Soft tissue sarcomas

SOFT TISSUE SARCOMAS

Dr Ankit Sharma

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INTRODUCTION Constitute a heterogeneous group of rare solid tumors of mesenchymal cell

origin with distinct pathological and clinical features. Divided into two main categories Sarcomas of soft tissues (fat, muscles, nerve and nerve sheath, blood

vessels and other connective tissues) Sarcomas of bone

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CTND… Rare & unusual neoplasms 1% of adult human cancers, 15% of paediatric malignancies Develop at any anatomical site, 60 histologic types & subtypes which pose

challenge in diagnosis and management

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HISTOLOGICAL SUBTYPES

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COMMON HISTOLOGICAL SUBTYPES Liposarcoma Dermatofibrosarcoma protuberans Desmoid fibromatosis Leiomyosarcoma Unclassified sarcoma Synovial sarcoma

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CTND… Malignant peripheral nerve sheath tumor Rhabdomyosarcoma Fibrosarcoma Ewing sarcoma Angiosarcoma Osteosarcoma Epithelioid sarcoma Chondrosarcoma Clear cell sarcoma Alveolar soft part sarcoma Malignant hemangiopericytoma

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AGE AS FACTOR In childhood, embryonal rhabdomyosarcoma is most common Synovial sarcoma is more likely to be seen in young adults (<35 years old) An even distribution of liposarcoma and malignant fibrous histiocytoma as

the predominant types in the older population

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ETIOLOGY Most are sporadic Cause unknown Genetic factors, environmental factors, prior radiation therapy, viral

infections, immunodeficiency Sites – Scar tissue, fracture sites, prior soft tissue trauma

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CTND... Other aetiological factors • Radiation exposure (osteosarcoma, angiosarcoma) • Chronic lymphoedema • Trauma • Chemical exposure eg. arsenic, polyvinyl chloride (hepatic angiosarcoma) • Infections eg. Human Herpes Virus-8: causes Kaposi’s Sarcoma in

immunocompromized patients

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GENETIC SYNDROMES Desmoid tumors – Pts with familial adenomatous polyposis syndrome (APC

gene mutation) Neurofibromatosis - Malignant peripheral nerve sheath tumors Li Fraumeni syndrome (P53 mutation) – 80% develop cancer by 45yrs of

age. Soft tissue sarcomas in 36% Retinoblastoma (Rb mutation) – 36% develop soft tissue sarcomas by 50.

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DISTRIBUTION 45% - Extremity (Thigh) 20% - Visceral 15% - Retroperitoneal 10% - Truncal or Thoracic 10% - Other locations

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CLINICAL FEATURES Extremities and superficial trunk: (60%) Painless primary soft tissue mass. Retroperitoneum: (15%) Abdominal mass, Pain, grows to large size before

symptoms. Viscera: (15%) Anemia, melena, abdominal pain, wt loss, painless P/V bleed H&N: (10%) Smaller, Mechanical problems: compression or invasion of

adjacent critical structures.

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CTND… Asymptomatic painless masses Venous thrombosis in extremities Sometimes painful (Compress adjoining structures) Edema and swelling when bone or nearby neurovascular bundles are

involved

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RADIATION EXPOSURE STS – Most common radiation associated STS – Heavy radiation exposure (50Gy or more) Median interval – 10yrs (1.3 – 74yrs) Shortest – Liposarcoma (4.3yrs) Longest – Leiomyosarcoma (23.5yrs) Survival - Radiation associated < Sporadic

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MOLECULAR BASISDifferent types of known mutations are ∗ Point Mutations ∗ Translocations ∗Amplifications ∗Oncogenic Mutations ∗Complex Genomic Rearrangements

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MOLECULAR GENETICS Myxoid round cell liposarcoma – [t(12;16)(q13;p11), t(12;22)(q13;q12)] Synovial sarcomas – [t(X;18)(p11;q11)] Desmoid tumors - APC/Beta-catenin mutations (Trisomies 8 and 20) GIST – Mutations in KIT or PDGFRA (Monosomies 14 and 22) Ewing’s sarcoma – t(11;22)(q24;q12) DFSP – t(17,22) Liposarcoma – MDM2 & CDK4 amplification

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CTND… Cytogenetic changes Divided into 2 categories: – One group has specific changes and relatively simple karyotypes eg. fusion

gene or point mutation Other group has non-specific changes and complex karyotypes. Genetic syndromes associated with STS include

–Neurofibromatosis, – Retinoblastoma, – Li-Fraumenii syndrome, – Gardener’s syndrome (Familial adenomatous polyposis)

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SCREENING AND DIAGNOSIS No screening tests. Incidence too low. Physical exam: 1. Size of the mass 2. Mobility 3. Superficial/deep 4. Relation to nearby NV and bony structures. 5. Regional lymph nodes. Biopsy - Symptomatic, enlarging, >5cm or more

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EVALUATION It is recommended to obtain a diagnostic biopsy prior to definitive

treatment for all soft tissue masses which are symptomatic/enlarging, superficial mass >5cm, for all subfascial, deep seated masses irrespective of sizes.

Biopsy Techniques – Fine-Needle Aspiration Biopsy Core Needle Biopsy (choice) Incisional Biopsy Excisional Biopsy

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CTND… Biopsy technique – Open incisional/core needle Core needle Bx – High diagnostic accuracy, ease of performance, low cost,

less complications Excisional Bx – small cutaneous or subcut <5cm CT guided core Bx – Abdominal lymphoma, germ cell tumor

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CTND… Sampling – Limb masses (longitudinal sampling) so that entire biopsy tract

excised during definitive resection. Incision biopsies should not interfere with subsequent surgery Incision – centered over mass at most superficial location, no tissue flap to

be raised Meticulous haemostasis should be ensured to prevent cellular

dissemination by haematomas FNA Biopsy - limited value, mostly to diagnose recurrence In most pts- exploratory lap – diagnosis on table

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CTND… Extremity sarcoma present late – painless mass, no functional impairment. Physical exam - assessment of size of the mass, depth in relation to superficial fascia, relation to neurovascular and bony structures.

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DIAGNOSTIC IMAGING Should be before any invasive procedure MRI is the choice in extremities CT may be helpful in intra abdominal and few types of sarcomas CT chest and MRI brain may be required to see metastasis Ultrasonography if MRI is contraindicated CT to look for lung Mets.

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CTND… Mets - Common in extremity lesions. Retroperitoneal lesions- liver Mets. Lymph node mets rare 3.7% Higher in RMS, angiosarcoma. Primary lesion - CT or MRI of the local site- extremity or H&N. Abdominal- Spiral CT to know the relation with neuro-vascular structures

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CTND… MRI preferred: enhances the contrast between tumor and muscles and

with blood vessels. Also provides multi planar definition of the lesion. Pelvic lesions: MRI may provide superior single modality imaging. Follow up 3 monthly MRI are done to see recurrence Role of PET not well defined. Correlates well with CECT.

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CTND… PET scan is only a slight better than CT PET frequently fails to distinguish benign lesions from low grade sarcomas. Imaging: metastatic sites An X ray may help in bone involvement Chest X ray: for low grade lesions <10 cm or intermediate or high

grade<5cm.

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HISTOLOGY Electron Microscopy Cytogenetics: Immunohistochemistry and molecular genetic testing. Light Microscopy for morphology Molecular diagnostic techniques include Flow cytometry, fluorescence in

situ hybridization (FISH), and polymerase chain reaction

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HISTOLOGY The biologic behavior of sarcomas is extremely variable Histologic grade is a major prognostic determinant and is based on Degree of mitosis, Cellularity, Presence of necrosis, Differentiation, and Stromal content

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CTND… Pathologic Assessment and Classification (Prognosis) Type of tumor Histologic Grade of Aggressiveness Nodal Metastasis (Rare in adult sarcomas) Distant Metastasis (CT chest) Staging

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CTND… Low-grade sarcomas better-differentiated Less cellular Tend to resemble the tissue of origin to some extent Cytological abnormalities are less prominent Mitotic rate is low Grow slower, low risk of metastasis.

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CTND… Histopathology is determined by anatomic site Common subtypes in the extremity are liposarcoma and malignant fibrous

histiocytoma In the retroperitoneal location liposarcoma and leiomyosarcoma are the

most common histotypes In the visceral location gastrointestinal stromal tumors are found almost

exclusively

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PROGNOSTIC FACTORS 1. Tumor grade 2. Anatomic site 3. Tumor size 4. Depth 5.Histological subtype 6. Age

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LAYOUT Trunk & extremity sarcomas

Malignant Peripheral Nerve Sheath Tumors

Desmoid Tumor

Angiosarcoma

DFSP

Retroperitoneal & Visceral sarcomas

GIST

Leiomyosarcomas

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TRUNK & EXTREMITY SARCOMAS No defined standard for adequate surgical margin Surgical resection

Plane of least resistance is usually along tumor pseudocapsule

Resection along pseudocapsule yields positive margins

Traditionally 1-2 cm grossly negative margin beyond pseudocapsule is recommended

Neoadjuvant therapy thickened pseudocapsule populated by fewer tumor cells

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TRUNK & EXTREMITY SARCOMAS Need to balance ‘degree of limb function’ & ‘tumor control’

Volume of tissue resected direct effect on post-op limb function

Presently – shift towards limb preservation

Goal – Minimum possible functional deficit with enough scope for rehabilitation & prosthetic reconstructions

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TRUNK & EXTREMITY SARCOMAS With adjuvant RT

Slight increase in recurrence in limb sparing group Equal disease free and overall survival Improved local control (independent of tumor grade, tumor depth or margin

status)

If adjuvant RT planned Place metallic clips at boundaries of resection Skin exit point of drain to be near the incision

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TRUNK & EXTREMITY SARCOMAS Neoadjuvant RT

Better target tissue oxygenation more FRs and tumor cell destruction Small volume of adjacent non tumor tissue included Lower pre-op dose is required Not much of measurable tumor shrinkage but varying degree of histological

necrosis

Neoadjuvant EBRT associated with increased risk of wound complications (O’Sullivan B, Davis AM, Turcotte R, et al: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: A randomised trial. Lancet 359:2235–2241, 2002.)

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TRUNK & EXTREMITY SARCOMAS Post-op radiation boost of no benefit if surgical margins positive after

neoadjuvant RT. Positive margins

Increased risk of local recurrence Overall survival remains unchanged Offer re-resection to achieve margins of 1cm

Almost equal rates of negative surgical margins Pre-op RT – 83% Post-op RT – 85%

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TRUNK & EXTREMITY SARCOMAS A retrospective review of 112 patients NACCRT/ NART/ Surgery alone

Equivalent oncological outcomes NACCRT/ NART – better survival of pts with tumor > 5cm NACCRT surgery additional chemo

Increased overall survival Chemotherapeutic agents

Doxorubicin, ifosamide & dacarbazine Doxorubicin – statistically significant improvements in local, distant & overall

recurrence Conflicting data no clear-cut recommendations for CT

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TRUNK & EXTREMITY SARCOMAS Metastases Lungs >> Liver > Bones Predictors of metastasis

Tumor grade Tumor size Bone/neurovascular involvement Tumor depth (Superficial/ deep)

Isolated lung mets – metastatsectomy (repeat if reqd) Chemo agents in metastatic disease

Doxorubicin, dacarbazine, ifosamide, gemcitabine & docetaxel Promising new agents

Trabectedin, sorafenib, pazopanib, palifosamide

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MALIGNANT PERIPHERAL NERVE SHEATH TUMORS MPNSTs

Malignant form of benign schwannoma

Not all arise from Schwann cells (not malignant schwannoma)

Sporadical = as part of NF1

None better than the other

Age: 20 – 50 yrs

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MALIGNANT PERIPHERAL NERVE SHEATH TUMORS Often painless but aggressive

20 % local recurrence

Prognostic factors Tumor size at presentation Tumor grade

Rx: margin negative resection

Adjuvant RT : decreased local recurrence in extremity & superficial trunk lesions

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DESMOID TUMOR - EPIDEMIOLOGY Aggressive fibromatosis

Majority Sporadic (75-85%) Age: 30-40 yrs Recent pregnancy Antecedent trauma

Others – related to FAP Seen in 20% pts with FAP Preceded by colonic polyposis Occur at prior colectomy scar Detailed family history to r/o unappreciated FAP Consider screening colonoscopy

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DESMOID TUMOR – MOLECULAR GENOMICS Related to WNT signaling pathway

Sporadic cases: CTNNB1 mutation Stabilized form of β-catenin Accumulates & transported to nucleus Activated transcription factors proliferative effects

FAP cases: APC mutations β-catenin stabilization Specific APC codon mutations confer higher risk of desmoid

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DESMOID TUMOR – CLINICAL FEATURES Common sites: Extremity, intra-peritoneal, extra-peritoneal, abdominal wall

& chest wall

Asymptomatic firm mass

Painful mass

Bowel obstruction/ ischemia

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DESMOID TUMOR – INVESTIGATIONS CT & MRI both useful Homogenous & solid appearance Distinct/ infiltrating boundary Sporadic type – confused with other types of STS on imaging alone Core needle biopsy – when treatment depends on tumor histology

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DESMOID TUMOR – TREATMENT Margin negative resection Difficult – large/ infiltrating crucial anatomical structures FAP associated desmoids – high recurrence rates Active surveillance rather than reflexive resection

Show very little growth after presentation Resection may warrant significant functional deficits

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ANGIOSARCOMA Origin – endothelial lining of blood vessels Sites –

Trunk H & N (Scalp) Viscera

Maximum - sporadic 40% are radiation associated Other association - lymphedema 7th – 8th decade High regional node involvement

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ANGIOSARCOMA Metastasis

20% at presentation Commonest – lung; breast angiosarcoma - liver

Histology Extremely well differentiated to very poorly differentiated IHC – CD31 & FLI-1

Poor prognostic factors Tumor > 5 cm Epitheloid component on histology

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ANGIOSARCOMA Treatment

Often locally advanced and unresectable at presentation Margin negative resection whenever possible Poor outcome – 5 yr disease free survival is 53%

Mastectomy in pts with recurrence after BCS Distant failure > local failure Chemo & radio-responsive Unresectable/ metastatic disease

Paclitaxel + doxorubicin f/by RT (except when RT is the etiological factor)

Future TKIs; Angiogenesis inhibitors + cytotoxic agents

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DERMATOFIBROSARCOMAPROTUBERANS Uncommon M = F African Americans > whites 4th – 7th decade Translocation t(17;22)(q22;q13) PDGFB overexpression Trunk = upper extremity = lower extremity > H & N Reddish/ brown, firm, indurated nodules Usually painless – can be large at presentation May be mistaken for keloid/ hypertrophic scar

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DERMATOFIBROSARCOMAPROTUBERANS Treatment: margin negative resection

PDGFB overexpression: Neoadjuvant Imatinib may be useful

Recurrence: re-resection

5 yr survival – 92%

Metastasis Rare Implies degeneration to fibrosarcoma

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RETROPERITONEAL & VISCERAL SARCOMA – EPIDEMIOLOGY Retroperitoneal sarcomas:15 % of all STS

Avg size at presentation: 15 cm

Predominant retroperitoneal STS Liposarcoma Leiomyosarcoma MFH

Predominant intraperitoneal STS GIST Leiomyosarcoma

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RETROPERITONEAL & VISCERAL SARCOMA – EPIDEMIOLOGY M = F

Avg age = 54 yrs

Overall survival: 33 – 39 %

Relapse: 70% (even after optimal resection)

Appx 12% metastatic on presentation (Pulmonary/ hepatic)

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RETROPERITONEAL & VISCERAL SARCOMA – CLINICAL FEATURES Asymptomatic

Pain abdomen, early satiety, weight loss

Nausea, vomiting

Back/ flank pain

Paresthesias

weakness

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RETROPERITONEAL & VISCERAL SARCOMA - DIAGNOSIS CT scan:

Rapid image acquisition Easy availability Concise image set Better interpreted than MRI by non-radiologist Enough information to proceed for treatment

MRI: Wide range of soft tissue differentiation Motion artifact Limited availability Implant related contraindications

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RETROPERITONEAL & VISCERAL SARCOMA - DIAGNOSIS Rule out following:

Lymphoma Germ cell tumor Metastasis from other primary tumor

Pre-op biopsy: Not mandatory Ruptures tumor seeds the operative field Reduces possibility of margin negative resection Can be misleading in large tumors (sampling bias) If required taken from most concerning area under image guidance

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RETROPERITONEAL & VISCERAL SARCOMA - TREATMENT Margin negative resection Large tumors – 100% margins cant be evaluated Complete gross resection to be achieved

May need to resect contiguous/ inseparable adjacent organs Kidney, bowel, pancreas & vascular structures

Predictors of poor outcome Gross residual disease after resection Unresectable disease (metastatic/ locally advanced)

Median survival with unresectable disease = 10 mth (with optimal CT & RT)

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RETROPERITONEAL & VISCERAL SARCOMA - TREATMENT Radiotherapy

Can’t use conventional 60-70 Gy used in extremity STS 50-55 Gy – significant enteritis

Neoadjuvant RT Tumor displaces bowel anteriorly higher dose posteriorly 45 Gy to target 65 Gy boost to at-risk margins Well tolerated

Metastatic retroperitoneal sarcoma 1st line - Single/ combination with anthracyclines 2nd line – gemcitabine & docetaxel Novel agents - trabectedin, TKIS, PPAR-γ agonists.

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GIST - PATHOLOGY Most common type of visceral STS Origin – interstitial cells of Cajal within myenteric plexus These cells function as pacemakers in viscera, mediating contractions Sites – Stomach, small bowel, rectum. Majority – Sporadic Syndromic association

NF1 Germ line SDH mutations Carney-Stratakis syndrome VHL disease

Classically a spindle cell neoplasm of smooth muscle origin

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GIST - GENOMICS Markers: CD 34, CD 117 (KIT gene), DOG 1 expression

KIT gene (CD 117) (Chr 4)↓

c-kit (TK transmembrane receptor)A proto-oncogene (PDGFR superfamily)

↓Natural c-kit ligand (a stem cell factor) binds with c-kit receptor

↓Activates multiple pathways

(RAS, RAF, MAPK, AKT, STAT3) c-kit receptor mutation constitutive activation cellular proliferation

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GIST - GENOMICS c-kit receptor mutation constitutive activation cellular proliferation

PDGFRA (PDGFRα) – strikingly similar to c-kit

70% GIST – KIT gene mutations 07% GIST – PDGFRA mutations 15% GIST – Wild type KIT & PDGFRA genotypes

Other mutations – SDH (Carney- Stratakis syndrome), BRAF, KRAS and NF1 (NF type 1)

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GIST - CLINICAL FEATURES Asymptomatic (incidental)

Pain

Nausea, vomiting

GI blood loss (rare; implies mucosal ulceration)

Associated syndromic features

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GIST - INVESTIGATIONS Endoscopic: smooth submucosal tumor, extrinsically impinging on visceral lumen DD on endoscopy : GIST, NET, intrmural lipoma, lymphoma Serosally pedunculated tumor – no obstruction CT findings

Well encapsulated Heterogeneous contrast enhancement

Biopsy: non-diagnostic (submucosal tumor) Endoscopic US guided needle biopsy – spindle cell neoplasm Double balloon enteroscopy/ capsule endoscopy Pre-op staging: CECT chest, abdomen, pelvis

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GIST - TREATMENT Surgery: margin negative excision Wide surgical margins

Don’t improve local recurrence/ overall survival Don’t compromise the capsule Document integrity of tumor capsule (affects adjuvant therapy) Lymphadenectomy not mandatory Ideal pathology report:

Tumor site and organ of origin Tumor focallity, mitotic rate*, CD 117 status (IHC),

* - Total count of mitoses per 5 mm2 ; synonymous with tumor grade. DD: melanoma, paraganglioma, NETs & nerve sheath tumors.

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GIST – AJCC STAGING

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GIST – GASTRIC & OMENTAL

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GIST – NONGASTRIC GIST

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GIST – RECURRENCE National Institute of Health Consensus Criteria for GIST estimated risk of

recurrence Based on several sets of independently validated criteria and validated

subsequentlyEstimation of risk Largest tumor dimension (Cm) Mitoses, per 50 HPFVery low risk <2 <5Low Risk 2-5 <5Intermediate risk <5 6-10

5-10 <5High risk >5 >5

>10 Any mitotic rateAny size >10

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GIST – ADJUVANT THERAPY Molecular phenotype of GIST dictates success of adjuvant therapy KIT mutation in exon 11 (70%) & 13 ( resides in TKI domain)

Imatinib sensitive KIT mutation in exon 9 (small bowel/ colonic GIST) (extracellular domain)

Less sensitive to Imatinib Systemic therapy indicated in

Adjuvant therapy in resected GIST Neoadjuvant therapy of metastatic/ unresectable/ locally advanced GIST

Agents 1st line – Imatinib (oral TKI inhibitor of c-KIT) Others – Sunitinib, regorafenib

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GIST - IMATINIB Imatinib

Dramatic improvement in metastatic GIST survival Median overall survival 20 mth 57 mth

1yr Vs 3yr adjuvant imatinib after resection of c-kit – positive GIST Improved recurrence free survival & overall survival

Non gastric GIST & high mitotic count – adversely affects recurrence free survival (Joensuu H, Eriksson M, Hall KS, et al: Risk factors for gastrointestinal stromal tumor recurrence in patients treated with adjuvant imatinib. Cancer 120:2325–2333, 2014.)

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GIST – SDH MUTATION SDH mutation associated GIST

Younger patients Multifocal gastric GISTs Poor response to imatinib

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LEIOMYOSARCOMA Malignant smooth muscle cell tumor 2nd most common STS after liposarcoma Sites

Retroperitoneum > Peritoneal cavity (uterus) 25% - trunk & extremity

Predisposition Prior radiation exposure Immunosuppression EBV related tumors

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LEIOMYOSARCOMA Gross

Heterogeneous, well circumscribed Cystic/ necrotic central area

IHC (no reliable marker) Desmin positive Smooth muscle actin positive

Treatment Margin negative resection Uterine – TAH + BSO

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LEIOMYOSARCOMA Tumors invading/ closely abutting IVC

Already have high degree of collateralization Neoadjuvant RT may be useful Tumor resection + IVC ligation Patching of IVC Interpositioning graft of IVC Collaterals preserved – ligation of IVC without reconstruction (post-op lower extremity edema well tolerated)

Metastasis Mainly haematogenous Lung > liver Poor response to chemo – doxorubicin, ifosamide, docetaxel, gemcitabine

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MALIGNANT FIBROUS HISTIOCYTOMA Previously defined as malignant pleomorphic spindle cell tumor with

fibroblastic & histiocytic differentiation. UPS – pleomorphic sarcomas with no definable line of differentiation Uncommon, cutaneous, spindle-cell STS Sites

Extremities (lower >> upper) Head & neck Previous RT site Site of chronic ulceration (rare)

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MALIGNANT FIBROUS HISTIOCYTOMA Elderly patients (peak @ 60-70 yrs) Solitary, painless, soft – firm, skin colored, deep seated mass Rx – margin negative resection Adjuvant RT for local control Recurrence: 30-35% Mets: in 50% at presentation – contraindication for surgical resection 5 yr disease specific survival – 65%

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SUMMARY Strong understanding of tumor biology

Physiological consequences of various resection strategies

Plan and develop multidisciplinary oncology apch

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REFERENCES Devita’s principles & practice of oncology, 10th Ed, 2015, Wolters Kluwer

Sabiston textbook of surgery, 20th Ed, 2016, Elsevier

Schwartz’s principles of surgery, 10th Ed, 2015, Mc Graw Hill

http://www.ncbi.nlm.nih.gov/pubmed