Sarcoma Flashcards
What’s the epidemiology for extremity sarcoma?
Incidence (Australian statistics)
- Rare 1% of adult, 12% paediatric
- 75% ST, 25% bone
- 2000 cases annually
- By subtype:
○ Leiomyosarcoma (20%)
○ Undifferentiated pleomorphic sarcoma/MFH (16%)
○ Liposarcoma (10%)
○ Dermatofibrosarcoma (7%)
○ Rhabdomyosarcoma (4%)
○ Angiosarcoma (4%)
○ Synovial sarcoma (3%)
Retroperitoneal lesions are uncommon within STSs (15% of all STSs)
Broad age range (typically 55-65yo); 4th most common in childhood (~20%)
Approximately equal incidence in males and females
Distribution age dependent:
- Children – RMS, Ewing’s/PNET
- Young adults – synovial sarcoma, Ewing’s
- Middle to late adulthood – liposarcoma, LMS, MFH ([primary undifferentiated]pleomorphic sarcoma), fibrosarcoma.
Site distribution:
- Extremities: 60% > LS, MFH, FS
- Retroperitoneal 20% > LS, LMS
- H&N 20% > RMS (kids)
- GIT - GIST
- GN - LMS (adults), RMS (kids)
List the risk factors for extremity sarcoma
Aetiology
Majority sporadic; small minority genetic
Limited evidence for environmental causes
1) Previous radiotherapy (HD, Breast) Angiosarcoma, MFH, fibrosarcoma 2) Familial/genetic factors ○ Nevoid basal cell carcinoma syndrome (Gorlin syndrome: PTCH1 gene mutation) ○ Gardner syndrome (APC mutation) à Aggressive fibromatosis (+ FAP) ○ Li-Fraumeni syndrome (p53 mutation) à soft tissue sarcomas ○ Tuberous sclerosis (Bourneville disease: TSC1 or TSC2 mutation). ○ von Recklinghausen disease (neurofibromatosis type 1: NF1 mutation) à malignant peripheral nerve sheath tumour (MPNST) ○ Werner syndrome (adult progeria: WRN mutation à premature aging) ○ Retinoblastoma – germline mutation in RB1 locus 3) Chemical carcinogens a. Thorotrast (old radiology contrast 1930-1950) b. Arsenic (hepatic angiosarcomas) c. PVC (hepatic angiosarcoma) 4) Burns foreign implants, scars
Special cases
- HHV8 –> Kaposi sarcoma (immunosuppression)
- Chronic Lymphoedema –> lymphangiosarcoma
- NF1 mutation –> MPNST
Patterns of spread:
a) Local disease
a. Along tissue planes, may invade and envelop NV structures
b. Periphery has outer perimeter of oedematous tissue “pseudocapsule”
c. Satellites within the same compartment
d. Extends longitudinally within muscle compartment
e. Tends to respect barriers eg. bone, fascia; exploited in tissue preservation procedures
f. Hence RT fields are long sup/inf (5cm) but less in axial direction (3cm).
b) Nodal
a. Uncommon, 4%; except in synovial, clear cell, angiosarcoma, RMS, epithelioid; “SCARE” >15-20% nodal involvement
c) Mets
a. Haematogenous: inc with size (>5cm), and HG; lung most common; liver 1st for RP sarcoma
Describe the classification and subtypes for sarcoma.
Pathological
Classification
- Broad classification as arise from embryonal mesenchymal cells > can diff into any connective tissue subtype
- Subclassification based on presumed tissue of origin; the normal tissue the tumour most closely resembles
- Needs expert pathological review (centralised)
WHO classifies ‘soft tissue tumours’ into 4 groups based upon biologic behaviour:
1. Benign – tend not to recur following local excision, non-destructive.
2. Intermediate – locally aggressive – often recur locally and assoc with infiltrative and locally destructive growth pattern, rarely metastasise
3. Intermediate – rarely metastasise – tend to recur locally, but also able to metastasise
4. Malignant – locally destructive and substantial risk of mets
Describe the grading for extremity sarcoma. List the common subtypes of extremity sarcoma
Grading:
- Indicates degree of malignancy, probability of DM and death from sarcoma
- Grade not a good predictor of local recurrence (surgical margins).
- 3 tier system: low, intermediate and high grades.
- US and French systems of grading:
1. US – histo type, cellularity, pleomorphism, mitotic rate, extent of necrosis
2. French (FNCLCC) – differentiation/histo type, mitotic rate (<10, >20), extent of necrosis.
▪ Grade 1: 2 - 3 points
▪ Grade 2: 4 - 5 points
▪ Grade 3: 6 - 8 points
Always grade 3 * Extraskeletal Ewing sarcoma / primitive neuroectodermal tumor (PNET) * Extraskeletal osteosarcoma * Mesenchymal chondrosarcoma * Malignant triton tumor
Describe the pathology for rhabdomyosarcoma
Rhabdomyosarcoma
- Can impact both adults and children alike
○ Paediatric tumours often arise in sinuses, H+N or genitourinary tract
- HIGHER RISK OF NODAL METASTASES
- Four key subtypes ○ Embryonal (50% - children) ○ Alveolar (20% - children) --> poorer prognosis ○ Pleomorphic (20% - adults) ○ Spindle Cell (10% - all) - Macroscopic ○ Soft, fleshy, grey infiltrative mass ○ Botryoid variant (embryonal) --> cluster of grapes (polypoid projections into a lumen) § e.g. vaginal wall with protrusion through introitus - Microscopic ○ Embryonal § Sheets of primitive mesenchymal cells with variable degrees of muscle differentiation § Mixed areas of hypo- and hyper-cellularity § Cells with scant cytoplasm ○ Alveolar § Nests of cells with scant cytoplasm arranged in alveolar spaces § Cells may gave hobnail appearance to adhere to alveoli § Cells may appear non-cohesive ○ Pleomorphic § Sheets of large atypical multinucleated cells - Immunohistochemistry ○ POS = desmin, MyoD1, myoglobin, Vimentin, Actin ○ NEG = CK7, EMA, synaptophysin - Molecular ○ Alveolar RMS --> FOX01-PAX3 fusion gene. Translocation (2,13) or (1,13) ○ Otherwise, complex karotypes
Describe the pathology for angiosarcoma
Angiosarcoma
- Rare, primarily impacting adults
- Usually associated with “field cancerization”. Most are superficial and in H&N area. Presents as a spreading bruise that is blue to red in color. Nodules may develop over time and ulcerate. Clinical exam underestimates imaging.
- A margin of at least 3 cm is desired, but some centers deem 0.5 cm acceptable.
- Affects endothelial cells of blood vessels.
- Accounts for < 2% of all STS and < 1% of H&N cancer cases.
- Can arise anywhere, including scalp, breast, and extremities.
○ Also occurs in irradiated skin (e.g. chest wall after breast ca)
- Scalp angiosarcomas account for > 60% of all cases.
- Associated with RT, lymphoedema, Thorotrast, arsenic
- HIGHER RISK OF NODAL METASTASES
- The most common site of metastasis is the lung, followed by bone and liver.
- MDACC Angiosarcoma [Guadagnolo H&N ‘10]: Retro. Surgery ± RT.
Tumor size > 5 cm and satellitosis were prognostic for inferior OS and DSS.
○ 70 pts with nonmetastatic angiosarcoma. MFU 2y.
○ 5y OS 32→ 68%, 5y DSS 33→ 76%, 5y LC 24→ 84%.
- Macroscopic ○ Presents as a purple or maroon nodule on the skin ○ If deep, presents as a slow-growing, painful mass ○ Cut surface = haemorrhagic or necrotic - Microscopic ○ Heterogenous appearances ○ Numerous irregularly shaped anastomosing vascular channels lined by atypical endothelial cells § Plump, pleomorphic and mitotically active cells § Degree of vasoformation is variable ○ Generally highly infiltrative with poor demarcation - Immunohistochemistry ○ POS = CD31, CD34, ERG, VEGF (endothelial markers), CK, EMA ○ NEG = HHV8 --> DISTINGUISH FROM KAPOSI - Molecular ○ Upregulation of multiple vascular-specific tyrosine kinases ○ As well as HIF1/HIF2 & cMYC
Describe the pathology for synovial sarcoma
Synovial Sarcoma
- The histogenesis is NOT the synovium (unknown origin)
- Predominance towards adolescents and young adults (AYA)
- Typically presents in the extremities (70%), but can arise anywhere
- HIGHER RISK OF NODAL METASTASES
- Macroscopic ○ Typically well circumscribed and multinodular ○ Cut surface is variable = tan to yellow & soft to firm § Necrosis, calcification, myxoid change may be present ○ On CT, there are focal calcifications seen - Microscopic ○ Monophasic spindle § Monotonous cells with scant cytoplasm and spindled nuclei § Hypercellular fascicular architecture with little stroma § Infiltrative borders ○ Biphasic § Mixed areas of spindle cells with epithelial cells § Gland-like formation in areas of epithelial differentiation (mucin production is seen) - Immunohistochemistry ○ POS = TLE1, EMA, beta-catenin, CKs (incl CK7, CK20) - dependent on subtype ○ NEG = CD34 (vascular), desmin, myoD1, FLI, WT1, SOX10, S100 - Molecular ○ 90% of cases show SS18-SSX1 fusion gene (t[X:18])
Describe the pathology for fibrosarcoma
Fibrosarcoma
- Rare subtype of sarcoma
○ Includes high-grade DFSP
- Commonly affect adults (rare in children)
- Typically occur in the deep tissue of the lower extremities
- Macroscopic ○ Well circumscribed, but non-encapsulated ○ Cut surface = fleshy white-tan tumour with haemorrhage and necrosis - Microscopic ○ Highly cellular fibroplastic proliferative lesion § Herringbone pattern ○ Cells have scant cytoplasm and elongated dark nuclei ○ Mitotic activity is present ○ No pleomorphism allowed --> undifferentiated pleomorphic sarcoma (UPS) - Immunohistochemistry ○ POS = Vimentin, p53, reticulin ○ NEG = S100, CKs, SMA, p40 - Molecular ○ Aneuploidy (abnormal chromosomal number)
Describe the prognostic factors for sarcoma
Patient Factors
- Age (>50) and performance status
- Previous radiotherapy (RT-induced)
Tumour Factors
- TNM stage
○ Size > 5-10cm worse for OS + DM
○ Nodal
○ Distant
- Grade
○ single most imp PF for DM + OS
○ Including high mitotic counts
- Location (including deep)
○ Extremity<Trunk< H+N and retroperitoneum is worst
○ Deeper worse
▪ depth is based on the tumor’s location in relation to the deep muscle fascia.
- Histopathology
○ Fibrosarcoma and liposarcoma are best prognosis
○ “LAMMES”: LMS, angio, MFH, MPNST, epithelioid, synovial worse OS
- Some molecular mutations
○ EWS-FLI1 in Ewing’s
○ SS18-SSX in synovial –> worse outcome
○ FOX01-PAX3 translocation in alveolar RMS –> worse outcome
Treatment Factors
- Surgery
○ Type of resection (local vs compartmental)
○ Complete resection with clear margins; most important for LR
- Radiotherapy
○ RT dose <63Gy= worse outcome
○ Delay b/w surg + RT >30days
- Treatment in a high-volume centre (retrospective evidence supports this)
Describe the history, examination and investigations for extremity sarcoma
Consultation
History
- Clinical presentation: Mostly asymptomatic, pain due to invasion of surrounding structures, rarely constitutional symptoms such as fever
- Primary lesion
○ Pain (most are asymptomatic)
○ Gradually enlarging
○ Duration and growth rate
○ Subjective functional impairment (due to mass: pain, oedema, pressure Sx)
- Constitutional symptoms
- PMHx
○ Previous radiotherapy or cancer
○ Genetic syndromes
§ e.g. Li Fraumeni, Lynch syndrome, NF1
- Medications
○ Contraindications to radiotherapy
Examination
- Primary mass
○ Location of tumour (thigh is most common)
○ Deep vs superficial
○ Extent (approx size, multiple compartments, skin involvement, etc.)
- Neurovascular compromised
- Function of the involved limb
○ Power and ROM
○ Functional use
- Palpable lymphadenopathy
- Lymphodema
UK criteria for mass concerning for STS:
- Soft tissue mass >5 cm (golf ball size or larger)
- Painful lump
- Lump that is increasing in size
- A lump of any size that is deep to the muscle fascia
- Recurrence of a lump after previous excision
Investigations
- All soft tissue masses > 5cm (especially if deep) should be considered sarcoma until otherwise proven - Upfront imaging (Prior to biopsy) ○ CT of region of interest (e.g. ipsilateral thigh, abdomen for retroperitoneal structures) ○ MR of region of interest (good for delineation between muscle, tumour and blood vessels) ○ PET high grade vs low grade and presence of nodal/distant mets - Biopsy (core or incisional) ○ MUST be performed under guidance of sarcoma surgeon + MDT § In general symptomatic/enlarging mass, >5cm and persists >4 weeks ○ Core preferred (FNAB unacceptable) § Incision biopsies should be most superficial part of mass and meticulous to prevent tumour spill or haematomas - Staging imaging (following confirmation of diagnosis) ○ FDG PET-CT (preferred) ○ Alternative is CT CAP ○ MRI brain for angiosarcoma ○ If myxoid liposarcoma, include CT A/P due to frequent mets to peritoneum. Consider MRI spine.
For extremity sarcoma, describe the advantages and disadvantages for Core biopsy, FNA and incisional biopsy
Core biopsy:
- Advantages:
* Provides architectural information sufficient for accurate diagnosis of histological subtype and grade (high diagnostic yield).
* Can be image guided in consultation between sarcoma surgeon and interventional radiologist and biopsy tract excised at the time of the definitive surgery to reduce risk of biopsy track seeding.
○ Few cases of seeding with closed biopsy, can tattoo or mark the site to ensure later excised with specimen
* Non-invasive, rapid procedure, low complication rates.
* Can be done under sedation or local anaesthetics.
* Reduced cost
- Disadvantages:
* Smaller tissue sample compared to incisional biopsy as such that incisional biopsy may be required to provide enough specimen for flow cytometry, cytogenetics and molecular analysis- incidence of follow-up biopsy is up to 20%
* Needle core instruments required.
* Might require repeat biopsy if inadequate sampling
* Risk of seeding if not performed appropriately or planned according to resection
Fine needle aspiration (FNA)
- Advantages:
* Can be useful in confirmation of recurrence or nodal/distant metastatic disease where further surgery is not being considered.
- Disadvantages:
* Not preferred for primary tumour due to lack of architectural information for histological subtype and grade.
* Risk of insufficient tumour sample for IHC, cytogenetics and molecular genetic testing.
Open/incisional biopsy- typically reserved when core biopsy is not diagnostic
- Advantages:
* Allows excision of the biopsy tract.
* Provides architectural information and sufficient tissue for immunohistochemistry and cytogenetics (high diagnostic yield).
* Allows surgeon to choose area of tumour to sample that is likely to yield highest diagnostic information.
* More tissue sample compared to core biopsy.
* Specimen can be sent fresh and oriented
- Disadvantages:
* Invasive
* May require general anaesthetics
* Must be done by sarcoma surgeon (local surgeon may be able to perform only after appropriate consultation with STS surgeon)
* More expensive
Describe the staging for extremity sarcoma.
T1 <5cm in greatest dimension
T2 5-10cm
T3 10-15cm
T4 >15cm
N1 Regional nodal metastasis
M1Distant metastasis
G1 Histological Grade
G2
G3
Describe the role of radiotherapy in sarcoma management
Role of Radiotherapy
- Controversial
- RT Indications:
○ Low Grade:
§ Positive margins
§ LR s/p prior surgery alone (with re-resection)
§ Location not amenable to salvage surgery
○ High Grade:
§ Standard of care Limb Salvage Surgery + adjuvant RT
- Adjuvant RT proven to improve LR and OS in lesions >5 cm or high grade ○ No adjuvant RT if <5cm, low grade, clear margin. - No consensus between neoadjuvant vs adjuvant RT
Neoadjuvant vs Adjuvant radiotherapy
RCT closed early
Similar oncological outcomes LC and OS similar w pre and post op RT, <15% LR
Neoadjuvant radiotherapy generally preferred
Exceptions:
- High risk of wound healing issues (e.g. T2DM)
- Fungating extremely painful tumour
Neoadjuvant radiotherapy
- Radiotherapy is required for nearly all soft tissue sarcomas of the extremity
○ Consider omission if small (<5cm), superficial AND low-grade
- Addition of radiotherapy improves local control & rate of limb-sparing surgery
○ Local failure 0-5%
○ No OS benefit
- Two basic recipes can be delivered
○ 50Gy/25F
○ Modified Eilber technique = 30Gy/20F BD with infusional doxorubicin for 72 hours prior
- If positive margin found post-operatively, consider subsequent in-field boost (16-20Gy/8-10F)
○ This is discouraged by NCCN unless essential
- Note that myxoid liposarcoma is exquisitely sensitive to radiotherapy with high pCR
○ Continue with standard dose
○ Dose reduction is undergoing trial ( ph2 DOREMY trial - 36Gy/18F)
Adjuvant radiotherapy
- Alternative to neoadjuvant treatment
○ 50Gy/25F with in-field sequential boost as follows:
§ Gross residual –> 70Gy/35F
§ Microscopic residual –> 66Gy/33F
§ No residual –> 60Gy/30F
- If no NA radiation and has positive margin, and not amenable to salvage surgery, or follow-up poor compliance
Discuss the pros and cons for adjuvant vs neoadjuvant radiotherapy in sarcoma management
Describe surgery for extremity sarcoma
Surgery
- Consider surgery alone for superficial tumour (not involving muscle fascia) <5cm and can be treated wide R0 resection (LR <15%, OS 90%) - High-rates of local control can be achieved with WLE if: ○ Clear margins ○ No tumour violation ○ Adjuvant therapy - WLE obviously imparts marked improvement in quality of life over amputation. In general neurovascular structures (careful dissection) and bone can be preserved (rarely invades bone). Amputation may be required if neurovascular or bone involvement - Consider ○ Vascular ○ Joint ○ Tissue plane –bone, periosteum removal, need for prophylactic fixation ○ Reconstruction with plastics - Margins ○ Aim for >10mm visual intra-operative margin § Will be closer at anatomical barriers (fascia, bone, neurovascular bundle) ○ Consider periosteal stripping and neurolysis § Only perform if convincing invasion § Increased risk of toxicity when RT used (fracture or nerve dysfunction) - Lymphadenectomy + SLNB ○ Standard is LN dissection only if proven nodal metastases (not electively) ○ No clear benefit to SLNB § Small reports involving SCARE histopathology demonstrating uncertain results
Inadvertant sarcoma surgery management:
- Often smaller subcut tumours with inappropriate skin incision (transverse)
- Residual gross disease 25-75%
Treat with neoadjuvant RT and LSS = gives similar outcomes
Discuss chemotherapy use in management of extremity sarcoma
Chemotherapy
Chemo controversial – generally doxorubicin based for more advanced tumours
Adjuvant chemotherapy (Doxorubicin+ifosfamide)
- Uncertain role for adjuvant chemotherapy (default is NO)
○ Decision to be individualised based on patient and tumour factors
○ Best benefit in G3 to reduce local recurrence +- OS
- Conflicting evidence ○ Meta-analysis of 18 RCTs and 1953 patients (Pervaiz, 2008) § Improved LR (OR 0.73) § OS advantage also proven (OR 0.56) ○ Pooled analysis of 2 EORTC trials (Le Cesne, 2014) § Much larger than the other trials (819 patients) § No OS benefit demonstrated in overall group □ Trend to OS benefit if R1 resection (HR 0.64; p=0.048)
Neoadjuvant
- No clear role for neoadjuvant chemotherapy
○ Phase II EORTC trial
§ 150 patients randomised to doxorubicin/ifosfamide vs surgery alone
§ No OS advantage
Discuss alternative management options to surgical resection for extremity sarcoma
1) Amputation
a. Remains a curative option when limb-sparing surgery is not necessary
b. This would mean that in the absence of positive margins, there is no role for adjuvant radiotherapy
2) Isolated limb perfusion chemotherapy a. This is an approach with considerable response and limb salvage rates in unresectable STST b. Technique i. Access primary artery and vein of limb, before placing a proximal pneumatic tourniquet ii. Infusion of doxorubicin 3) Definitive RT a. Aim for doses >70Gy as tolerated by OARs b. Reasonable local control achieved (LC decreases as volume increases) 4) Palliation 5) Recurrent and metastatic disease * Lung most common sites of mets (50% chance or recurrence of extremity sarcoma in the lung) * Local recurrence at the surgical scar/operative bed * If isolated local recurrence or isolate lung mets --> resection --> ? Either neoadjuvant or adjuvant chemoRT * If unresectable or multiple mets --> doxorubicin chemotherapy
Describe the treatment paradigm for extremity sarcoma based on stage.
Literature supports sarcoma centre (>10 cases per year)
-Improved patient outcomes
-MDT and clinical trials
-Whoops procedures (Accidental excision, inappropriate skin excision/seeding)
-aim for Limb salvage surgery +- RT
Mx SUM
* Stage I < 5c cm, G1 ○ Surgery WLE -> R1/R2 re-reesct or Adj RT * Stage II-III >5cm, G2-3 ○ Preop RT 50Gy/25F or Postop RT 60Gy/30F (66Gy if R1, 70Gy if R2) ○ mEilber technique pre-op 36Gy/20F BD- no diff in LC, PFS, or toxicity compared to std preop- but less acute postop comlications rates * Stage IV Resect primary, chemotherapy, target therapy- immunotherapy
Subtypes chemo/RT
* myxoid liposarcoma is exquisitely sensitive to radiotherapy
○ Continue with standard dose
○ Dose reduction is experimental only at this stage (DOREMY trial - 36Gy/18F, 79 patients)
○ Tumour volume can shrink dramatically during RT
* Doxorubicin as single agent chemo ○ Doxorubicin is regarded as first-line treatment for liposarcoma ○ Addition of ifosamide improved response in liposarcoma and leimyosarcoma * Taxanes first line choice for angiosarcoma, reserving doxorubicin +ifosfamide for second line treatment
Describe the evidence to support the efficacy of radiotherapy in management of extremity sarcoma
Addition of Radiotherapy
- 1982 NCI study randomised patients to amputation + chemo, or limb salvage surgery + 60-70Gy RT + chemo: ○ No OS survival difference ○ More local recurrences in limb salvage surgery + RT arm - 2x RCTs - Pisters, 1996 and Yang, 1998 § Adjuvant post-operative radiotherapy was delivered (Pisters = BT and Yang = EBRT) § Improvement in local control (without OS benefit) Surgery alone vs. Surgery + RT: Yang (JCO 1998;16:197) Low grade randomised to obs vs post op EBRT. High grade randomised to postop chemo vs post-op chemoRT ○ RT: 45Gy large field à boost to 63Gy. 140 pts, resectable extremity STS. WLE vs. WLE + RT. ○ Marked ↓in LR: High grade – 22% vs. 0% (SS) Low grade – 33% vs. 4% (SS) ○ No OS difference. No relapses in any patient with margin > 1cm. ○ Toxicity of lymphoedema, joint stiffness. Pisters MSKCC (JCO 1996): 160 pts with extremity and superficial trunk sarcoma. Treated with WLE and randomised to brachy (Ir-192 to 42-45Gy over 4-6 days) vs observation - RT to tumour + 2cm margin - Brachy increased LC for high grade tumours but not low-grade lesions LC 80-90% vs 65% (SS) - No diff in DSS or DM - Disease specific survival 80% (NS) - 1x NCDB study (Kachare, 2015) - 2600 patients with stage III sarcoma - RT associated with 5% improvement in 5yr OS (p = 0.01)
Describe the evidence comparing neoadjuvant to adjuvant radiotherapy in extremity sarcoma.
Neoadjuvant vs Adjuvant radiotherapy
- SR2 - Phase III RCT (O'Sullivan, 2004) - 190 patients randomised to pre vs post-op RT - Outcomes § Local control, PFS and OS rates were all unchanged. □ However, LC affected by surgical margin, OS/DFS effected by grade and size. § Acute wound complications worse in neoadjuvant group (35% vs 17%) § G3+ late toxicity is worse in the adjuvant group (36% vs 23%) § 2yr FU, ↑ late toxicity with post-op RT (30% vs 50%, p0.07): ↑ fibrosis, joint contractures, necrosis (85% vs. 70%). § No diff in QoL or functional outcomes. Pre-op RT may reduce seeding during surgical manipulation of tumour. Pseudocapsule may thicken and become acellular, easing resection and reducing risk of recurrence
Smaller CTV trial for neoadjuvant
Phase 2 RTOG 0630 neoadjuvant RT 50Gy with image guidance
CTV for <8cm tumour =2cm longitudinal, 1cm radial
>8cm= 3cm longitudinal, 1.5cm radial
3.6year FU: 94% 2 year local control, late toxicity 10%
Likely will become standard with more followup
Radiation deintensification
- DOREMY ph2
- Phase 2 36Gy/18F neoadjuvant RT for myxoid liposarcoma with less round cells
- 25 months –no local relapse, improved wound complication 17%, 14% late toxicity
- Summary: efficacious and safe
Hypofractionation
- 2014 study: 25Gy/5# single arm -wound 32% complication, local control 81% (low)
- Only 40Gy eqd2
- 2020: 30Gy/5# 50pt wound complication 32%, local control 94%
- 2022 42.74/15# local control 93% (120pt)
Late Toxicity: fractures, skin ulceration, lymphedema –data still maturing
Describe the evidence for limb sparing surgery in extremity sarcoma.
- Landmark RCT (Rosenberg, 1982)
- 43 patients randomised to amputation or limb-sparing RT with adjuvant RT
- Outcomes
§ Slight increase in LR (p=0.06)
□ No difference when adjusted for surgical margin
§ No difference in DFS or OS
Describe the neoadjuvant radiotherapy technique for extremity sarcoma
Neoadjuvant
Patients
Prior to oncological resection
- preferred for most patients
-more wound healing complications (35 vs 17% for adjuvant)
Pre-simulation
MDT discussion
Fertility discussion
Aim to commence surgery at 3-4 weeks post RT
Simulation
Supine in vacbag
Mark biopsy site
Position as appropriate
- separate tissues (e.g. avoid contralateral leg, trunk, head)
eg. frog leg the contralateral leg (straight is more reproducible)
-separate the thighs eg. wedge
- minimise creases
- anticipate beam angles
-reproducible immobilisation, prevent rotation
No bolus (skin will be resected)
Generous CT (2mm with IV contrast)
Fusion
MRI (T1 GAD and T2 FLAIR)
FDG-PET (if performed)
Dose prescription
Standard
- 50Gy/25F
Modified Eilber
- 30Gy/20F BD
- doxorubicin infusion 72 hours prior
Consider HypoFx on clinical trial or in situations where conventional is not possible (d/w pt absence of long term FU data)
VMAT technique
10 days per fortnight
Volumes
GTV = visible macroscopic disease (T1-GAD)
CTV = GTV + 15mm radial and 30-40mm craniocaudally
- Respect anatomical boundaries
- Include biopsy tract
- Include T2 FLAIR signal (peri tumoral oedema)
PTV = 7mm
Target Verification
Daily CBCT
OARs
Spare strip of skin at least 2cm
Bone –lower fracture risk if
* Dmax<59
* Mean <37
* V40<64%
Depends on location of tumour.
Testes (50% < 3Gy)
(lung V20 < 20%)
fem neck (V60 < 5%)
SC < 45Gy
kidneys (50% < 14Gy)
ovary (?)
brachial plexus < 60gy in 33#
Haas paper (sarcoma): Bone—Max dose <60Gy, Mean dose <45Gy, V40 < 64%
Describe the adjuvant radiotherapy technique for extremity sarcoma
Adjuvant
Patients Adjuvant after resection
- concerns for wound healing
- “oops” unintended resection
Pre-simulation MDT discussion
Fertility discussion
Simulation
Supine in vacbag
Mark biopsy site and surgical scar/drain sites
Position as appropriate
- separate tissues (e.g. avoid contralateral leg)
- minimise creases
- anticipate beam angles
Generous CT (2mm with IV contrast)
Fusion Pre-op MRI (T1 GAD and T2 FLAIR)
FDG-PET (if performed)
Dose prescription
2 Phases sequentially
Phase 1: standard = 50Gy/25F to tumour bed + surg bed
Phase 2: Sequential Boost to tumour bed only
Dose Levels
- no residual = 10Gy/5F
- microscopic residual = 16Gy/8F
- macroscopic residual = 20Gy/10F
VMAT technique
10 days per fortnight
Volumes
CTV50 = tumour bed (clip/preop GTV) + 15mm radial and 30-40mm craniocaudally
- Respect anatomical boundaries
- Include operative field (surgical scars and drain sites)
CTVboost = tumour bed clip/preop GTV) + 15mm radial and 20mm craniocaudally
PTV = 7mm
Target Verification
Daily CBCT
OARs
Spare strip of skin
Bone –lower fracture risk if
* Dmax<59
* Mean <37
* V40<64%
Depends on location of tumour.
Testes (50% < 3Gy)
(lung V20 < 20%)
fem neck (V60 < 5%)
SC < 45Gy
kidneys (50% < 14Gy)
ovary (?)
brachial plexus < 60gy in 33#
Haas paper (sarcoma): Bone—Max dose <60Gy, Mean dose <45Gy, V40 < 64%
Describe the prognosis and follow up for extremity sarcoma.
International studies suggest that focussing adult-onset sarcoma treatment to specialist centres contributes to improved patient outcomes
-Allows for MDT approach and involvement of clinical trials
Follow-Up
- Consider referral to: ○ Physiotherapist to ensure ROM and function maintained ○ Lymphoedema clinician - Clinical review every three months for the first 2 years (shared care with sarcoma surgeon) ○ Clinical examination ○ MR imaging every six months ○ CT Chest every six months - Clinical review every six months for years 3-5 ○ Clinical examination ○ MR imaging every twelve months CT Chest every twelve months
Describe the epidemiology and risk factors for retroperitoneal sarcoma.
Incidence (Australian statistics)
- 2000 cases annually
- By subtype:
○ Leiomyosarcoma (20%)
○ Undifferentiated pleomorphic sarcoma (16%)
○ Liposarcoma (10%)
○ Dermatofibrosarcoma (7%)
○ Rhabdomyosarcoma (4%)
○ Angiosarcoma (4%)
○ Synovial sarcoma (3%)
Retroperitoneal lesions are uncommon within STSs (15% of all STSs)
- Most commonly: Liposarcoma (40%), LMS (25%), then UPS
- DDX:
○ Desmoid
○ Germ cell tumour
○ GIST
○ Lymphoma
Broad age range (typically 55-65yo)
Approximately equal incidence in males and females
Aetiology
Limited evidence for environmental causes
1) Previous radiotherapy 2) Familial/genetic factors a. TP53 (Li Fraumeni) b. APC (Gardner syndrome / FAP) 3) Chemical carcinogens a. Thorotrast b. Arsenic
Special cases
- HHV8 –> Kaposi sarcoma
- Lymphoedema –> lymphangiosarcoma
- NF1 mutation –> MPNST
Describe the pathology for Leiomyosarcoma.
Leiomyosarcoma
- Accounts for 15-20% of soft tissue sarcomas
○ Female predominance
○ Typically a tumour of adults
○ Complex chromosomes: loss in chromosomes 10q(PTEN) and 13q (RB1) and gain at 17p (TP53)
- Occurs in the deep tissue of the extremities or the retroperitoneum
○ May arise from the IVC (particularly poor prognosis)
○ Clinically aggressive neoplasms with frequent local recurrences and distant metastases
- Macroscopic ○ Low-grade = hard mass with a white whorled cut surface ○ High-grade = softer with necrosis/haemorrhage/cystic degeneration on cut surface - Microscopic ○ Fascicular pattern --> cells are arranged in interweaving fascicles § Eosinophilic spindle cells with cigar-shaped hyperchromatic nuclei § Mitoses are common, pleomorphism, necrosis and focal fibrosis ○ Tumour often merges with blood vessel wall - Immunohistochemistry ○ POS = Vimentin, Desmin, HHF35 (muscle-specific actin), SMA ○ NEG = CD117 - Molecular ○ Complex molecular mutations
List the common subtypes of retroperitoneal sarcoma.
Histopathology (retroperitoneal)
Common retroperitoneal tumours
- Liposarcoma (60%)
- Leiomyosarcoma (20%)
- Undifferentiated Pleomorphic Sarcomas
- Malignant Peripheral Nerve Sheath Tumour
Describe the pathology for liposarcoma.
Liposarcoma
- Most common type of sarcoma in adults (median age 65 years)
- Typically involves the deep tissue of the proximal extremity or retroperitoneum
- Subtypes ○ Intermediate risk = well-differentiated liposarcoma ▪ Lipoma ▪ Sclerosing -bands ▪ Inflammatory –plasma, lymphocytes - Biological behaviour: Behavior is dependent upon location, with deep seated lesions having the ability to dedifferentiate and subsequently metastasize * Resection is curative * site * Spread * speed ▪ ○ High risk = de-differentiated, myxoid and NOS ▪ Progression to other type of sarcoma (well diff may not be identifiable) -can look like any sarcoma including solitary fibrous. Retains MDM2. ▪ Most in RP (not limbs) ▪ Grade matters, 20% distant mets - Macroscopic ○ Large, firm mass with coarse lobulations § Well differentiated may be softer and more fat-like ○ De-differentiated component may be discrete or gradual ○ Necrosis common in high-grade areas - Microscopic ○ Well-differentiated § Mature adipocytes with scattered atypical spindle cells –variation in size § Associated bands of fibrotic stroma § Cam have lipoblasts ○ De-differentiated § More cellular and non-lipogenic (but also can be lipogenic or any other sarcoma) -can be nodular or graduated, surrounded by well differentiated tumour § Marked pleomorphism with increased mitotic rate § 5% may have heterologous sarcomatous components § BB: * Site most common in retroperitoneum. Also can occur in spermatic cord. Not in subcut tissue * High rates of local recurrence (slow), and risk of metastasis ○ Myxoid –small cells, fine vessels ○ Pleomorphic liposarcoma –MDM2 negative § Necrosis, high mitosis - Immunohistochemistry ○ POS = MDM2, CK4, p16, S100 ○ NEG = HMB45 - Molecular ○ Liposarcomas tend to have MDM2 gene amplification in 99% § Ring chromosome § Other sarcomas may also demonstrate (e.g. MPNST, parosteal osteosarcoma, sclerosing RMS) ○ Myxoid liposarcoma has a characteristic t(12:16) translocation - Vs lipoma (rare in retroperitoneum) ○ Lipoma not uncommon to have some sclerosis or fat necrosis ○ If deep, growing, recurrence, size >10cm: MDM2 (via FISH)
Describe the evidence for management of retroperitoneal sarcoma.
- Randomised trial (x1)
STRASS 1/EORTC 62092—RCT. 266pts RPS (75% liposarc)->
En bloc surgery +- randomised Neoadjuvant RT 50.4Gy/28
§ Nil sig diff in 3yr abdo RFS ~60% and median RFS ~5yr.
▪ Too unwell for operation, tumour inoperable, peritoneal disease or R2 resection
§ Overall no benefit to neoadjuvant radiotherapy
§ Not pre-planned subgroup analysis by subtype & grade—Preop RT improves local recurrence in LG Liposarc and LG RPS (3yr abdo RFS 60-> 72% HR 0.64, 3yr DMFS ~78%) but NOT leiomyosarcoma & HG RPS (eg HG pleo or HG liposarcoma).
§ Marked increased in serious AEs w/ RT (10-> 24%).
§ 15 of 19 pts who progressed on RT had macroscopically complete resection. 3 developed DM
§ Criticism: unusual 1o endpoint -abdo RFS (included DM, which would exist prior to def tx), short MFU (43mo) and subgroup analysis demonstrate benefit in liposarc grp.STRASS 2—assessing role of NAC for HG DD-LS and LMS.
doxorubicin or epirubicin hydrochloride [epirubicin] with ifosfamide or dacarbazine
ACOSOG Z9031 “A randomized trial of preoperative radiation plus surgery versus surgery alone for localized primary retroperitoneal soft tissue sarcoma” Goal: accrue 370 pts in 4.5 yrs, primary outcome PFS at 5 yrs, closed early, in 2006. Awaiting results publication –> still waiting (2019) - Retrospective Data
○ NCDB study (Nussbaum, 2016)
§ 563pts, comparing survival of RPS pts receiving preop RT vs surg alone OR postop RT vs surg alone
§ MS is sig longer w/ preop RT (MS 110mo vs 66mo, HR 0.7).
§ MS is sig longer w/ postop RT (MS 54mo vs 47mo, HR 0.78).
There is a suggestion of 5yr OS benefit of 8% in both post- and pre-op RT. Improved OS (HR 0.70)
List the subtypes of bone sarcoma.
Histopathology (malignant)
1) Osteosarcoma 2) Ewing's sarcoma 3) Chondrosarcoma 4) Chordoma
Describe the pathology for chordoma.
Describe the staging for bone sarcoma.
Ewing Sarcoma
- No commonly used staging systems - Just note localised or distant metastases
Describe the prognosis and follow up for Ewing’s sarcoma
Follow-Up
Clinical review every 3 months for the first 2 years
- CT imaging of the primary site
- Chest imaging (CXR or CT Chest)
- Consider PET-CT every twelve months
Clinical review every six months for years 2-5
- CT imaging of the primary site
- Chest imaging (CXR or CT Chest)
Annual review thereafter
- CT imaging of the primary site
- Chest imaging (CXR or CT Chest)
Describe the prognosis and follow up for Osteosarcoma
Follow-Up
Clinical review every 3 months for the first 2 years
- CT imaging of the primary site
- Chest imaging (CXR or CT Chest)
- Consider PET-CT every twelve months
Clinical review every six months for years 2-5
- CT imaging of the primary site
- Chest imaging (CXR or CT Chest)
Annual review thereafter
- CT imaging of the primary site
- Chest imaging (CXR or CT Chest)
Describe the pathology for desmoid tumours
- Macroscopic
○ Typically large (5-10cm) masses with variable circumscription
○ Cut surface = firm, white and gritty (appears like a scar)- Microscopic
○ Long fascicles of elongated spindle cells of uniform appearance
○ Abundant collagenous stroma
○ Minimal nuclear atypia and low mitotic rate - Immunohistochemistry
○ POS = SMA, Vimentin, Cyclin D1, beta-catenin
○ NEG = S100, CKs, MUC4, DOG1 & cKIT (GIST) - Molecular
○ CTNNB1 (beta-catenin gene) mutation found in 90%
APC gene mutation found in FAP patients
- Microscopic
Describe the staging for desmoid tumours.
Describe the prognosis and follow up for desmoid tumours.
Prognosis
Cause-specific death is low (1% in sporadic cases)
Prognosis is worse in:
- Intra-abdominal tumours
- Associated with FAP (up to 10% die as a result of desmoid)
Follow-Up
- Should be seen every six months for the first two years to establish growth pattern
○ CT imaging every six months
- Consider reducing follow-up to every twelve months thereafter
○ CT imaging every twelve months
