Soft tissue sarcoma

SOFT TISSUE SARCOMA

Department of General SurgerySree Balaji Medical College Medical College and

Hospital

UNIT 1 & 4

All are true exceptA. soft tissue comprises of mesenchymal

derivatives like fat, fibrous tissue, muscles, cartilage, blood vessels and lymphatics

B. soft tissue sarcoma includes tumor arising from mesodermal derivatives alone

C. though soft tissue contributes to large portion of our dry tissue weight, it accounts only 1% of all neoplasm

D. all STS develops de novo from adult cells

All are true exceptA. soft tissue comprises of mesenchymal

derivatives like fat, fibrous tissue, muscles, cartilage, blood vessels and lymphatics

B. soft tissue sarcoma includes tumor arising from mesodermal derivatives alone

C. though soft tissue contributes to large portion of our dry tissue weight, it accounts only 1% of all neoplasm

D. all STS develops de novo from adult cells

INTRODUCTION• Soft tissue - includes supportive tissue of various

organs and the non epithelial, extra skeletal structures exclusive of lympho hematopoietic tissues

• non osseous soft tissues account for 75% of dry TBW

• primary neoplasm of these connective tissues are rare, accounting for 1% of adult and 15% of pediatric malignancies

Tissue of origin• Histologic, morphologic, experimental &

immunohistochemical data suggests, sarcomas arise from primitive, multipotential mesenchymal cells (MESODERM), which in the course of neoplastic transformation differentiate along one or more cell lines

• except malignant peripheral nerve sheath tumors, Ewing’s Sa which are neuroectodermal in origin

• Except for MPNST in NF1, STS do not seem to result from progression or dedifferentiation of a benign STT, they arise de novo

• HISTIOGENESIS IS NOT DEFINABLE except for – subcutaneous lipoma – leiomyoma

• Develops from sites that are devoid of adult counterpart, ex:– Liposarcoma develops from area that lacks

adipose tissue– Rhadomyosarcoma develops from area that lacks

voluntary muscles

All are true except

A. STS incidence increases with increasing ageB. benign soft tissue tumors are more common

than malignant soft tissue tumorsC. synovial sarcoma arises from synoviumD. Rhabdomyosarcoma is more common in

childrenE. Neuroma is a benign tumor of nerve

elements

All are true except

A. STS incidence increases with increasing ageB. benign soft tissue tumors are more common

than malignant soft tissue tumorsC. synovial sarcoma arises from synoviumD. Rhabdomyosarcoma is more common in

childrenE. Neuroma is a benign tumor of nerve

elements

INCIDENCE• 1.4 and 5.0 cases / lakh population– 1 – 2 /lakh at 15 years of age– 6/lakh at 49 years of age– 20/lakh at 80 years of age

• < 1% of overall human burden of malignant tumors

• Mortality rate - 40% of the newly diagnosed cases per year

EPIDEMIOLOGY

• Median age 65 years• 2nd to 4th decades translocation-associated

sarcomas• 5th to 6th decades in the complex sarcoma

types

Age & STS

• Benign : malignant STS = > 100 : 1• Rhabdomyosarcoma, hemangioma,

neurofibroma, alveolar sarcoma - seen more frequently in children and young adults.

• Synovial sarcoma arises in young adults.• Malignant fibrous histiocytoma and

liposarcoma generally occur in older adults

SYNOVIAL SARCOMA

• Two kinds of cells - spindle or sarcomatous cell & epithelial cells

• unique t(X;18)(p11;q11) chromosomal translocation

• human multi potent mesenchymal stem cell malignancy resulting from dysregulation of self-renewal and differentiation capacities driven by SS18-SSX fusion protein.

SYNOVIAL SARCOMA

• 8% of all soft tissue sarcomas• 15–20% of cases in adolescents and young

adults• peak of incidence is before the 30th birthday• Males > females (1.2 : 1)• Arises near the large joints of arm & leg• documented in brain, prostate, and heart too

HISTIOGENESIS BENIGN MALIGNANT

fat lipoma liposarcoma

fibrous tissue fibroma Fibrosarcoma

skeletal muscle rhabdomyoma Rhabdomyosarcoma

smooth muscle leiomyoma leiomyosarcoma

bone osteoma osteosarcoma

cartilage chondroma chondrosarcoma

blood vessels hemangioma angiosarcoma

lymphatics lymphangioma lymphangiosarcomamalignant hemagio pericytoma

nerve neurofibroma neurofibrosarcoma

mesothelieum benign mesothelioma malignant mesothelioma

Risk factors for the development of soft tissue sarcoma include all of the following except:

• A. Retinoblastoma • B. Li-Fraumeni syndrome • C. von Hippel-Lindau syndrome • D. Lymphedema • E. External beam radiation

Risk factors for the development of soft tissue sarcoma include all of the following except:

• A. Retinoblastoma • B. Li-Fraumeni syndrome • C. von Hippel-Lindau syndrome • D. Lymphedema • E. External beam radiation

A 51-year-old man has worked for 10 years in a factory producing plastic pipe. He has noted weight loss, nausea, and vomiting worsening over the past 5 months. On examination he is afebrile. There is generalized muscle wasting. His sr. ALP-405 U/L with AST 67 U/L, ALT 55 U/L, and TB- 1.2 mg/dL. An abdominal CT scan reveals a 12 cm right liver lobe mass. Liver biopsy reveals a neoplasm composed of spindle cells forming irregular vascular channels. The cells demonstrate vimentin +ve & cytokeratin negativity . What is the tumor? Its probable etiology

A Benzene B Cyclophosphamide C Asbestos D Vinyl chloride

• Vinyl chloride – hepatic angiosarcoma

ETIOLOGY• Sporadic > genetic • Genetic(cancer syndromes associated with STS)– FAP– Li Fraumeni syndrome– Retinoblastoma– Neurofibromastosis - 1– Gardner syndrome– Werner syndrome– Basal cell nevus syndrome

Li-Fraumeni syndrome• autosomal dominant • germline mutation of the p53 tumor suppressor

gene, which is located on chromosome 17p13 • Includes– soft tissue sarcoma (12% – 21%)– breast cancer, – osteosarcoma, – brain tumors, – acute leukemia, – adrenocortical carcinoma, and germ cell tumors

• Before 45yrs of age

FAP

• AD• Germline mutations in APC gene – chr 5q21• Colorectal polyps • Desmoid tumors (7.5% to 16%)

Gardner syndrome

• FAP variant– Osteomas– Skin cysts– Congenital hypertrophy of retinal pigmented

epithelium– Desmoid tumors

Carney Stratakis syndrome

• AD• Germline loss of function mutations within

SDH gene subunits• Predisposition to – GIST– paragangliomas

Hereditary retinoblastoma

• Germline mutation in RB tumor suppressor gene (RB1)

• Leiomyosarcoma – m/c STS subtype diagnosed after RB

Neurofibromatosis 1

• Mutation in neurofibromin gene (NF1), chr.17q11.2

• 5% - 10% pts. develop STS • m/c – malignant peripheral nerve sheath

tumors

Predisposing factors

• Prior radiation therapy• Chronic lymphedema• Carcinogens• Chemical agents• Trauma• Infections• Foreign bodies

True statements?

A. radiation induced STS arises from the tumor bed

B. they are low grade tumorsC. they are associated with better prognosis as

they are highly responsive to chemotherapyD. Stewart Treves syndrome is a radiation

induced sarcoma

• none

Prior radiation

• STS – m/c radiation associated tumor both in general population and cancer susceptibility syndromes

• Seen in survivors of– Breast cancer– Lymphoma– Genito urinary tumors – Head and neck cancer

Radiation • Median time between exposure and radiation

associated STS – 10yrs (1.3 to 74.0)• Shortest latency – liposarcoma (MT- 4.3 yrs)• Longest latency – leiomyosarcoma(MT- 23.5 yrs)• m/c tumors– Pleomorphic malignant fibrous histiocytoma(26%)– Angiosarcoma(21%)– Fibrosarcoma(12%)– Leiomyosarcoma(12%)– Malignant peripheral nerve sheath tumor(9%)

Radiation

• Site : close to vicinity of radiotherapy fields• Incomplete damage in normal tissues may

result in mutagenic response and disorganized proliferation that can eventually trigger tumor induction

• Poor prognosis (ex: PMFH 5yr DFS 44% vs 66%) – Younger age of exposure – Exposure to chemotherapy – histology

• Post irradiation sarcomas are associated with high-grade lesions,

• less responsive to chemotherapy than their de novo counterparts

Lymphedema• STEWART TREVES SYNDROME : – lymphangiosarcoma in a post mastectomy post

irradiated lymphedematous arm– 0.07% of patients undergoing ALND– NOT A RADIATION INDUCED SARCOMA (cancer

develops both inside and outside the irradiated field)

– Latency period of 10yrs after initial therapy– Average survival – 19 months

• FILARIASIS

Lymphedema & STS

• Blocked lymphatics stimulates growth factors and cytokines – proliferation of vessels and lymphatics

• edematous tissue results in a regional immune deficiency that enables mutant cells to escape recognition by the host's immune surveillance

Chemical agents• Hepatic angiosarcoma– Thorotrast– Vinyl chloride– Arsenic

• Phenyl herbicides• Wood preservatives(chlorophenols)• Asbestos• Pesticides(hexachlorobenzene)• Dioxins(agent orange)• Tamoxifen – uterine sarcomas

Trauma• Controversial• No proven causal relationship has been proved

yet• An injury may be merely the factor that draws

attention to the presence of a mass, rather than being a causative factor

• Rare exceptions include dermatofibrosarcoma arising in a burn scar or fibrosarcomas arising at old orthopaedic fracture sites or in the surgical scars of patients with Gardner's syndrome.

Infections

• Viral factors – avian sarcoma virus, (Rous virus)– HIV, HHV-8 being implicated in Kaposi's sarcoma.

• It is unclear, however, whether Kaposi's sarcoma is caused by the virus alone or by a combination of viral effect and immunologic suppression (probably the latter).

Foreign body• Rare human cases have also been described,

involving surgical implants, plastic, bullets, surgical sponges, bone wax, or Teflon-Dacron prostheses.

• The largest study was done by Engel* and colleagues, who looked at the rate of sarcoma in thousands of women with breast implants but did not find a statistically significant increase

* Human breast sarcoma and human breast implantation: a time trend analysis based on SEER data (1973-1990).Engel A, Lamm SH, Lai SH,J Clin Epidemiol. 1995 Apr; 48(4):539-44

False statement?

A. most common site of STS is extremityB. most common STT is lipomaC. most common STS is liposarcomaD. most common STS of extremity is

liposarcomaE. most common STS of viscera is GISTF. most common STS of retroperitoneum is

liposarcoma

• none

Anatomical location

• Extremities 41%– Lower limb – 29% (m/c:proximal thigh)

• Intra abdominal 36%– Visceral – 21%– Retroperitoneal – 15%

• Truncal 10%• Head and neck 5%

STS distribution

• liposarcoma > leiomyosarcoma > PMFH > GIST > desmoid > myxofibrosracoma > synovial sarcoma

Extremity STS

• Liposarcoma > PMFH > myxofibrosarcoma > synovial sarcoma

retroperitoneum

• Liposarcoma 47%• Leiomyosarcoma 22%• MPNST 2%• Fibrosarcoma 1%

Visceral STS

• GIST > leiomyosarcoma > desmoid

• Classify STS based on molecular genetics

Classification

• Molecular genetics and cytogenetic characterization

• STS with simple karyotypes – Simple genetic alteration(translocation/activation

mutation)– Near diploid

• STS with complex karyotypes

STS with simple karyotypes

• Translocation– Myxoid and round cell liposarcoma– Synovial sarcoma

• Specific gene mutation– APC or beta catenin – desmoid tumor– KIT or PDGFRA – GIST

30s and 40s, younger adults

STS with complex karyotypes

• Alteration in cell cycle genes TP53,MDM2,RB1 And INK4a

• Defects in specific growth factor signalling pathways

• Ex:– Dedifferentiated and pleomorphic liposarcomna– Leiomyosarcoma– Pleomorphic malignant fibrous histiocytoma– Myxofibrosarcoma

• 50s and 60s

• WHO classification of STS

WHO classification

• Benign• Intermediate(locally aggressive)• Intermediate(rarely metastasizing)• Malignant

LOCAL RECURRENCE

LOCAL INVASION

METASTASIS EXAMPLE

BENIGN -/+ NO NOlipoma. Fibroma,

neurofibroma

INTERMEDIATE(LOCALLY

AGGRESSIVE)+ + NO

Desmoid tumor

INTERMEDIATE(RARELY

METASTASIZING)+ +

Yes, <2%, to

lungs/lymph node

Plexiform fibrohistiocytic tumor

MALIGNANT + +Yes,

10 – 100%Rhabdomyosarcoma,

angiosarcoma,

• Classify STS based on metastatic potential

• Tumors with– Limited– Intermediary– Substantial metastatic potential

Tumors with limited metastatic potential

• desmoid, • atypical lipomatous tumor (also called well

differentiated liposarcoma),• dermatofibrosarcoma protuberans,and• solitary fibrous tumor.

Tumors with an intermediate risk of metastatic spread

• large myxoid component and include myxoid liposarcoma myxofibrosarcoma,

• extraskeletal myxoid chondrosarcoma.

Tumors with substantial metastatic potential

• angiosarcoma,• clear cell sarcoma, • pleomorphic & dedifferentiated liposarcoma, • leiomyosarcoma, • MPNST, • rhabdomyosarcoma, and • synovial sarcoma

• Histologic type is an important prognostic factor– Ex: increase in myogenic differentiation increases

risk of metastasis • low-grade lesions < 15% chance of metastasis • high-grade lesions > 15% chance of metastasis

• Which is the most common route of metastasis for STS?

• What is the most common site of metastasis for a STS in lower limb?

METASTASIS

• Hematogenous– Extremities : 70% - lungs– Visceral and retroperitoneal : liver >>> lungs

• Lymph node – uncommon

• Lymph node involvement in STS?

LYMPH NODE INVOLVEMENT

• synovial sarcoma• angiosarcoma• myxoid sarcoma• epitheliod sarcoma• clear cell sarcoma• lymphangiosarcoma• rhabdomyosarcoma

• What are the clinical presentation of an extremity STS?

clinical presentation-extremity STS• painless mass• 33% complain of pain (indicates poor prognosis)• pain - often the first complaint in patients with

MPNST, which tend to spread along nerve bundles• rapidly growing or aggressive tumor subtypes are

more likely to be painful• systemic symptoms such as fever, weight loss, or

malaise (uncommon)• tumor impingement on bone or neurovascular

bundles produces pain, edema, and swelling

• Of the patients who present with pain, about half eventually undergo amputation

• Rapidly increasing size• sudden appearance of a new large mass• sudden appearance of pain, particularly in a

lesion that was previously painless, suggests malignancy

Clinical presentation - intra abdominal sarcoma

• Asymptomatic abdominal mass• Pain • GI bleeding• Obstruction• Neurological symptoms due to invasion of

retroperitoneal invasion/ pressure• Weight loss(uncommon)

• Which kind of lesion hints towards malignancy?

• tumor larger than 5 cm• located deep to the deep fascia• rapidly growing, change in color• painful or tender • occurring in older individuals

A 27-year-old woman in excellent health has a routine health maintenance examination. No h/o trauma. A 2 cm firm, rounded mass is palpable beneath the skin of the left forearm. She has no difficulty using the arm and there is no associated pain with the mass, either in movement or on palpation. No associated LNP. The overlying skin appears normal. The mass does not change in size over the next year.Which of the following neoplasms is she most likely to have?

A Metastatic carcinoma

B Melanoma

C abscess

D Lipoma

E hematoma

A 27-year-old woman in excellent health has a routine health maintenance examination. No h/o trauma. A 2 cm firm, rounded mass is palpable beneath the skin of the left forearm. She has no difficulty using the arm and there is no associated pain with the mass, either in movement or on palpation. No associated LNP. The overlying skin appears normal. The mass does not change in size over the next year.Which of the following neoplasm is she most likely to have?

A Metastatic carcinoma

B Melanoma

C abscess

D Lipoma

E hematoma

• Differential diagnosis for STS?

Differential diagnosis• 18% benign mesenchymal tumors • 18% isolated carcinoma metastases, • 5% inflammatory processes(abscess)• 2% lymphomas• 2% old hematomas• others– pulled muscle– myositis ossificans– cyst– cutaneous malignant neoplasm– hypertrophic scar

DD for RP STS

• Pseudocyst of pancreas• Cystic lesions of pancreas• Mesentric cyst• Aortic aneurysm• Secondary RP lymph node deposits• RP hematoma• RP abscess, cold abscess• PCKD, renal malignancies and cysts

A 37-year-old woman has developed a 6-cm mass on her anterior thigh over the past 10 months. The mass appears to be fixed to the underlying muscle, but the overlying skin is movable. Which of the following is the most appropriate next step in her management?

A. AK amputationB. Excisional biopsyC. Incisional biopsyD. Bone scanE. Abdominal CT

A 37-year-old woman has developed a 6-cm mass on her anterior thigh over the past 10 months. The mass appears to be fixed to the underlying muscle, but the overlying skin is movable. Which of the following is the most appropriate next step in her management?

A. AK amputationB. Excisional biopsyC. Incisional biopsyD. Bone scanE. Abdominal CT

A 50-year-old man has felt vague abdominal discomfort for the past 4 months. There is no history of altered bowel and bladder habits. On physical examination he has no generalized lymphadenopathy, no organomegaly or free fluid is present. Bowel sounds are present. A non ballottable retro peritoneal lump of size 20 cm occupying the right lumbar region found on further examination. A stool specimen tested for occult blood is negative. Which of the following neoplasms is this man most likely to have? What is the next logical step of investigation?

A Melanoma

B Adenocarcinoma

C Lymphoma

D Liposarcoma

• biopsy• IVP/DMSA• CECT abdomen • MRI & PET CT

A 50-year-old man has felt vague abdominal discomfort for the past 4 months. There is no history of altered bowel and bladder habits. On physical examination he has no generalized lymphadenopathy, no organomegaly or free fluid is present. Bowel sounds are present. A non ballottable retro peritoneal lump of size 20 cm occupying the right lumbar region found on further examination. A stool specimen tested for occult blood is negative. Which of the following neoplasms is this man most likely to have? What is the next logical step of investigation?

A Melanoma

B Adenocarcinoma

C Lymphoma

D Liposarcoma

• CECT abdomen

IMAGING before BIOPSY• all imaging studies prior to any biopsy,

because :• it is impossible to accurately place a biopsy site

that will be consistent with future limb salvage procedures without detailed information about the lesion and its relationship to the normal anatomy that is now distorted by the mass

• biopsy inherently causes hemorrhage, edema and other changes that can interfere with interpretation of any subsequent imaging

MRI• imaging of choice for primary extremity

sarcoma• enhances the contrast between tumor &

adjacent structures & provides excellent three-dimensional definition of fascial planes

• MRI accurately defines tumor size, multiplicity, and location

• superior soft tissue contrast resolution• better delineation of neurovascular bundle

MRI

• T1 weighted image – for disease extent• T2 weighted image – for peritumoral edema

Drawbacks of MRI

• Cannot reliably predict histologic diagnosis and biologic behavior unlike PET CT

• Cannot be used in pts. with pacemakers, other metallic implants that would generate a lot of magnetic interference

• air-tissue interface and motion artifacts - degrades MRI quality

• Lengthy time of study

CT SCAN• For the primary intra abdominal and chest

sarcoma, a spiral CT scan is preferable over MRI• with spiral CT - both primary and metastasis

can be assessed in a single study• bone involvement (though rare) and

calcification is better appreciated in CT

• CT is a predominantly anatomic imaging modality.

• It is limited in the differentiation of subtle soft tissue differences.

• CT plays mainly a complementary role to MRI in evaluation of the extent of tumor.

• How will you investigate for metastasis?

METASTASIS

• Extremities : – Low grade /small superficial high grade – CXR– High grade/deep lesions – CT chest

• Intra abdominal sarcoma : CT• CT chest less sensitive for pulmonary

metastasis < 1cm in size• Identifies only 60% lesions < 6mm

METASTASIS

• CT chest adds little clinical benefit when risk for pulmonary metastasis is low

• In pts. In whom CXR are difficult to interpret due to scarring , emphysema – CT chest is indicated

• What is the role of PET CT in metastatic work up?

Role of PET• standard uptake value ( SUV) in 18 F fluoro

deoxyglucose (FDG) PET has been associated with histo pathological grade, cellularity, mitotic activity, MIB labeling index, and p53 overexpression and hence grade

• PET assessment of proliferation with the thymidine analogue 3 ' -deoxy-3 ' (18F) fluoro thymidine correlated significantly with tumor grade and was superior to traditional FDG-PET for the grading of sarcoma

Role of PET CT in metastasis

• PET is an alternative for CT showing suspicious pulmonary lesions and lesions < 1cm

• What is the role of PET CT in monitoring tumor response?

Role of PET CT in monitoring of tumor response

• primary extremity sarcomas, the association with outcome after treatment with neoadjuvant chemotherapy was stronger for PET response than for radiologic tumor size changes

• Similar results have been found for pediatric sarcomas.

• early prediction of chemo sensitivity in pts. with STS who received NACT and has been found to have an accuracy of 83 % and a PPV for responders of 92 %

• What are the pitfalls of PET ?

Drawbacks of PET CT

• PET though sensitive lacks specificity• Low grade sarcoma & certain high grade

tumors like round cell sarcoma are not FDG avid

• False positive in benign conditions like granulomatous inflammation

• Bone scans have no role in the preoperative investigation of a soft tissue sarcoma

• Is pre operative biopsy a must for abdominal sarcoma?

• What is indication for biopsy in truncal STS?

Role of biopsy in TRUNCAL STS

• Usually diagnosis is clear without biopsy • FNA biopsy and CT guided core biopsy limited

role in routine diagnosis• Pre operative biopsy is only indicated in– patients with distant metastasis– tumor is unresectable (planning to start

neoadjuvant CT/RT to downstage the disease)

CT guided core biopsy

• Useful in conditions where treatment modality changes completely – Abdominal lymphoma– Germ cell tumor– Carcinoma – Inflammatory conditions

• Is pre op biopsy a must for extremity sarcoma?

Diagnostic biopsy in extremity STS

• Recommended prior to definitive treatment in all lesions– Deep seated lesions– Superficial lesions > 5cm except subcutaneous

lipoma• any soft-tissue mass in an adult that is

enlarging (even if asymptomatic), is larger than 5 cm, or persists beyond 4 to 6 weeks should be biopsied

• When will u do an excision biopsy?

EXCISIONAL BIOPSY

• For lesions < 3cm• Cutaneous/ subcutaneous

• Which is better, incisional or core cut or FNAC?

INCISIONAL BIOPSY• Excisional biopsy > incisional biopsy > core cut

biopsy > frozen section• should be performed at centres where pt is

planned to get operated• Incision should be placed along the axis of limb• Incision should be placed such that the entire

tract can be excised along with the tumor during definitive surgery

• No tissue flaps to be raised• Complete hemostasis to be achieved

ROLE OF CORE CUT BIOPSY• Accuracy lower than incisional biopsy• Easy to perform, low cost, low complication

rate, can be repeated readily• Tumor characteristics can be identified pre op– Histologic type – Histologic grade– Immunohistochemistry– Cytogenetics

• Enables planning of optimal treatment plan & extent of surgery

FROZEN SECTION

• Only for diagnosis of malignancy intra operatively (unsuspected pre operatively)

• Not accurate for subtypes and grade

• Only indication for FNAC in STS?

ROLE OF FNAC

• Only for confirmation of recurrence rather than primary diagnosis

• Limited sampling• Lack of tissue architecture• Difficult molecular diagnostic studies• Not representative• Difficult in grading and subtyping

• How will you stage STS?

STAGING

• AJCC (American Joint Committee on Cancer) 7th edition,2010

• Incorporates – Histologic type– Histologic grade– Tumor size– Depth– Regional lymph node involvement– Distant metastasis

AJCC staging

• Correlates for stage and disease specific survival for extremity sarcoma

• Does not adequately correlate for intra abdominal sarcoma

• What are the changes in 7th edition AJCC?

Changes in AJCC 7th edition• Excludes:– GIST– Desmoid tumor– Kaposi sarcoma– Infantile fibrosarcoma

• Adds:– Angiosarcoma– Extraskeletal Ewing’s sarcoma– Dermatofibrosarcoma protuberans

• Reclassifies N1 from stage 4 to 3• 4 grade to 3 grade system

Primary Tumor (T)• TX Primary tumor cannot be assessed

• T0 No evidence of primary tumor

• T1 Tumor 5 cm or less in greatest dimension• T1a Superficial tumor• T1b Deep tumor

• T2 Tumor more than 5 cm in greatest dimension• T2a Superficial tumor• T2b Deep tumor

Regional Lymph Nodes (N)

• NX Regional lymph nodes cannot be assessed• N0 no regional lymph node metastasis• N1 Regional lymph node metastasis

Distant Metastasis (M)

• M0 no distant metastasis• M1 distant metastasis

HISTOLOGIC GRADE (G)

– GX Grade cannot be assessed– G1 grade 1 (low-grade) well differentiated– G2 grade 2 intermediate differentiation– G3 grade 3 (high-grade) poorly differentiated

Grading systems

• National Cancer Institute grading system

• Comprises of – Histology– Necrosis– Mitosis/HPF

• Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system

• Comprises of– Tumor differentiation– Mitotic count– Tumor necrosis

• Histological grading is assessed based on what pathological features?

• histologic grade is determined by assessment of several features:

• (1) degree of cellularity, • (2) cellular pleomorphism or anaplasia, • (3) mitotic activity, • (4) degree of necrosis, and • (5) expansive or infiltrative and invasive

growth

• Define superficial and deep tumor

DEFINITION

• Superficial is defined as lack of any involvement of the superficial investing muscular fascia in extremity or trunk lesions

• Deep is defined as partly or completely within one or more muscle groups, deep to fascia within the extremity.

• Intra thoracic, intra-abdominal, retroperitoneal, and visceral lesions are considered to be deep lesions

Nomenclature

• cTNM - clinical• pTNM - pathological• ypTNM/ycTNM - post neoadjuvant• cT(m)NM – multiple primary tumors • rTNM – recurrent• aTNM – at autopsy

• What are the various prognostic factors?

Prognostic factors

• Age >50yrs• Size > 8cm• Vascular invasion• Local infiltration• Deep location• High grade tumors• Recurrent disease• Non lipomatous histology

Clinical course

• clinical course depends on – histology– aggressiveness of the original tumor

• varies between the major histologic categories & also among individual lesions of the same type.

• How will you treat a patient with stage 1 STS?

• Surgery with intent to obtain negative margin• Surgery is definitive if margins are > 1cm,

fascial plane is intact• If margins < 1cm, fascial plane is breached –

re resection is necessary

Stage 1

• How will you treat a patient with stage 2 or 3 STS?

Stage 2 & 3

• Pre op chemoradiation increases:– OS– DFS– LOCAL CONTROL RATES

• To be considered in high grade tumors (>8 – 10 cm)

• Post operative ERBT improves local control in patients with high grade lesions

• How will you manage patient with regional lymphadenopathy?

Lymph node disease

• Radical lymphadenectomy – long term survival benefit ( median survival 4.3 vs 16.3 months) when compared with control

• regional nodal involvement is an important prognosticator of survival

• patients with multiple positive nodes, a single lymph node, and distant metastatic disease all have similar survival

• What is the treatment approach for unresectable STS?

Unresectable disease

• Primarily RT / CRT/ CT then • If resectable –– surgery– f/b RT (if not previously irradiated) with/without post op

CT• If unresectable / resectable with adverse functional

outcomes– Asymptomatic: observation– Symptomatic: CT/ palliative surgery/ amputation/ best

supportive care/ induction into trial

Regional limb therapy

• Isolated limb perfusion/ isolated limb infusion can be considered as limb saving procedures in unresectable intermediary / high grade STS

• TNF alpha• Melphalan• Doxorubicin• Dactinomycin

• How will you treat a stage 4 metastatic disease ?

Stage 4 – synchronous metastatic dis

• Poor prognosis• No DF interval• Clinical trial is one of the preferred treatment

LIMITED METASTASIS

• Limited organ• Limited tumor bulk- amenable to local therapy

are managed in line with stage 2 or 3 disease

DISSEMINATED METASTASIS

• If asymptomatic: watchful waiting is a reasonable option (esp. for minimal tumor bulk , ex: sub centrimetric pulmonary nodule)

• Symptomatic : palliative RT/ Surgery/ CT• Ablation procedures – RFA / cryotherapy

• What is the recommended surveillance protocol after treatment?

surveillanceH & P IMAGING

STAGE 1 every 3 to 6 months for 2 to 3 yrs and then

annually

chest imaging every 6 to 12

months

STAGE 2 , 3, 4

every 3 to 6 months for 2 to 3 yrs then every 6 months for next 2 years

and then annually

• What is the role of surgery in STS ?• Which is the preferred surgical approach ?

Limb saving or amputation?

Aim of surgery

• minimizing local recurrence, • maximizing function, and • Improving overall survival

ROLE OF SURGERY- extremity sarcoma

• surgery remains the principal therapeutic modality in soft tissue sarcoma, the extent of surgery required, along with the optimum combination of radiotherapy and chemotherapy, remains controversial.

Limb sparing surgery

• Wide en bloc resection• obtain a 1- to 2-cm margin of uninvolved

tissue in all directions• most extensive resection is clearly

amputation. • This should be only rarely indicated in soft

tissue sarcoma because limb-sparing operations are possible in at least 95 % of patients with extremity sarcoma.

Limb saving procedure vs amputation

• The issue of amputation versus limb-sparing surgery for extremity lesions has been addressed by a prospective, randomized trial at the NCI with well over 10 years' follow-up .

• Limb sparing surgery with RT for high grade STS showed local recurrence of 15% and no difference in OS & DFS as compared to amputation

• The limiting factor for LSS(limb saving surgery) is usually neurovascular or, occasionally, bony juxtaposition.

• very few STS invades bone directly , bone resection is rarely needed

• Few STS involve the skin, and so major skin resection should be limited.

• What is the contra indication for limb saving surgery?

Contraindications for limb sparing surgery

• margin-free resection is impossible and/or when radiation therapy is risky

• if major vessels and nerves are involved at the site where resection would critically compromise function

• Is 1cm margin a dictim for all STS?

Only surgery

• surgery alone (adequate wide excision with a good 1 cm cuff of surrounding fat and muscle) can be done in– subcutaneous or intramuscular high-grade sarcoma

smaller than 5 cm – low-grade sarcoma of any size

• low-grade histologic types (atypical lipomas and well-differentiated liposarcoma of the extremities), margins < 1cm is enough(minimal surrounding margin) , provided excision is complete

• Sarcomas tend to expand and compress tissue planes, which produces a pseudo capsule comprising normal tissue interlaced with tumor tissue.

• When surgical resection does not include the plane of tissue adjacent to the pseudo capsule, the local recurrence rates are between 33 and 66%.

• Wide local resection with a margin of normal tissue surrounding the tumor is associated with better results; local recurrence rates of approximately 10 to 30%

• How will you classify surgical margins?

• Positive surgical margin is a strong predictor of local recurrence for patients with extremity STS

• Risk of patient to develop local recurrence with positive margin is 3.76 times than those with negative margin (6yr follow up – 38% vs 12%)

Role of surgery – intra abdominal sarcoma

• OS , DFS , Median survival time depends upon– complete surgical resection (preferably R0)– grade of the lesion

• RP sarcomas are large, making it difficult to obtain adequate margins of resection

• mandates a multi modality treatment: combined chemotherapy and radiotherapy as a neoadjuvant to surgery.

• Surgery remains the mainstay of treatment

• proximity of normal organs such as small bowel, large bowel, kidney, and liver makes delivery of therapeutic doses of radiation therapy either difficult or impossible

• retroperitoneum is a site that may be particularly suited to preoperative radiotherapy for sarcoma, because the tumor has frequently displaced bowel from the target volume

• Postoperatively, in contrast, loops of bowel are frequently tethered or fixed within the target area.

• The most common histologic types encountered in the retroperitoneal location (well-differentiated liposarcoma, dedifferentiated liposarcoma, leiomyosarcoma, and MPNST) are typically not very responsive to conventional chemotherapy, and chemotherapy has never been shown to improve survival

• What are the particulars or details you will ensure in a pathological report after STS surgery?

Pathological assessment of Sa specimens

• Organ , site and operative procedure• Primary diagnosis (WHO nomenclature)• Depth of tumor (superficial/deep)• Size of tumor• Histologic grade(atleast low / high grade)• Necrosis (+/-, micro/macroscopic, %)• Status of margin (uninvolved, involved, close)

Pathological assessment of Sa specimens

• Status of lymph nodes (site, no. examined, no. of +ve nodes,)

• Results of ancillary study(electron microscopy, IHC, cytogenetics)

• Additional tumor factors of potential clinical value (mitotic rate, vascular invasion,character of tumor margin- well circumscribed/ infiltrative, inflammatory infiltrate – type & extent)

• TNM stage

• What is the indication for adjuvant radiotherapy?

Role of radiation

• adjuvant radiation therapy should be added to the surgical resection to reduce the probability of local failure for :– deep, – greater than 5 cm, – high grade sarcomas – if the excision margin is close, • with extra muscular involvement • local recurrence would necessitate amputation • the sacrifice of a major neurovascular bundle

Goals of adjuvant RT

• enhance local control • preserve function• achieve acceptable cosmesis by contributing

to tissue preservation

• What are the various RT modalities applicable in STS?

• Which is better, ERBT / BRT/ IMRT?

ERBT POST OP RT• allows for sterilization of microscopic nests of residual

disease without the need to postpone surgery• enhance local control compared to conservative

surgery alone.• Though adjuvant RT results in – significantly worse limb strength – edema– Loss of range of motion

• these deficits were often transient and had few measurable effects on activities of daily life or global quality of life.

• What are the pros and cons of post op RT?

Post op RT

• Advantage : entire pathology specimen & final margins are available for pathologic analysis, helping to determine the need for further therapy.

• Limitation : is that the target is less precisely defined, and therefore volume is larger and dose is higher, resulting in greater late tissue morbidity

• More hypoxic tissue – radiobiological disadvantage• High incidence of delayed toxicity(irreversible)

• What are the pros and cons of pre op RT?

Preoperative EBRT

• treatment volume well defined• blood supply is intact• intact vascular supply and relative absence of

actively proliferating tumor clonogens and radio resistant hypoxic cells decrease the dose needed compared to post op RT(radiobiological advantage)

• Reduced treatment time• Tumor down staging• irradiation increases the risk of acute wound

complications upon surgery(reversible)

• Which is better, pre op RT or post op RT?

Pre op RT Post op RT

Local control 93% 92%

Metastatic free relapse survival

67% 69%

5yr overall survival 73% 67%

5yr cause specific survival

78% 73%

Time Pre op RT Post op RT

6 wks Inferior function, worst body pain score

3 – 12 months

No difference in pain rating scores

2 year • deteriorating late tissue sequale (fibrosis & edema)• increased bone fracture

• What is IMRT? What are its advantage? When is it indicated?

IMRT

• IMRT may be particularly applicable to complex anatomic volumes such as retroperitoneal sarcoma juxtapositioned to liver or paraspinal lesions, for which conformal avoidance of liver or of kidney and spinal cord is necessary.

• Avoidance of bone is also possible and may reduce the risk of the radiation-induced fracture of weight- bearing bone

• Superiority of IMRT over conventional EBRT due to a reduction in late toxicity(bone fracture)

• the 5-year local control rate for IMRT in one study was very similar to those with conventional EBRT in both arms of the trial that compared preoperative to postoperative radiotherapy

Conventional RT

Conformational RT

IMRT

• RT is not a substitute for definitive surgical resection with negative margins and re resection to negative margins is preferable

• Pre op dose is 50Gy• Post op RT is recommended for all patients

with positive margins

Post op RT in patients with positive margins who received pre op RT

R1 R2

ERBT 16 – 18 Gy 20 – 26Gy

BRACHYTHERAPY LDR – 16 TO 26Gy HDR -14 TO 24Gy

IORT 10 – 12.5Gy 15Gy

Post op RT in patients with positive margins who has not received pre op RT

• ERBT – 50 Gy irrespective of R1 / R2 in 25 fractions• IORT – 10 – 16 f/b 50Gy ERBT• ERBT is delivered to target tissue after surgical;

healing is complete after 3 – 8 weeks to allow acute radiation changes to subside

• Conventional fractionation is usually 1.8 to 2 Gy per day

• The optimal radiation margin is not well defined: a margin of 5 to 7 cm is standard, but some centers advocate wider margins for tumors larger than 15 cm

EBRT boost to tumor bed

• R0 – 10 – 16 Gy• R1 – 16 – 18Gy• R2 - 20 – 26 Gy

• What are the complications of RT?

Pre op RT - complications

• wound dehiscence, • wound necrosis• persistent drainage,• infection, • seroma formation, • ulceration,• and cellulitis

Chronic effects of RT

• > 1 yr after RT– fibrosis/contractures,– Lymphedema,– neurologic injury,– osteitis, and – fractures

• Factors ass. With poor outcome– larger tumors,– Higher doses of radiation (>63 Gy), – longer radiation fields (>35 cm),– poor radiation technique, – neural sacrifice, – postoperative fractures,and – wound complications

BRT

• BRT is an attractive approach because patients usually complete all their treatment in about 2 weeks compared to 6 to 7 weeks with EBRT

• The rapid dose fall-off with BRT usually spares more normal tissue than EBRT, except when precision techniques such as IMRT are used.

• Drawback : unlike in postoperative irradiation, no attempts are made to treat large margins or to include the scar and the drainage site

IMRT vs BRTIMRT BRT

5yr control rate 92% 80%

• Of importance, the catheters are loaded no sooner than the sixth postoperative day to allow enough time for wound healing.

• most commonly used isotope – low-dose-rate 192Ir– high-activity 125I is occasionally used in young

patients or to protect the gonads. • High-dose rate 192Ir has been advocated to take

advantage of its radiation safety and dose-optimization capabilities

When not to omit RT

• positive surgical margin of resection(even for smaller lesions < 5cm)

• Whether pt. had prior unplanned excision (i.e., excision without adequate preoperative staging or consideration of the need to remove normal tissue around tumor)

Unplanned resection

• An intralesional or an unplanned microscopically positive margin is associated with high recurrence rates, despite adjuvant radiation therapy

• patients who have undergone previous surgery with +ve margins should receive preoperative radiation and a complete resection of the previous surgical bed if this is feasible.

• Even with this aggressive treatment, these patients still have inferior outcomes, underscoring the importance of appropriate diagnosis and management by the initial treating physician.

• patients with positive margins, radiotherapy reduces the risk of recurrence compared to no adjuvant treatments, although their 5 -year local recurrence rates continue to be higher than those of patients with negative margins.

• Surgery with negative margin is the standard of care

• What is the role of chemotherapy?• What is the chemotherapeutic agent of

choice?• What is the most common regimen used?

Role of chemotherapy

• anthracyclines are the agents most active against metastatic sarcoma

• A question that remains unanswered is the timing of chemotherapy with respect to surgery and radiation.

• Chemotherapy was started within 10 weeks of surgery if radiation was used or within 6 weeks if no radiation was used

• Preoperative chemotherapy has been very successful in the management of predominantly pediatric sarcomas such as Ewing sarcoma and osteo sarcoma.

Advantages of NACT

• makes subsequent surgery easier • potentially treats micro metastatic disease early

before acquisition of resistance (before surgery the primary vasculature is still intact for) drug delivery

• Preoperative chemotherapy response can guide postoperative treatment based on pathologic review of the tissue response after chemotherapy

• In experimental models, preoperative chemotherapy eliminates a postoperative surge in growth of metastases noted after resection of primary tumors

• Doxorubicin-most active at doses of 75 mg/m2 @ 48- to 96-h continuous infusion

• Ifosfamide - 10 g/m2 or higher when administered as a 2- to 3-h infusion has a greater efficacy as opposed to a 24-h infusion

CT response rates• response rates according to histology

– malignant fibrous histiocytoma (MFH) 69%, – synovial sarcoma 88%, – unclassified sarcomas 60%,– non-GI–leiomyosarcomas 50%, – liposarcomas 56%, – angiosarcomas 83%, – neurogenic sarcomas 40%, – other miscellaneous histologies 45%

• Hence, sensitivity to chemotherapy depends on the histologic type of sarcoma underscores the importance of proper histologic diagnosis in determining prognosis

Various modalities

• Intra venous CT– Single agent– Combination therapy

• Intra arterial CT• Hyperthermia and limb perfusion• Combined chemoradiotherapy– MAID(doxorubicin,ifosfamide,mesna,dacarbazine)

interdigitated with two 22 Gy courses of radiation (11 fractions each)

• Concurrent chemotherapy and definitive radiotherapy for unresectable STS

• How will you manage a patient with recurrent STS?

RECURRENCE

• Difficult to treat • More likely to recur– Due to prior contamination of field – Intrinsically aggressive tumor biology

• Factors:– Size – timing

• Repeat resection is the treatment of choice for locally recurrent soft tissue sarcoma in almost any site that is amenable to low-morbidity surgical resection.

• When surgical resection can be achieved, then adjuvant radiation therapy should be considered in the vast majority of patients with recurrent disease.

RP Sa recurrence• Isolated local recurrence is most common following complete

resection of a primary retroperitoneal liposarcoma . • Retroperitoneal recurrences are often detected on routine

screening with imaging, or patients may present with pain or nonspecific symptoms.

• After workup to determine the extent of disease, patients with isolated local recurrence should be carefully evaluated for re-resection.

• As current chemotherapy is ineffective for the majority of patients with liposarcoma and toxicity limits adequate dosing by radiation therapy, complete surgical resection remains the most effective treatment modality.

RP Sa recurrence• Despite aggressive operative management, patients with a local

recurrence growth rate greater than 1 cm per month had poor outcomes that were similar to those of patients who were not treated with resection.

• Only patients with local recurrence growth rates of less than 0.9 cm per month had improved survival following aggressive resection of the local recurrence.

• Based on these results, for patients presenting with asymptomatic local recurrence and growth rates equal to or exceeding 1cm per month, the recommendation now is treatment with systemic chemotherapy or novel targeted therapy trials.

RP Sa recurrence

• Surgery is only considered in this subgroup if they develop symptoms, such as obstruction or bleeding, that do not respond to medical management.

• If the local recurrence growth rate is less than 1 cm per month, immediate surgery is recommended for all symptomatic patients and for asymptomatic patients whose local recurrence is impinging on critical structures (particularly if further growth may result in the need to sacrifice critical organs) or has a solid appearance on CT scan (suspicious for dedifferentiation)

RP Sa recurrence

• Debulking, however, has limited overall value in terms of long-term survival of patients with recurrent lesions.

• A 68-year-old male being treated with anticoagulants for atrial fibrillation presented with a soft tissue mass.

• mass was managed as a spontaneous hematoma with percutaneous drainage for several months.

• After the lesion became fungating , MR images were obtained. Subsequent biopsy confirmed malignant fibrous histiocytoma. A partial hemi pelvectomy was performed and systemic staging investigations identified metastatic lung lesions.