Specialty Guide · Path-iQ Global Pathology Review
Bone and soft tissue pathology is one of the most complex and rapidly evolving subspecialties in anatomic pathology. The WHO Classification of Soft Tissue and Bone Tumours (5th edition, 2020) recognises over 100 distinct benign and malignant entities defined by histology, IHC, and — increasingly — specific chromosomal translocations, fusion genes, and copy number alterations detected by FISH or RNA sequencing. Accurate diagnosis requires integration of clinical data, imaging, histology, and molecular testing within a specialist multidisciplinary sarcoma team.
Sarcomas are rare — approximately 13,000 new cases/year in the US, comprising <1% of all malignancies. Their rarity, combined with the diversity of over 70 malignant soft tissue and bone tumour subtypes, means that most individual pathologists encounter too few cases to develop deep expertise. Every suspicious soft tissue mass should be reviewed by or in consultation with a specialist soft tissue pathologist before treatment planning. Errors in sarcoma diagnosis include both false positives (treating a benign lesion as malignant, leading to unnecessary surgery or chemotherapy) and false negatives (treating a sarcoma as benign with inadequate excision margins).
The FNCLCC (Fédération Nationale des Centres de Lutte Contre le Cancer) three-tier grading system is the universally adopted grading scheme for soft tissue sarcomas, integrated into AJCC staging and used for prognosis and chemotherapy decision-making.
| Parameter | Score 1 | Score 2 | Score 3 |
|---|---|---|---|
| Tumour differentiation | Sarcoma resembling normal adult mesenchymal tissue (e.g., well-differentiated liposarcoma, low-grade fibromyxoid sarcoma) | Sarcoma with certain histological typing (e.g., myxoid liposarcoma with <5% round cells) | Embryonal, undifferentiated, or unclassified sarcoma; or any sarcoma of doubtful type |
| Mitotic count (per 10 HPF at 40×) | 0–9 mitoses | 10–19 mitoses | ≥20 mitoses |
| Tumour necrosis | No necrosis (score 0) | <50% of tumour necrotic (score 1) | ≥50% of tumour necrotic (score 2) |
Important caveat: FNCLCC grading is not applicable to all sarcoma subtypes. Ewing sarcoma, rhabdomyosarcoma, and small round cell sarcomas are by definition high-grade. Gastrointestinal stromal tumour (GIST) uses its own risk stratification (Miettinen criteria: size, mitotic rate, site) rather than FNCLCC. Retroperitoneal liposarcoma prognosis is primarily determined by histological subtype (well-differentiated vs dedifferentiated), not FNCLCC grade.
| Tumour | Histology | Diagnostic Alteration | IHC | Grade / Prognosis |
|---|---|---|---|---|
| Well-differentiated liposarcoma (WDLPS) / Atypical lipomatous tumour (ALT) | Mature adipocytes with atypical stromal cells; lipoblasts (may be scanty); fibrous septa; sclerosing or inflammatory variants | MDM2 + CDK4 amplification (12q13–15); FISH MDM2 or IHC MDM2/CDK4 | MDM2 nuclear (strong diffuse); CDK4 nuclear; S100+ (adipocytic areas) | Grade 1; low metastatic risk; local recurrence common; retroperitoneal ALT at higher risk of dedifferentiation |
| Dedifferentiated liposarcoma (DDLPS) | Abrupt transition from WDLPS to non-lipogenic high-grade sarcoma (pleomorphic, spindle, round cell); usually retroperitoneal | MDM2 + CDK4 amplification (same as WDLPS); dedifferentiated area may show additional alterations (ATRX loss in some) | MDM2+, CDK4+ in dedifferentiated area; S100+ only in adipocytic component | Grade 3 (dedifferentiated component); metastasis risk ~15–20%; MDM2 inhibitors (AMG-232) in clinical trials |
| Myxoid liposarcoma (MLPS) | Uniform round/oval cells in myxoid background; characteristic "chicken-wire" vasculature; lipoblasts in variable numbers; round cell component (>5% = high-grade) | FUS-DDIT3 fusion (t(12;16)(q13;p11)) in ~90%; EWSR1-DDIT3 in ~10% | S100+; DDIT3 nuclear IHC (positive); MDM2− | Pure myxoid: Grade 1–2; round cell (>5%): Grade 3; characteristic bone marrow metastasis; trabectedin approved for advanced MLPS |
| Synovial sarcoma | Biphasic (epithelial glands + spindle stroma) or monophasic (spindle only); haemangiopericytoma-like vasculature; mast cells; calcification; poorly differentiated variant (round cell) | SS18-SSX1 or SS18-SSX2 fusion (t(X;18)(p11;q11)) — diagnostic; RNA NGS or FISH | TLE1+++ (nuclear, most sensitive); CK7+, EMA+ (glandular areas); bcl-2+; CD99+; SMARCB1 (INI1) intact; SS18-SSX IHC (clone E9X9V) diagnostic | Grade 2–3; 10-yr OS ~50–60%; ifosfamide-sensitive; SS18-SSX fusion → larotrectinib not applicable; axitinib, pazopanib for advanced; CAR-T trials ongoing |
| Ewing sarcoma / EWS-FLI1-fused small round cell tumour | Sheets of uniform small round blue cells; scant cytoplasm; PAS-positive glycogen; rosettes (Homer Wright) in some; permeative bone destruction on imaging | EWSR1-FLI1 fusion (t(11;22)(q24;q12)) in ~85%; EWSR1-ERG in ~10%; FUS-FLI1 rare; FISH EWSR1 break-apart or RNA NGS | CD99+++ (strong diffuse membranous); NKX2-2+; FLI1+ (nuclear); synaptophysin+/−; cytokeratins−; SMARCB1 intact | Grade 3; 5-yr OS ~70% localised, ~30% metastatic; VDC/IE chemotherapy standard; immunotherapy under investigation |
| Gastrointestinal stromal tumour (GIST) | Spindle (70%), epithelioid (20%), or mixed; cytoplasmic vacuoles; stromal hyalinisation; nuclear palisading in spindle type | KIT (CD117) mutation (~75%; exon 11 most common); PDGFRA mutation (~10%; D842V exon 18 = imatinib-resistant); NF1-associated; SDH-deficient (paediatric, young adults) | CD117 (KIT)+++ (cytoplasmic/membranous); DOG1+++ (most sensitive and specific); CD34+ (~70%); S100−; SMA−/focal; SDHA/SDHB IHC for SDH-deficient subset | Risk stratified by size, mitotic rate, and anatomical site (Miettinen criteria); imatinib (CD117/PDGFRA non-D842V); avapritinib (PDGFRA D842V); sunitinib (imatinib-resistant KIT exon 9/13/14/17); ripretinib (4th line) |
| Undifferentiated pleomorphic sarcoma (UPS) | Highly pleomorphic cells; giant cells; storiform pattern; high mitotic rate with atypical mitoses; necrosis; diagnosis of exclusion after extensive sampling and IHC panel | No defining alteration; complex karyotype; must exclude: leiomyosarcoma, liposarcoma, myxofibrosarcoma, and carcinosarcoma before diagnosing UPS | Vimentin+; SMA/desmin+/−; MDM2−; S100−; all epithelial markers negative; exclude metastatic sarcomatoid carcinoma (CAM5.2+) | Grade 3; 5-yr OS ~50–60% for localised; anthracycline-based chemotherapy; pembrolizumab in TMB-high UPS; trabectedin option in advanced disease |
| Tumour | Age / Site | Histology | Molecular | Prognosis |
|---|---|---|---|---|
| Osteosarcoma (conventional) | 10–20 yr; distal femur, proximal tibia, proximal humerus | High-grade spindle cells producing osteoid / bone matrix directly — minimum for diagnosis; chondroblastic, fibroblastic, or teleangiectic variants | Complex karyotype; TP53, RB1 alterations; MDM2 non-amplified (distinguishes from parosteal osteosarcoma); DLK1 surface marker | 5-yr OS ~70% localised with MAP (methotrexate, adriamycin, cisplatin); poor histological response (<90% necrosis) = adverse; pulmonary metastasis = worst |
| Chondrosarcoma (conventional) | Adults (>40 yr); pelvis, femur, humerus, ribs | Malignant hyaline cartilage; lobular growth; myxoid areas; nuclear atypia and binucleation correlate with grade; permeation of cortex / soft tissue in high grade | IDH1/IDH2 mutations (~50%); IDH1 IHC (H09 clone); COL2A1 mutations; CDKN2A deletion in dedifferentiated | Grade 1 (low): excellent; Grade 2–3: 5-yr OS ~50–75%; Grade 3 / dedifferentiated: <20%; IDH inhibitor (enasidenib) trials ongoing |
| Giant cell tumour of bone (GCTB) | 20–45 yr; epiphysis of long bones; distal radius, proximal tibia, distal femur | Multinucleated osteoclast-like giant cells evenly distributed among mononuclear stromal cells; uniform nuclei; haemosiderin; secondary ABC change | H3.3 G34W mutation (H3F3A exon 2) in >90%; specific IHC (G34W antibody) pathognomonic; telomere maintenance via H3.3 G34W mechanism | Benign but locally aggressive; 15–20% recurrence after curettage; 2–5% pulmonary metastases (benign histology); denosumab (RANK-L inhibitor) for unresectable/recurrent; malignant transformation rare |
| Chordoma | 40–60 yr; sacrum (>50%), clivus, vertebral body midline | Physaliferous cells (bubbly cytoplasm); chords and lobules in myxoid matrix; notochordal differentiation | SMARCB1 loss in poorly differentiated chordoma; T (brachyury) expression: nuclear IHC + FISH amplification; dedifferentiated variant (loss of brachyury) | Locally aggressive, low metastatic rate but high local recurrence; en-bloc resection with wide margins curative; imatinib, erlotinib for inoperable; larotrectinib (NTRK-fused rare variant) |
| Probe / Assay | Target | Entity Confirmed |
|---|---|---|
| EWSR1 break-apart FISH | EWSR1 locus (22q12) rearrangement | Ewing sarcoma family; DSRCT; extraskeletal myxoid chondrosarcoma; clear cell sarcoma; myxoid liposarcoma (10%); others — partner gene confirms entity |
| MDM2 FISH (amplification) | MDM2 copy number (>4× reference) | WDLPS / DDLPS (vs lipoma, myxoid liposarcoma); parosteal osteosarcoma (vs conventional osteosarcoma) |
| SS18 break-apart FISH | SS18 (18q11) rearrangement | Synovial sarcoma; SS18-SSX1/SSX2 confirmation |
| FUS break-apart FISH | FUS (16p11) rearrangement | Myxoid liposarcoma (FUS-DDIT3); low-grade fibromyxoid sarcoma (FUS-CREB3L2); sclerosing epithelioid fibrosarcoma |
| DDIT3 break-apart FISH | DDIT3 (12q13) rearrangement | Myxoid liposarcoma (with FUS or EWSR1 as partner) |
| ALK break-apart FISH | ALK (2p23) rearrangement | Inflammatory myofibroblastic tumour (IMT); ALK IHC screening first |
| CDK4 FISH (amplification) | CDK4 copy number (12q14) | WDLPS / DDLPS (co-amplified with MDM2); osteosarcoma (some cases) |
RNA NGS fusion panels (e.g., FoundationOne RNA, Anchored Multiplex PCR) are increasingly replacing FISH for sarcoma fusion detection — they simultaneously detect hundreds of gene fusions with high sensitivity, identify both fusion partners (important for rare or novel fusions), and work on FFPE tissue with standard DNA extraction. RNA NGS is now the preferred modality at specialist sarcoma centres for all round cell and spindle cell sarcomas where a defining fusion is expected.
Editor-in-chief of WHO Classification of Soft Tissue and Bone Tumours (5th edition, 2020) and the definitive soft tissue pathology textbook (Diagnostic Histopathology of Tumors). The world's leading authority on soft tissue tumour classification, novel entity definition, and FISH-based diagnosis in sarcoma.
Europe's foremost bone tumour pathologist; co-editor of WHO 2020 bone tumours section; authority on chordoma, osteosarcoma heterogeneity, giant cell tumour RANKL biology, and the molecular underpinning of cartilaginous tumours. Past chair of the European Musculoskeletal Oncology Society pathology committee.
Authority on immunohistochemistry in soft tissue tumour diagnosis; expert on novel soft tissue entities (SMARCA4-deficient thoracic sarcoma, CIC-DUX4 sarcoma, NTRK-fused spindle cell sarcoma); contributor to WHO 2020 soft tissue volume. Author with Christopher Fletcher of Enzinger and Weiss Soft Tissue Tumors (7th edition).
Pioneer in FISH-based sarcoma diagnosis; contributed to the molecular characterisation of Ewing sarcoma (EWSR1-FLI1), myxoid liposarcoma (FUS-DDIT3), and synovial sarcoma (SS18-SSX). Established cytogenetics and FISH as essential tools in clinical sarcoma pathology diagnosis.
Discoverer of H3.3 G34W mutation as the defining event in giant cell tumour of bone; leading authority on osteosarcoma molecular biology, IDH-mutant chondrosarcoma, and molecular pathology of primary bone tumours. Director of the RNOH Pathology department — Europe's largest bone tumour referral centre.
One of Europe's most productive soft tissue pathologists; describer of multiple novel soft tissue tumour entities including fibroma of tendon sheath variants and PEComa subtypes. Expert on fibrohistiocytic tumours, myofibroblastic neoplasms, and vascular lesion classification.