: cords/strands, spindle/rhabdoid/epithelioid cells, myxoid areas.

    • CD99: patchy/weak; NKX2.2: negative

    • WT1 and ETV4: strong, diffuse nuclear positivity

    • Pitfall: ERG and CD31 co-expression in subset

    • Rare expression: keratin, S100, desmin, EMA

  • Primary fusion:

    • CIC::DUX4 (95%)

    • DUX4 located on 4p35 or 10q26.3

    • Rare fusion partners: AXL, CITED1, LEUTX, SYK, FOXO4

  • Diagnostic challenges:

    • Fusions may be cryptic on FISH/RNA-seq

    • Manual inspection of CIC reads may be needed

  • Molecular markers:

    • ETV1/4/5 upregulation is common (detected by RNA-seq)

  • Expanding spectrum:

    • CIC fusions also seen in CNS tumors (e.g., CIC::NUTM1)

    • Recently described in angiosarcoma

    • Some non-CIC rearrangements (e.g., ATXN1::DUX4) may mimic CIC sarcoma morphologically and epigenetically

BCOR-Altered Sarcomas

  • Defined by BCOR overexpression due to either:

    • BCOR::CCNB3 fusion

    • BCOR internal tandem duplication (ITD)

  • Age-related presentation:

    • BCOR::CCNB3: typically in childhood to young adulthood, marked male predominance

    • BCOR ITD: most common in infants and young children

  • Sites of involvement:

    • BCOR::CCNB3: bones > soft tissue; also reported in lung, kidney, head & neck

    • BCOR ITD tumors: seen in kidney (CCSK), PMMTI, and occasionally lung or breast in adults

  • Histology

    • Monotonous spindle to oval cells

    • Dense fascicles, swirling patterns, nuclear palisading

    • Edematous/myxoid stroma, hypervascular

    • Organoid trabecular structures sometimes present

  • Prognosis: Similar to Ewing sarcoma, More favorable than CIC-rearranged sarcoma

Benign Chondroid Tumors

  • Common benign tumors of bone and soft tissue

  • Importance of radiologic-pathologic correlation

  • Osteochondroma

    • Accounts for ~35% of benign bone tumors

    • Solitary or multiple (Multiple Hereditary Exostosis)

    • Associated with EXT1, EXT2, EXT3 mutations

  • Pathogenesis

    • EXT gene mutations disrupt IHh/PTHrP signaling pathway

    • Leads to abnormal chondrocyte proliferation and differentiation

    • Sporadic forms: homozygous EXT1 deletions

  • Clinical Features

    • Usually asymptomatic; detected incidentally

    • Symptoms: mass effect, nerve compression, stalk fracture

    • Male predominance; typically in young patients

  • Chondroma

    • Benign cartilage neoplasm

    • Locations: inside bone (enchondroma), surface (periosteal chondroma), soft tissue (soft tissue chondroma)

  • Clinical Features

    • Typically asymptomatic

    • Common in small bones of hands and feet

    • Detected incidentally or after fracture

  • Imaging

    • Well-circumscribed medullary lesion

    • No endosteal cortical erosion

    • Often shows speckled calcifications

  • Histopathology

    • Hypocellular lobules of cartilage

    • Chondrocytes in lacunae; small, inconspicuous nuclei

    • Occasional binucleated cells

Malignant Cartilage Tumors

  • Chondrosarcoma

    • Lobulated growth pattern with abundant hyaline cartilage matrix

    • Separated by thin fibrovascular bands

    • Mildly hypercellular compared to enchondromas

    • Binucleated cells and occasional multinucleation

    • No significant nuclear pleomorphism

    • Significantly increased cellularity compared to Grade 1

    • Marked cytologic atypia: enlarged, hyperchromatic, irregular nuclei

    • Permeation of cortical and/or medullary bone:

      • Extends through haversian canals of cortex (key distinguishing feature from enchondroma)

    • Markedly increased cellularity

    • Severe cytologic atypia:

      • Enlarged, pleomorphic nuclei

      • Hyperchromasia

      • Open chromatin pattern with prominent nucleoli and occasional macronucleoli

    • Atypical mitotic figures may be present

    • Tumor necrosis common in high-grade lesions

Benign Osteogenic Tumors

  • Osteoid Osteoma

    • Represents ~12% of benign bone tumors

    • Strong male predominance

    • Typically affects teenagers and young adults (2nd decade)

    • Common sites: metaphysis/diaphysis of long bones (cortical location favored)

  • Radiologic and Gross Features:

    • Radiograph: radiolucent nidus with surrounding dense sclerosis

    • CT scan: best for nidus localization

    • Gross: small, red, granular nidus within sclerotic bone

  • Histopathology:

    • Nidus: interlacing thin osteoid trabeculae with prominent osteoblastic rimming

    • Intertrabecular spaces contain bland spindle cells and capillaries

    • Sometimes prominent nerve fibers near nidus (explains pain)

  • Osteoblastoma

    • Anastomosing woven bone trabeculae rimed by plump osteoblasts

    • Intertrabecular spaces: spindle cells and capillaries

    • Zonal architecture: more mineralized osteoid at periphery

    • No permeation between existing bone

    • Secondary aneurysmal bone cyst-like changes may be present

Malignant Osteogenic Tumors

  • Osteosarcoma

    • Clinical and Epidemiologic Features:

      • Most common primary bone sarcoma (~20% of malignant bone tumors)

      • Peak incidence: adolescents and young adults

      • Male predominance

      • Predisposing genetic syndromes: Li-Fraumeni (TP53), Retinoblastoma (RB1), Rothmund-Thomson, Paget disease

    • Radiology and Gross Features:

      • Aggressive bone destruction + soft tissue mass

      • Codman triangle (periosteal elevation) classic but not always seen

      • Fish-flesh gross appearance; sometimes heavily mineralized or chondroid

    • Histology:

      • Highly pleomorphic malignant spindle cells.

      • Matrix production:

        • Osteoblastic (75-80%): fine trabeculae of osteoid

        • Chondroblastic (10-15%): lobules of malignant cartilage

        • Fibroblastic (10%): spindle cells, minimal matrix

      • Other variants: Giant cell-rich, epithelioid, osteoblastoma-like

    • Special Subtypes of Osteosarcoma

      • Chondroblastic Osteosarcoma

        • A subtype of conventional high-grade osteosarcoma

        • Characterized by malignant cartilage production along with osteoid

        • Accounts for 10-15% of osteosarcomas

        • Occurs primarily in adolescents and young adults

        • Common sites: long bones, especially metaphysis

      • Histologic Features:

        • Anaplastic chondrocytes in lacunae

        • Lobules of malignant cartilage with:

          • Peripheral spindling of tumor cells

          • Osteoid matrix seen between spindle cells or within cartilage lobules