Editing Soft tissue sarcoma (section)

== '''Common subtypes and treatment''' ==

=== '''Metastases''' ===

** Isolated mets can be resected when feasible

=== '''Extremity or trunk wall STS''' ===

** Proximal limb more commonly affected than distal, with 44% of examples found in thigh
** Imaging alone is rarely diagnostic, with the exception of well-differentiated liposarcoma - these can be directly excised based on imaging
** Others will need biopsy
*** Incisional biopsy: longitudinally-oriented incision in such a way that the incision can be excised when a definitive resection is done.
*** Excisional biopsies are appropriate with lesions <2cm in size and superficial location
** Excision:
*** Two options
**** Amputation
**** Limb salvage (now standard of care)
***** Consider size, grade, type, any adjacent involvement, fitness, future functional capacity of limb going to be better than amputation
***** The margin size is inversely proportional to risk of recurrence
***** Treat margin with radiotherapy in almost all cases
*** The pseudocapsule will be seen as a characteristic plane of thickened tissue that gives the impression of being the interface between tumour and normal tissue. This will seem to be the plane of least resistance during excision. However, that will generally lead to positive margins. Need to go 1-2cm beyond it.
*** Include entire tumour without rupture of pseudocapsule and 1-2cm margin (quantitative definition of what constitutes an adequate margin has never been established)
*** Patients with positive margins should be offered re-resection to a new margin of 1cm
*** Place clips at the boundaries of the resection bed in case adjuvant radiotherapy is needed
*** If margin is positive, radiotherapy will be required
*** Planned positive margins at critical structures can be treated with pre-op RTX, with no change to overall survival
*** Excise skin if it is within margin
*** Superficial tumours involving fascia should include a margin of fascia and maybe underlying muscle
*** Include periosteum as margin
*** Consider involving vascular or plastic surgeons for reconstruction of vessels/nerves
*** Use orientation sutures on specimen
*** Drains may be necessary, especially after neoadjuvant RTX, or in setting of recurrent tumours. If placing a drain, have the skin exit site within a planned radiotherapy field - the whole drain tract will be treated.
** Radiotherapy
*** Limb-sparing surgery requires radiation to treat margin
*** Studies have shown no difference between pre-op and post-op RTX
** Chemotherapy
*** Conflicting data regarding efficacy
*** Consider in those with concerning features - >10cm tumour, deep, high-grade histology, certain higher-risk subtypes
*** Usually doxorubicin/ifosfamide
*** Hyperthermic isolated limb perfusion/infusion has been investigated for locally advanced disease in whom limb-sparing, function-sparing surgery may not be possible
*** Immunotherapies considered as part of a trial

=== '''Retroperitoneal''' ===

** Often >15cm at diagnosis
** Present with pain, weight loss, early satiety, nausea, emesis, back or flank pain, paraesthesias and weakness
** Most common subtypes are liposarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma
** DDx - lymphoma (peripheral lymphadenopathy and constitutional symptoms), primary germ cell tumour, testicular cancer metastatic to retroperitoneal nodes (need testicular examination + AFP and bHCG)
** Imaging alone rarely diagnostic
** Locoregional recurrence is most common pattern, rather than distant
** Patients with complete gross resection have a median survival of 103 months, as opposed to 18 months for patients with incomplete resections. Patients with unresectable tumours have a median survival of 10 months. 
** Biopsy
*** Most retroperitoneal masses should ideally be biopsied prior to treatment, although this is not always necessary
*** The main thing is to exclude major differentials as above - if it's possible to exclude these based on imaging/clinical history, then biopsy may not be necessary
*** Core needle under USS/CT is best - biopsy tract seeding is rare
** Excision is indicated when feasible
*** Needs to be R0 at first attempt - no chance for second attempt. No benefit to incomplete resection since patients with positive margins have the same survival rates as patients who were initially unresectable.
*** If needed, pancreatic tail, spleen, ipsilateral kidney (be sure to assess contralateral renal function), colon and mesocolon and at least a portion of psoas can be safely resected
*** More significant resections would involve vasculature, liver, femoral nerve, diaphragm, duodenum
*** Incision could be midline, oblique, flank or thoracoabdominal
*** Incomplete resection of well-differentiated liposarcomas seems to help regardless of persisting tumour
** Chemotherapy
*** Controversial - better in neoadjuvant setting when it's used
*** Clinical trials a possibility
*** Few effective treatment options for metastatic disease
** Radiotherapy
*** Controversial - not been proven to reduce risk of recurrence, and risk of damage to viscera. The doses given to extremity STS would cause significant bowel toxicity. 
*** Favoured to be done pre-op when used - allows better targeting to posterior structures, can still manage 45Gy, with boosts to projected at-risk margins. Long and short-term oncologic outcomes are favourable.
** Surveillance
*** Continue up to and beyond five years

=== '''Intraperitoneal''' ===

** Most commonly GIST and leiomyosarcoma

=== '''GIST''' ===

** See separate topics, primarily under UGIS

=== '''Leiomyosarcoma''' ===

** Malignant smooth muscle tumour
** Can originate from virtually any body part - most commonly retroperitoneum, peritoneal cavity (uterus); 25% arise from trunk and extremities
** Peak incidence 50-70yo
** Risk factors - radiation, immunosuppression, EBV-related tumour promotion. Does not arise from a degenerated leiomyoma.
** Heterogeneous, well-circumscribed tumour with an often cystic or necrotic central area
** Stains positive for desmin and smooth muscle actin (see table on 'GIST' page). Wide variety of cytopathologic aberrations but no reliable or pathognomic markers
** Treatment
*** First-line: resection with negative margins
**** Uterus - total hysterectomy and bilateral oophorectomy
*** Adjuvant therapy not currently recommended. Mets usually haematogenous, mainly lung and liver. 

=== '''Breast sarcoma''' ===

** Most common - angiosarcoma and phyllodes
** '''Primary angiosarcoma'''
*** Arises in young women
*** Rare vascular tumour (1% of all breast tumours)
*** Forms an ill-defined parenchymal mass
*** Responsive to chemotherapy, but tends to recur once chemotherapy stopped
*** Should have mastectomy as opposed to lumpectomy, and partial pec major resection may be necessary to achieve margins
*** Needs staging with CT CAP and breast MRI
*** No proven benefit from contralateral prophylactic mastectomy
** Secondary angiosarcoma
*** Affects older women, a/w either lymphoedema or breast RTX
*** Cutaneous malignancy as opposed to primary breast angiosarcoma which is parenchymal
*** Purplish vascular proliferation in the irradiated skin
*** Can develop in the ipsilateral arm to surgery - Stewart-Treves syndrome, secondary to chronic lymphoedema (can also be atypical vascular proliferation)
*** If no metastases, needs complete R0 excision (usually mastectomy + resection of all the breast skin)
*** Axillary dissection not required, lymph node metastases are extraordinarily rare
*** Will need extensive reconstruction
*** Adjuvant chemotherapy generally recommended
** '''Phyllodes tumour'''
*** Epidemiology/risk factors
**** Uncommon fibroepithelial tumour
**** Median age 45yo
**** Li-Fraumeni
**** BRCA
*** Pathophysiology
**** Stromal atypia/dysplasia, made up of mixed connective tissue and epithelium
**** Leaf-like papillary projections seen on histopathology
**** Malignant features (two S, two M):
***** Higher degree of stromal cellular atypia
***** Mitotic activity per 10 high powered fields: borderline 4-9, malignant >9
***** Infiltrative margins
***** Presence of stromal overgrowth (i.e. pure stroma devoid of epithelium) - this is the most important feature
**** Metastasises via haematogenous spread - lung, bone, abdominal viscera, mediastinum
**** Recurrence mostly within 2 years
*** Presentation:
**** Clinically firm lobulated mass, average size 5cm, similar to fibroadenoma. Suspect phyllodes with more rapid growth, older patient, and larger size.
**** Mammography - round density with smooth borders, indistinguishable from fibroadenomas
**** USS - discrete structure with cystic spaces
**** CNB is useful, but difficult to accurately assess malignant potential
*** Classification/management:
**** Needs surgery to truly classify, with negative margins
***** Benign phyllodes tumour - 'clear margin' is adequate
***** Borderline/intermediate tumour: excision with negative margins (often suggested to be 1cm margins). 
***** Malignant:
****** Complete surgical excision with a margin of normal tissue - can be WLE or mastectomy
****** Radiation indicated with fascia/chest wall involvement, >5cm size, or only WLE performed.
**** Lymph node biopsy not necessary
**** Systemic therapy has very limited success.
**** Contralateral prophylactic mastectomy not indicated

=== '''Liposarcoma''' ===

** Most common STS subtype. Also represents 45% of retroperitoneal sarcomas.
** Large clinical overlap with lipoma - see separate topic
** Defining mutation is '''MDM2'''
** Histological subtypes
*** Well-differentiated liposarcoma
**** Low-grade tumour with low recurrence rate, no risk of metastatic spread and death unless dedifferentiation occurs
**** Often multifocal
**** Can be resected with negative or limited positive margin in extremities
**** More threatening in retroperitoneum - local control is often difficult - patients often die of locoregional failure with no mets
**** Resistant to radiotherapy and most chemotherapy
*** De-differentiated liposarcoma
**** De-differentiated liposarcoma can metastasise more commonly
**** Can be differentiated from well-differentiated liposarcoma fairly well on imaging - hypervascularity, areas of necrosis or cystic change, adjacent organ invasion, areas of focal nodularity or water density
**** Consider adjuvant radiotherapy
*** Pleomorphic liposarcoma
**** Commonly arises in extremities
**** Poor prognosis
*** Myxoid liposarcoma
**** Commonly arises in extremities
**** Very sensitive to CTX and RTX - often neoadjuvant will shrink it
**** Propensity to metastasise to unusual sites including paraspinal tissue
**** 10-year disease-specific survival of 87%
** Treatment approach
*** Extremity - goal is limb-sparing resection with a negative surgical margin
*** Retroperitoneal - need a gross complete resection. Some suggest 'complete compartmental resection' - frequent multi-visceral resections. 
*** Recurrence - resect if growth is <0.9cm/month, otherwise palliative chemotherapy

=== '''Malignant fibrous histiocytoma''' ===

** A now-defunct term - now these are called unclassified or undifferentiated pleomorphic sarcoma

=== '''Dermatofibrosarcoma protuberans''' ===

** Superficial tumour that infiltrates soft tissue for centimetres beyond the obvious margins of the lesion and can recur locally after inadequate resection
** Pathogenesis relates to chromosomal translocation leading to abnormal fusion protein COL1A1-PDGFB
** Usually involves dermis and subcutis
** Usually fairly low-grade, metastases uncommon
** Surgery - need negative margins. Frozen section doesn't work because the fat doesn't freeze well for analysis!
** Usually superficial tumour, so deep resection of muscle is not generally necessary
** Radiotherapy can be used for positive or close margins, or for unresectable recurrences
** Imatinib can be effective adjuvant therapy
**

=== '''Myxofibrosarcoma''' ===

** Invades through soft tissue and fascia, moving centimetres beyond the ostensible margins
** Most common in extremities of elderly people
** Needs aggressive local therapy with 2-4cm margins beyond palpable mass
** Consideration of RTX

=== '''Angiosarcoma general''' ===

** Rare and aggressive
** Derived from blood or lymphatic vessel endothelium
** Sensitive to systemic chemotherapy
** 40% associated with previous radiation
** Higher frequency of involved regional lymph nodes
** '''Angiosarcoma of scalp'''
*** Predominantly elderly white patients
*** Smooth, firm or spongy subcutaneous growth that develops a violaceous erythema similar to a bruise
*** Insidious
*** Commonly multifocal, with skip areas of normal skin
*** Surgery is rarely curative, should not be considered first-line therapy. Reserved for patients who are experiencing problems with local control (bleeding from a fungating tumour) or who only appear to have a solitary site of disease
*** Attempt a gross margin of 2cm
***

=== '''Radiation-induced sarcoma''' ===

** High propensity to recur

=== '''Malignant peripheral nerve sheath tumours''' ===

** Malignant form of benign schwannoma
** Previously known as malignant schwannoma, neurogenic sarcoma and neurofibrosarcoma
** Either sporadic or in a/w NFT1 - roughly equal proportions
** Generally painless, presenting 20-50yo
** Generally aggressive
** Wide margins - aim 4cm of macroscopically healthy nerve
** Frozen section useful
** Adjuvant radiotherapy is generally indicated

=== '''Desmoid fibromatosis''' (aka desmoid tumour, fibromatosis, aggressive fibromatosis) ===

** Non-metastatic neoplasm but aggressive locally
** Can be a/w FAP/Gardner syndrome/Turcot syndrome, concurrent with a pregnancy (often stabilises post-partum), or sporadically
** Pathophysiology
*** Clonal proliferations of myofibroblasts - well-differentiated bundles of spindle cells with abundant collagenous matrix
*** Often indolent tumours which show no growth after presentation
*** Sporadic (75-85%):
**** Associated with mutations of CTNNB1 gene -> beta-catenin accumulation and nuclear effects including proliferation
**** Can occur after surgery, trauma, pregnancy, OCP use
**** Those occurring in pregnancy have a good prognosis, and can usually be monitored throughout pregnancy
*** Associated with FAP:
**** 10-15% of patients with FAP will develop a desmoid tumour, mostly within mesentery or abdominal wall, at the site of the scar
**** Caused by germline APC mutations -> beta-catenin accumulation and nuclear effects including proliferation
**** Aggressive, often involving mesentery, occasionally encasing mesenteric vessels
** Workup
*** MRI or CT - homogenous and solid - indistinguishable from other STS subtypes
*** Diagnosis established by core biopsy, if tumour histology will alter treatment
** Management
*** Primary non-operative management, especially for tumours in difficult locations, due to the high risk of local recurrence and possibility of regression (20-30%)
*** Systemic therapies should probably be trialled prior to surgery
**** Nirogacestat - oral gamma secretase inhibitor
**** Tyrosine kinase inhibitors - sorafenib
**** Cytotoxic chemotherapy can be used for locally aggressive or symptomatic tumours
**** It's unclear whether NSAIDs and hormonal therapies are effective
*** Radiotherapy can be used for extremity tumours, or other locations without other good treatment options
*** '''Asymptomatic or mildly symptomatic:'''
**** Initial active surveillance (imaging every 3-6 months)
*** '''Moderately or severely symptomatic:''' 
**** ''Depends on FAP status, location, toxicity of therapy, and desired urgency of response''
**** FAP - usually trial systemic first
**** Sporadic
***** Abdo wall - resection and reconstruction
***** Other location - prefer systemic therapy first
*** '''Imminent threat to life (e.g. bowel obstruction):'''
**** Surgery, if resectable
*** '''Recurrent/relapsed disease:'''
**** Surgical resection +/- adjuvant radiotherapy as salvage
** Prognosis
*** 30% spontaneously regress
*** Sporadic abdo wall desmoids do have a good surgical outcome though

=== '''Kaposi sarcoma''' ===

** Low-grade soft tissue malignant neoplasm
** Arises from lymphatic vascular endothelial cells in the skin
** Most often seen with AIDS and other immunosuppressed states
** Caused by human herpesvirus 8
** Most effective treatment in AIDS patients is aggressive antiretroviral therapy
** Symptomatic skin lesions can be treated with radiation, intralesional injection of chemotherapeutic agents, cryotherapy or excision
**