Define sarcoma
- Sarcoma = malignant tumour of mesenchymal cells (i.e., of connective tissue)
- OMA = BENIGN
- SARCOMA = MALIGNANT
Name some examples of benign and malignant neoplasms of soft tissue origin
Briefly describe sarcomas
- Malignant tumour of mesenchymal/connective tissues.
- Rare in adults (~1%) but significant in paediatric/teenage malignancies (~15%).
- Arise anywhere, often hidden deep in the limbs (has a predilection for joints and proximal limbs)
- > 80 subtypes with distinct clinical characteristics, natural history, and biology
- Distinct clinical characteristics, natural history and biology
– Classified by tissue of origin +/- molecular genetic alteration
– Classified as Bone or Soft Tissue sarcomas for Staging
Incidence of Subtypes Differs with Age:
- Typically in children/teens/young adults: Ewing sarcoma, Osteosarcoma, Rhabdomyosarcoma, Synovial Sarcoma.
- Typically in older adults: Angiosarcoma, Chondrosarcoma, Leiomyosarcoma, Liposarcoma, Malignant peripheral nerve sheath tumour, Synovial sarcoma, Undifferentiated pleomorphic sarcoma
List sarcoma risk factors
- De-novo (no risk factors) = common. ^[vast majority are sporadic]
- Inherited (rare)
- Hereditary cancer syndromes (e.g., Li Fraumeni ^[germline cancer], Neurofibromatosis type 1)
- Neurofibromatosis type 1 (NF1 gene mutation, malignant peripheral nerve sheath tumours [MPNST])
- Acquired
- External beam radiotherapy particularly at a young age ^[if angiosarcoma inquire about this]
- Angiosarcoma, undifferentiated pleomorphic sarcoma, leiomyosarcoma and MPNST
- Chronic lymphoedema eg after breast cancer surgery
- Aggressive form of angiosarcoma (Stewart-Treves syndrome)
- External beam radiotherapy particularly at a young age ^[if angiosarcoma inquire about this]
Describe the stem cell theory of cancer as it relates to sarcoma
STEM CELL THEORY OF CANCER: that many cancers form from malignant stem cells that choose a path of differentiation.
Neoplastic cells with stem cell properties are present within malignant neoplasms which makes them resistant to therapy.
Describe the two broad groups of sarcoma
- Two major groups:
- 2/3: complex unbalanced karyotype, with genomic instability and heterogeneous mutations between tumours of the same type
- 1/3: disease-defining recurrent genetic alteration, specific translocation or characteristic point mutation i.e. every cell in the sarcoma has this aberration (eg synovial sarcoma, Ewing sarcoma, clear cell sarcoma)
- Implications for therapy: Heterogeneous neoplasms have varied response to treatment, Advances in targeted therapies/inhibitors for specific gene fusions.
Note:
- tumours with translocations (where each cell has the same molecular aberration) are often composed of uniform/monotonous cells e.g. Ewing
- tumours with complex karyotypes are typically polymorphic e.g. dedifferentiated lipomyosarcoma
Describe the spectrum of connective tissue tumour behaviour
- Spectrum from benign to malignant
- benign (eg lipoma)
- intermediate, locally aggressive (eg desmoid type fibromatosis)
- intermediate, rarely metastasizing (eg giant cell tumour of soft tissue)
- malignant (eg Ewing sarcoma)
- Sarcomas usually spread via bloodstream (compared to carcinoma via lymphatic spread)
- Grading reflects aggressiveness.
Describe sarcoma grading
- Tumour Differentiation: (1, 2, or 3 points based on how closely it resembles normal tissue)
- Mitotic Count: (1, 2, or 3 points based on how many mitoses per 10 high power fields)
- Tumour Necrosis: (0, 1, or 2 points if no necrosis, <50% or >50% necrosis)
- Grade = Sum total of scores for differentiation, mitotic count, and necrosis
- 2-3 points = Grade 1 (low grade)
- 4-5 points = Grade 2 (intermediate grade)
- 6-8 points = Grade 3 (high grade)
Compare and contrast sarcoma and carcinoma
- Sarcoma
- Arises from connective tissues (e.g., bone, cartilage, muscle, fat, nerve)
- Rare
- Usually haematogenous spread
- Mostly affects children/young adults
- Carcinoma
- Arises from epithelial tissues (e.g., lung, breast, prostate, colon, skin)
- Common
- Usually lymphatic spread
- Mostly affects people >50
List the most common tymours in bone
Most Common Malignant Tumour in Bone?
- METASTASIS! (Breast, Lung, Kidney, Prostate, Thyroid)
Non Neoplastic Bone Conditions
- Cystic lesions in bone: Solitary bone cyst, Aneurysmal bone cyst
- Reactive bone lesions simulating tumours: Osteoid osteoma, Osteoblastoma, Non-osteogenic fibroma (metaphyseal fibrous defect), Giant cell granuloma
- Hamartomas of bone: Osteoma, Osteochondroma, Enchondroma (chondroma)
- Infection (osteomyelitis): Tuberculosis, Bacteria
- Malformation: Fibrous dysplasia
List some general facts about bonetumours
Bone Tumours: General Comments
- Most common Primary malignancies arising in Bone:
- Myeloma ^[in elderly]
- Osteosarcoma
- Chondrosarcoma
- Most common during time of active skeletal growth = younger age, up to 30yrs, M> F
- Common in bones with highest growth rate i.e., Distal femur, proximal tibia
- High-grade sarcomas can also arise in damaged bone (areas of infarction, chronic osteomyelitis, irradiation, or Paget’s disease) - especially in older adults
- Some bone tumours are difficult to classify as benign or malignant (e.g., Giant Cell Tumour is locally aggressive and sometimes metastasizes) i.e. intermediate
Disntiguish between primary sarcomas of bone on the basis of age
- <40 years: Osteosarcoma, Ewing sarcoma
- >40 years: Chondrosarcoma
List and briefly describe the essential information required for diagnosing bone tumours
- Age: Skeletally immature vs mature
- Location: Which bone? (Long bone, flat bone, digits, vertebra, craniofacial bones) and Which part of bone? (Epiphysis, Metaphysis, Diaphysis)
- Radiology: CRITICAL
- Biopsy:
Pathologist should not diagnose a bone tumour without radiological correlation
Describe osteosarcoma
Definition
- Malignant tumour differentiating towards osteoblasts, with production of osteoid/bone
Epidemiology
- Most common bone sarcoma (35%)
- M:F = 2:1
- Usually in children/adolescents (during maximal bone growth); also in older adults
Etiology
- Most cases = Unknown
- Patients with retinoblastoma (Rb) gene mutations = several hundred-fold greater incidence
- Associated with conditions of high bone turnover, such as Paget’s disease and fibrous dysplasia of bone, also if prior radiotherapy or bone necrosis
- Older adults with osteosarcoma often have one of these predisposing conditions (= ‘secondary’ osteosarcoma)
Clinical Features
- Metaphysis (most often distal femur, proximal tibia)
- Localized pain and swelling or pathological fracture
- ~10-20% of patients have pulmonary metastases at diagnosis
Describe investigarions necessary for diagnosis and staging osteosarcomas
- Imaging:
- XR
- CT: cortical irregularities/fracture sites/mineralisation
- MRI: extension into soft tissue/marrow/joint space
- PET scan: assess primary lesion; detect metastases elsewhere
- Radionuclide bone scan.
- Biochemistry: Elevated ALP ^[indicates osteoblast activity] + LDH ^[indicates high cell turnover].
- Biopsy: Core or open (incisional) biopsy preferred - core limits risk of recurrence; FNA is inappropriate due to loss of architectural information.
Describe the microscopic features of osteosarcoma
Compared to normal bone, osteosarcoma shows:
- Architecture: crowded/more cellular
- Cytology: Tumour cells often ‘spindle’ shaped, hyperchromatic, variable
- Pathognomonic feature = production of neoplastic osteoid/ matrix (appears pink due to lack of mineralisation)
- Often scanty, irregular/’lace-like’ & does not mineralize normally
- Tumor cells may also show predominantly fibrosarcomatous or chondrosarcomatous differentiation
Distinguish between soft tissue sarcomas occurring in adults vs children
Soft tissue sarcomas by frequency:
Adult:
1. Liposarcoma
2. Leiomyosarcoma
Paediatric:
1. Rhabdomyosarcoma
2. Ewing sarcoma (of soft tissue)
Describe WDLPS
Definition: Locally aggressive mesenchymal neoplasm with mature adipocytes and stromal cells showing focal nuclear atypia.
Epidemiology: Most common form of liposarcoma, affecting middle-aged to elderly adults.
- extremely rare in childhood
- Sex: M = F
Etiology: Unknown.
Molecularly characterized by ring or giant marker / rod chromosomes, with amplification of several genes including MDM2.
Clinical Features:
- Location:
- Deep thigh or other proximal limbs, retroperitoneum, trunk, spermatic cord, mediastinum
- May also arise in subcutaneous tissue; rarely in skin (‘atypical lipomatous tumour’)
- Less frequent in head/neck area - Slow-growing, painless, deep-seated mass
- Retroperitoneal tumours may only be discovered after attaining significant growth (> 20 cm)
List relevant investigations in WLDPS
- MRI preferred for imaging.
- Biopsy: Core, incisional, or excisional; FNA inappropriate.
Describe treatment and prognosis
Treatment:
- Complete excision with negative margins often curative
- Surgical debulking for large, multifocal retroperitoneal/intra-abdominal tumours
- May require partial or complete resection of intraabdominal organs
Prognosis: Behaviour depends on location.
- Superficial locations more surgically amenable – can resect with negative margins
- In skin it’s called an ‘atypical lipomatous tumour’ (ALT)
- Deep locations (eg retroperitoneum) more difficult to resect – often recur locally – and can undergo ‘de-differentiation’ and subsequently metastasise
- No metastatic potential unless dedifferentiation is present
Describe the macro and micro appearance of lipomyosarcoma
Macro:
- Well-circumscribed, lobular
- Cream/tan/grey, homogeneous cut surface
- Appears to arise from fat and bulge into muscle
- Thickened fibrous bands may be evident
- Fat necrosis may be seen in larger tumours (not pictured. Looks very pale yellow)
Micro:
Compared to normal fat, liposarcoma shows:
- Significant variation in size and shape of adipocytes
- Focal nuclear hyperchromasia and mild atypia
- Thickened, irregular fibrous bands/septa
- Often contain atypical spindle shaped cells
- Lipoblasts may be seen
* Multivacuolated
* Nucleus indented by the vacuoles
- Significant nuclear pleomorphism/atypia absent
List and describe the ancillary tests for WDLPS
Immunohistochemistry: S100 protein (+) in adipocytes and lipoblasts
Cytogenetics:
- Characteristic supernumerary ring and giant marker chromosomes
- Contain amplified sequences from 12q14-15 region
Molecular tests:
- MDM2 gene amplification detected via fluorescent in situ hybridisation (FISH) - necessary to distinguish between it and lipoma
