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

Staging

Stage IA G1,2 T1a,b N0 M0

Stage IB G2,2 T2a,b N0 M0

Stage IIA G3,4 T1a,b N0 M0

Stage IIB G3,4 T2a N0 M0

Stage III G3,4 T2b N0 M0

Stage IV Any G Any T N1 M1

Staging system predicts survival and risk of metastasis, but not local recurrenceDoes 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 2-3% 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/ high-grade 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 54-65%

• 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

MFH

Synovial sarcoma

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 Treve’s – 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 Clark’s levels continue to be used to predict prognosis: in patients with thin (less than 1.0 mm) melanoma, a Clark’s level IV or V lesion portends a worse prognosis. For this reason, pathologists continue to include the Clark’s 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