Soft tissue sarcoma

Epidemiology
Rare: only 8300 new cases annually in U.S. 1/2 die

Because they are rare=> no clear recommendations for every clinical situation (lack of many phase III studies)
Mesodermal origin

Risk factors
Radiation therapy Chemical exposure
Thorotrast, vinyl chloride, arsenic for hepatic angiosarcoma

Genetic syndromes
Neurofibromatosis nerve sheath tumors Familial gastrointestinal stromal tumor syndrome KIT mutation

Classification
By site
-viscera (gastrointestinal, genitourinary, and gynecologic organs) -nonvisceral soft tissues (muscle, tendon, adipose, pleura, and connective tissue)

By histology

Topography vs. histology

Classification-by genetics
I. Specific mutations (usually translocations)-1/3 of all sarcomas

II.

No specific mutations

Symptoms
Most present as painless mass leading to delayed diagnosis (DD with lipoma or hematoma)

Diagnosis
Core needle biopsy guided by palpation or by image guidance if not palpable
Few cases of tumor seeding with closed biopsy so some recommend tattooing site for later excision with specimen

Excisional biopsy for superficial small lesions if needle biopsy non-diagnostic Incisional biopsy
Longitudinal incision without tissue flaps with meticulous hemostasis to prevent tumor seeding in hematomas Send biopsy fresh and oriented

Tumor seeding after biopsy

Diagnosis (2)-Imaging
MRI
For extremity masses Gives good delineation between muscle, tumor and blood vessels

CT might be used for abdominal and retroperitoneal masses,

although MRI is better

PET
May help determine high vs. low grade May be helpful in recurrences

Staging
AJCC/UICC Staging System for Soft Tissue Sarcomas
T1: <5cm
T1a: superficial to muscular fascia T1b: Deep to muscular fascia

T2: >5cm
T2a: superficial to muscular fascia T2b: Deep to muscular fascia

N1: Regional nodal involvement Grading

G1: G2: G3: G4: Well-differentiated Moderately differentiated Poorly differentiated Undifferentiated

Staging
Stage IA Stage IB Stage IIA Stage IIB Stage III Stage IV G1,2 G2,2 G3,4 G3,4 G3,4 Any G T1a,b T2a,b T1a,b T2a T2b Any T N0 N0 N0 N0 N0 N1 M0 M0 M0 M0 M0 M1

Staging system predicts survival and risk of metastasis, but not local recurrence Does not take into account extremity vs. visceral

Survival vs stage

Treatment-surgery
Limb-sparing vs amputation
Limb sparing operation + adjuvant RT

Amputation still may be indicated for neurovascular or bone involvement

Surgery-how to?
Arbitrary 2 cm margin if no plan for post-op radiotherapy Negative margins necessary
Presence of positive margins increases local recurrence by 10-15%, and that can not corrected completely by adding RT

No need for lymph node dissection as only 23% have nodal metastasis

Treatment-adjuvant RT
1. EBRT (external-beam RT) 2. BT (brachytherapy)

For tumors >2 cm or high grade or if close margins (<2 cm)

Pre- vs post-op RT ?

Treatment-adjuvant chemotherapy
50% of patients with a large (>5 cm)/ deep/ highgrade soft-tissue sarcoma develop distant metastases (primarily in the lung) in metastatic disease the potential for cure drastically decreases and the 5-year survival is 25% in spite of aggressive surgical management of metastases and chemotherpy =>to decrease the rate of relapse in aggressive sarcomas adjuvant chemotherapy is used (proven beneficial in a 2008 meta-analysis)

Treatment-adjuvant chemotherapy (2)

ifosfamide + doxorubicin 2008 Sarcoma Meta-analysis Collaboration: -decreases local recurrence, distant recurrence, overall recurrence, and increases overall survival

Treatment-neoadjuvant chemo
In unresectable or marginally resectable tumors->reevaluation for surgery

Treatment-Hyperthermia
Might be used combined with neoadjuvant chemotherapy in locally advanced, high-grade sarcomas and improves tumor response, disease-free survival or progression-free survival

Special subtypes-rhabdomyosarcoma
70% in children younger than 10 yrs head and neck : ~40-50% *
orbit : ~ 20% oro / nasopharynx, palate : ~ 15% sinuses, mastoid, middle ear : ~ 15%

genito-urinary : ~ 25%
paratesticular : ~ 20% bladder : ~ 5%

extremities : ~ 15% other : ~ 10%

trunk and thorax : 7% gastrointestinal tract : 1%

Special subtypes-rhabdomyosarcoma
Lymph node mets are frequent The most common symptom of genital RMS: vaginal bleeding Good survival rate (75%)

Case #1
64 y/o male with increasing abdominal girth

Retroperitoneal Sarcomas
15% of all sarcomas Liposarcoma 42% and leiomyosarcoma 26% CT scan can show cystic/solid/necrotic components and relation to surroundings CXR to r/o mets, chest CT if CXR abnormal Biopsy not necessary unless suspect a lymphoma or germ cell tumor or plan preop chemo or radiation En bloc resection is standard treatment
bowel prep assess bilateral kidney function 50-80% need organ resection 78% of primary lesions can be completely resected

Liposarcoma

Survival after resection of primary retroperitoneal sarcoma

Prognosis for retroperitoneal sarcomas

5 year survival after complete resection of 5465%
Drops to 10-36% if incompletely resected

Recurrence occurs in 46-59% of completely resected tumors

Radiation or chemotherapy for retroperitoneal sarcomas

Radiation
GI and neurotoxicities limit delivery of sufficient doses May improve local control Recommended for use only in clinical trials given lack of data either way

Chemotherapy
Use for recurrent, unresectable or metastatic disease

Case #2
49 y/o female with GERD undergoing EGD

GIST
Separate subtype of sarcoma defined by expression of c-Kit (CD117) Surgery: complete resection without local or regional lymphadenectomy Very resistant to traditional chemotherapy Gleevec (imantinib mesylate)
c-Kit is constitutively active tyrosine kinase receptor Drug is tyrosine kinase inhibitor used in CML Initial studies showed 54% response rates Two RCTs currently looking at adjuvant treatment

GIST

GIST

Extremity sarcomas

Synovial sarcoma MFH

Breast sarcomas
1% of all breast cancers Wide excision with negative margins Adjuvant radiotherapy-probably helps (no phase III trial though)

Sarcoma after mastectomy

Vascular sarcomas
Angiosarcoma, hemangiosarcoma, lymphangiosarcoma, hemangiopericytoma Key points:
Hepatic angiosarcoma thorotrast, vinyl chloride, arsenic Stewart Treves lymphangiosarcoma in chronic lymphedema

High risk for bleeding during excision No clear role for chemo or radiation

Bone sarcoma

Melanomul

 Sursa: melanocite -cel mai frecvent din pielea fara nev -mai rar dintr-un nerv displastic -91% cutanate, 5% oculare, 1% la niv. mucoaselor, 3% nu se poate identifica tu. primara (doar metasatazele) Alte tu. ale pielii: -carc. scuamoase -carc. bazocelulare

Epidemiologia
6. prin incidenta in USA cel mai frecvent la rasa alba; I mult mai mica la cea neagra si asiatica B/F=1/1

Patogeneza-factori de risc
70%-mutatii sau deletii in gena CDKN2A =>activarea unor gene cu productia de proteine ce inhiba genele supresoare tumorale p53 si RB radiatia UV (UVC>UVB>UVA) pers. cu pielea deschisa -doar in 10% a cazurilor predispozitie genetica -sindromul nevilor displazici

Nevii displazici
ABCD mnemonic: asymmetry, border irregularity, color variation, diameter greater than 6 mm.

Extensia
locala limfatica hematogena

Indicele Breslow si Clark

Breslow Thickness First reported by Alexander Breslow in 1970, the Breslow thickness is defined as the total vertical height of the melanoma, from the very top (called the "granular layer") to the area of deepest penetration in to the skin. An instrument called an "ocular micrometer" is used to measure the thickness of the excised (removed) tumor. In general, the higher the Breslow thickness, the worse the prognosis (keep in mind that these survival rates are averages and may not reflect your individual case): less than 1 mm: 5-year survival is 95% to 100% 1 to 2 mm: 5-year survival is 80% to 96% 2.1 to 4 mm: 5-year survival is 60% to 75% greater than 4 mm: 5-year survival is 37% to 50% Due to its accuracy in predicting outcomes, the Breslow thickness has been incorporated into the standard TNM staging system for melanoma. In 2001, a large study confirmed the importance of Breslow thickness as one of the three most important prognostic factors in melanoma, along with tumor (T) stage and the existence of ulceration (broken skin, bleeding, swelling). Clark Level The Clark level refers to how deep the tumor has penetrated into the layers of the skin. This system was originally developed by W. H. Clark, MD back in 1966. Clark levels are officially defined as follows: Level I: confined to the epidermis; called "in situ" melanoma; 100% cure rate at this stage Level II: invasion of the papillary (upper) dermis Level III: filling of the papillary dermis, but no extension in to the reticular (lower) dermis Level IV: invasion of the reticular dermis Level V: invasion of the deep, subcutaneous tissue Since 2002, Clark's levels have been used less and less for calculating prognosis, since research has shown them to be less predictive of outcome, less reproducible and more subjective than the Breslow depth. Other disadvantages of this system are that it is often very difficult to differentiate between Clark Level II and Level III, and it can't be used on melanomas of the palms and soles. There is one instance in which Clarks levels continue to be used to predict prognosis: in patients with thin (less than 1.0 mm) melanoma, a Clarks level IV or V lesion portends a worse prognosis. For this reason, pathologists continue to include the Clarks level along with Breslow thickness and existence of ulceration in their reports

Tratament
Excizia pentru cele fara metastaze la distanta Metoda ganglionului santinela Chimioterapia pentru boala metastatica Terapia biologica

Excizia
Minim margine de 1 cm (pana la 2 cm) O margine mai mare (>3 cm) nu este dovedita de a creste supravietuirea (Cochrane review 2009)

Ggl santinela
Negativ=> fara alt tratament Pozitiv=> excizia ganglionilor limfatici de drenaj

Chimioterapia
Combinatii cu Dacarbazina

RT
Doar paleativa: meta. cerebrale/limfatice

Terapii biologice
IL2 vaccinuri cu celule tumorale

Melanom de canal anal-BT