Sarcoma

DEFINITION
Soft tissue sarcomas are uncommon malignant tumours arising from mesoderm-derived tissue (fat, muscle, c.t., vessels).
Cf bone and cartilage sarcoma.
Peripheral nerve sheath tumours are usually included as STS despite being ectodermal.

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EPIDEMIOLOGY

Incidence

Rare
Age
Any; median 50y
Gender
M=F

Risk factors
Vast majority are simply sporadic
Personal
Radiation exposure
- risk increases with dose and time
- angiosarcoma most common post-breast radioRx
- but rare; actuarial rate 0.2% in 15-20y after any full dose cancer radiotherapy
- higher in children
Chemotherapy also increases risk
Trauma is rarely a factor except desmoid tumours
- but recent trauma may bring attention to underlying mass
Familial
Genetic syndromes:
NF1 (15% risk of malignant peripheral nerve sheath tumour)
- and increase risk of GIST
Gardner syndrome (APC gene defect); increased risk of intra-abdominal / mesenteric desmoid tumours.
Hereditary retinoblastoma
Li-Fraumini syndrome
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AETIOLOGY

Mesodermal-derived malignant tumour
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BIOLOGICAL BEHAVIOUR

Pathophysiology

Heterogeneous with respect to anatomical distribution, histologic subtype and clinical behavior.

Distribution
Throughout body
- 50% on extremities
- 1/3 in abdo / pelvis
--> includes visceral sarcomes (leiomyosarcoma and gist) vs retroperitoneal (15%)

Histological Subtypes
50 subtypes exist
Most common:
- malignant fibrous histiocytoma (MFH)
--> myxofibrosarcoma and undifferentiated pleomorphic sarcoma.
- dermatofibrosarcoma protuberans
- liposarcoma
- leiomyosarcoma
- synovial sarcoma
- fibrosarcoma
Retroperitoneal 2/3 liposarcomas or leiomyosarcomas; rest v. mixed

Behaviour
Unique properties depend on subtype
But generally considered low-grade, intermediate-grade and high-grade.
- Low grade --> grow slowly, may recur locally, and have low risk of distant mets (<5%)
- High grade --> grow rapidly, recur locally, and added risk of distant mets (50% if large ie 8-10cm)
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MANIFESTATIONS

Given histological variability / many subtypes of 'sarcomas', workup and treatment can be confusing and quite challenging.

Extremity Sarcoma


Generally a painless mass felt for weeks to months
Pain or tenderness can precede detection.
Later oedema, neuropathy due to infiltration or pressure

Exam
Inspect mass
Note status of overlying skin
Neurovascular limb status
Presence of distal oedema

Retroperitoneal Sarcoma

Frequently asymptomatic until large
Often picked up incidentally.
May develop a mass or symptoms from compression or invasion of gut, nerves.

Differentials
Primary germ cell tumours
Malignant testicular tumours
Lymphoma

Dermatofibrosarcoma Protuberans
Second most common sarcoma
SLow growing red plaque on trunk in pts 30-40y old usually
- histology shows low-grade spindle cell tumour that stains for CD34 and unbalanced gene translocation on c22
Image with CXR; distant mets uncommon
Classifally there is subcliinical disease extending beyond visibly involved skin
--> treat with WLE and frozen section; typically to 3cm margins
Mohs reduces local recurrence substantially
Involved margins --> reecision
Radiotherapy if close or involved margins cannot be re-excised
Most local recurrences occur in first 5y; 25% beyond that
--> long term f/up.

Karposi Sarcoma
Most common skin sarcoma
HHV-8 (human herpes virus) infection; slow growing painless vascular appearing lesion on skin
- often face or groin
- often HIV or immunosuppressed
Biopsy the area
- confirm diagnosis and exclude bacillary angiomatosis
Solid organ disease excluded with FOB and CXR
Treatment is to optimise HIV with antiretrovirals
- then intralesional vinblastine or radiotherapy if local
- add doxorubicin if advanced

AngioSarcoma
Rare skin tumour; rapidly growing vascular lesion
- ulcerates and shows satellite nodules
- head and neck in the elderly and male.
Operate to wide margins (2cm), with reconstruction
Post op radiotherapy required
Prognosis is still poor; 20% 5y survival
Significant proportion already unresectable at presentation
- then do induction chemo (paclitaxel or doxorubicin) followed by surgery and radiorx
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INVESTIGATIONS

Bloods

Routine FBC and biochem panel
There are no specific tumour markers for STS.

Imaging
CT and / or MRI
MRI most useful for extremities
In retroperitoneum:
- characteristically may have large areas of abnormal fat (well differentiated liposarcoma)
- sometimes with higher density nodules (de-differentiated liposarcoma)
Staging
Chest CT for high-grade lesions
CXR probably ok alone for low-grade tumours
PET role as-yet undefined
- but most do show increased fluorodeoxyglucose uptake

Biopsy
Essential to establish a histologic diagnosis and to determine the definitive treatment strategy.
Core needle biopsy usually sufficient.
- palpable lesions can be biopsied in clinic under local anaesthetic
- deep tumours require image-directed core-biopsy; can guide toward solid regions in heterogeneous tumour mass.
- CT guided biopsy for retroperitoneal tumours
Open biopsy reserved for unusual cases when core-biopsy inadequate.
- orient these biopsies longitudinally so can incorporate in final dissection
- minimize bleeding and surrounding tissue contamination.
FNA can confirm metastatic or recurrent tumour when primary diagnosis already established
- but FNA inadequate for primary diagnosis
Note:
Need pathologists experienced in these tumours; 1-% are not STS, 20% assigned incorrect subtype.
- 10% may be misdiagnosed and 20% assigned wrong type

Staging
Task force of AJCC
Extension of TNM system to include G for histologic grade.
Determined on grade, size, depth, nodal or distant mets.

Grade
Histologic features
Cellularity, differentiation, pleomorphism, necrosis, mitotic activity.
Common to assign as grades 1-3.
- low, intermediate and high.

Tumour
TX = cannot assess
T0 = no tumour
T1 = <= 5cm in greatest dimension
T1a = superficial tumour
T1b = deep tumour
T2 = >5cm in greatest dimension
T2a = superficial tumour
T2b = deep tumour

Nodes
NX = cannot assess nodes
N1 = no regional nodes
N2 = regional nodes

Mets
MX = cannot assess distant mets
M1 = no distant mets
M2 = distant mets

Stage
IA =  G1, T1, N0, M0
IB =  G1, T2, N0, M0
IIA = G2-3, T1, N0 M0
IIB G2, T2, N0-1, M0
III G3, T2, N0, M0
IV Any G, Any T, Any N, M1

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MANAGEMENT

Principles

1. MDT management

Multi-modal therapy typically essential, so surgeons, rad and med onc involved from outset.

2. Rx specific to anatomic location.
- extremity and trunk tumours can generally be considered together
- retroperitoneal tumours separately
- GIST also separately

EXTREMITY SARCOMA

Surgical Therapy

1. Commonly surrounded by a pesudocapsule
- if they are shelled out recurrent rate is 90%.
Need more radical resection with a margin of normal tissue
- reduces recurrence rate to 10-30%.

2. Grow close to nerves, vessels and bones.
- used to be that amputation was the norm.
Revolutionized in 1982 by RCT showing equal outcome with limb sparing.
- now limb sparing in >90%; overall local recurrence rate <10% with adjuvant radiotherapy.

3. Preoperative imaging is critically important
- extent of tumour penetration
- relationship to vital structures
- need for vascular, reconstructive involvement.

4. Incisions should be longitudinal
- should extend beyond the beginning and end of the tumour.
- must take overlying subcut fascia and skin if reqd to achieve the margin

5. Can raise subcut flaps at Scarpa level
- then track past tumour, going deeper into fascia.
- it can be difficult to know where the tumour border is

6. Obtain a 2cm margin.
- if achievable without severe morbidity.
- work with non-dominant hand at edge of tumour.
- nb that some normal tissues like fascia probide better quality margin than fat and muscle.
--> thus a 1 mm margin to fascia may be ok, but be concerned if a close margin is next to fat or muscle.
- know that STS does not usually invade peri-adventitial tissue of arteries, peri-neurium or periosteum.
--> can dissect to these barriers to obtain negative margins.

7. Work to Histology
- e.g. an atypical lipoma has a relatively low recurrence with a positive microscopic margin
--> so don't need to be aggressive.
- but cutaneous angiosarcomas are highly irregular and infiltrative so aggressive surgical resection (and radioRx) essential)

8. Careful wound closure lowers complication rates
- handle skin and subcut tissue with care to avoid trauma.
- used closed-suction drains liberally
- wraps, extremity elevation, limited activity all decrease oedema and fluid accumulation.
For large defects, rotational and free flaps and skin grafts may be needed.
RadioRx doubles wound complication rates.
- reduces ability of tissues to absorb fluid and delays wound healing.

Adjuvant Therapy

Radio
Vast majority treated with adjuvant radiation; this allows limb-sparing surgery.
Several RCTs support this.
Obviously doesn't affect distant disease, but can dramatically reduce local recurrence rates
Generally external beam, but brachytherapy via catheters post-op or pre op.
- generally brachy reserved for patients with recurrence.
T1a tumours well circumscribed and resected with clear 1 cm margins may not require radio

Timing of radio with regard to resection is a matter of debate
Trials suggest no clear difference wrt to local recurrence.
Wound complications 2x with pre-op
But tissue fibrosis more frequent in post-op.

Difficult problem of T2b tumours.
High recurrence, high met rates.
?Aggressive chemo (MAID - doxorubicin, mesna, ifosfamide, dacarbazine)
Inter-digitated with pre-op radio
?Then post-op MAID.
May achieve overall survival of 70-80%.

Hyperthermic isolated limb perfusion (HILP)?
Vascular catheters inserted and limb isolated by a tourniquet.
- TNF-alpha and melphalan infusion at 38.5-40oC

Role of chemo
High risk metastasis patients
- surgery and radio ok in most; 25-50% with large, high grade STS will benefit from chemo
Doxorubicin and ifosfamid are most active.
- past trials suggested response rates 20-40%
- and that improves survival rates by maybe 10%
But mixed evidence.
--> recent large RCT of adjuvant doxofubicin and ifosfamide vs no chemo showed no impact on survival
Thus chemo often reserved for young high risk patients
Whereas in other centers, chemo is not used.
Consider that side effects are substantial
- doxorubiin - cardiotoxic
- ifosfamid - haemorrhagic cystitis

RETROPERITONEAL SARCOMA

Principals
Complete R0 resection
- quite difficult to achieve; e.g. only in ~60%.
Negative microscopic margins is frequently not achieved and local recurrence rates are high; 40%+
= primary cause of death.

1. Carefully evaluate imaging; as above.

2. Prep colon, and confirm contralateral kidney function.

3. Consider optimal patient positioning and incision
- often modified lateral decubitus
- may need thoraco-abdominal incisions

4. Dissect circumferentially; anterior to posterior.
- can help exposure with judicious bed tilts to move organs.
- don't work into deep holes as vessel injury can have serious implications
- general goal is to aggressively dissect to clear margins, taking involved organs en-bloc
- posterior margin taken under direct vision, sharp dissection to deep margin under direct vision.

5. Accurately orient lesion
- e.g. take lesion to pathologist and discuss.

Adjuvant

Radio
Controversial, again.
It is difficult to deliver high dose radiation to the abdomen, unlike the limb.
Usually preferred pre-op when given.
- margin around tumour at risk of local recurrence more clearly defined, and effective dose lower.
Post-op positive margins treated with a boost radio dose.
The future is intensity-modulated radiation therapy (IMRT), ie. 3D-guidance of rays to image-planning of tumour position.
- can also retract organs out the way and deliver high doses to the field intra-operatively.
Mix of targeted approaches tailored to individual patient context may be most effective.

METASTATIC DISEASE

Median survival is 12m with mets
Extremity -->  lung
Abdominal --> lung and liver.
Lymph nodes = rare; 5% except for certain subtypes including epithelioid sarcoma and synovial sarcoma

Chemo
Response rates are poor <15% with combo therapy, duration 8m on average.
Multi-agent approach = no proven benefit over sequential single agent approach.

Surgical resection can be attempted in highly selected cases.
- isolated lesions; 5-yr survival can approach 20%.


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REFERENCES

Cameron 10th