Soft Tissue Sarcomas PDF

SOFT TISSUE SARCOMAS PIO RUPERTO S. CALMA MD, FPCS,FPSGS,FSOSP G E N E R A L S U R G E RY – S U R G I C A L O N C O LO G Y FAT I M A U N I V E R S I T Y M E D I C A L C E N T E R D E PA R T M E N T O F S U R G E R Y OBJECTIVES : 1. to be familiar with the disease entiti...

SOFT TISSUE SARCOMAS PIO RUPERTO S. CALMA MD, FPCS,FPSGS,FSOSP G E N E R A L S U R G E RY – S U R G I C A L O N C O LO G Y FAT I M A U N I V E R S I T Y M E D I C A L C E N T E R D E PA R T M E N T O F S U R G E R Y OBJECTIVES : 1. to be familiar with the disease entities classified with soft tissue sarcomas 2. to demonstrate the epidemiology and burden of the disease 3. discuss the causes of disease entities under the classification of sot tissue sarcomas 4 approach to the patient with soft tissue sarcomas ◦ Diagnosis ◦ Staging ◦ Treatment ◦ Prognosis  SARCOMA A heterogenous group of solid tumors derived from tissues of mesenchymal origin Mesenchyme are loose connective tissues derived from the embryonic mesoderm bone muscle tendons, ligaments, fat, fibrous tissue, lymph and blood vessels nerve sheath , fasciae and synovial membranes OSTEOSARCOMAS sarcomas of the bone SOFT TISSUE SARCOMAS Refers to all tissues in the body that has not undergone ossification or calcification (hardening) Connects , surrounds or supports internal organs and bones SARCOMA : Epidemiology Ø 1% of all adult malignancies Ø 15% of pediatric malignancies Ø American Cancer Society 2022 projection for Soft Tissue Sarcoma Ø13,190 new cases ( 7,590 Males and 5,600 females) Ø5,130 expected mortalities ( 2740 males and 2,390 females ) ØUK SARCOMA : Risk Factors Radiation exposure radiation induced mutation of the p53 Gene External beam readiations for for cancer increases risk by 8-50 times Chemical exposure herbicides phenoacetic acid , chlorophenols in wood preservatives. Thorotrast ( thorium oxide ) Vinyl chloride arsenic Hepatic angiosarcomas Trauma – no ignificant correlation Chronic lymphedema – small association 0.07% angioliposarcoma Genetic factors SARCOMA : Molecular Pathogenesis 1. translocation or gene amplification ◦ Translocations have been identified in 14 subtypes of sarcoma ( 20%-30% of all sarcomas ) ◦ Frame mutations that encode for oncoprotein that act as tumor activator or oncogenes suppressor ◦ Ewing’ Sarcoma ( EWS-FL11) Clear cell sarcoma ( EWS-ATF1) myxoid/roundcell liposarcoma 2. oncogenic mutations ◦ malignancy is driven by a single activating mutation ◦ KIT Receptor tyrosine kinase in GIST 3. complex genetic rearrangements ◦ Accounts for the causation of the largest group of sarcomas: high gradespindle cell and pleomorphic sarcoma ◦ Rb (Retinoblastoma) gene deletion and p53 mutations ( li Fraumeni Syndrome) are the mos common  Soft Tissue Sarcoma: Generalities There are about 50 sub types of soft tissue sarcomas Most common types are : ◦ Undifferentiated pleomorphic sarcoma, ◦ Gastrointestinal stromal tumors ◦ Liposarcoma ◦ Leimyosarcoma Distribution by ANATOMIC LOCATION Extremities 43% Trunk 10% Visceral 19% Retroperitoneum 15% Head and neck 9 % Clinical Presentation Mass ◦ Usually painless / asymptomatic ◦ Discovered incidentally ◦ May present as deep venous thrombosis ◦ May be discovered because of compressive symptoms ◦ ( Gastrointestinal Obsruction, Nerve compression) ◦ Discovery is often influence by the relationship of the mass to the location ◦ Superficial vs deep ◦ Proximal vs distal extremeties ◦ Trunk vs intrabdominal STS Clinical Presentation ◦ LYMPHADENOPATHY ◦ Not common ◦ Found in about 5% of soft tissue sarcoma ◦ DISTANT METASTASES ◦ Most commonly found in the lungs for extremity , trunk and head and neck sarcomas ◦ Liver may be the first site for Intraabdominal or retroperitoneal sarcomas PATTERN OF DISTANT METASTASIS : HEMATOGENOUS Differential diagnosis v benign soft tissue masses vLipoma vSebaceous cyst vFibroma vMetastatic subcutaneous lesions vLymph node metastasis vLymphoma Approach to the patient History ◦ Symptomatology ◦ Past medical History ◦ Previous illness requiring radiation treatment ◦ Family History ◦ Familial Syndrmes ( Li Fraumeni syndrome, Familial adenomatous polyposis, Hereditary retinoblastoma) ◦ Exposure ( work, Hobbies, environment) ◦ Radiation ◦ Chemicals Approach to the patient PHYSICAL EXAMINATION MASS ◦ Size ◦ Shape ◦ Consistency ◦ Location ◦ Mobility LYMPHATICS ◦ Presence or absence of palpable regional lymph nodes OTHER SURRONDING STRUCTURES ◦ Erythema / Discoloration ◦ Swelling ◦ Sensory / motor deficit Approach to the patient : Ancillary procedures Characteristics of the tumor location of the tumor Tissue of origin Involved structures Local extension of the tumor Distant metastasis Approach to the patient : Ancillary procedures RADIOGRAPH ( X - RAYS ) Useful in osteosarcomas Determine bone changes in the areas adjacent to the soft tissue sarcoma Used as alternative in surveillance for lung metastasis Approach to the patient : Ancillary procedures ULTRASONOGRAPHY Characterizing the tumor Determine the depth of invasion and involvement of other sturctures (vascular ) Used to evaluate regional lymph node metastasis Operator dependent results MAIN USES for STS Guide for needle biopsies MRI Contraindicated Patients Surveillance of recurrence Approach to the patient : Ancillary procedures CT SCANS ( COMPUTED TOMOGRAPHY ) Intraabdominal and retroperitoneal sarcoma Distant Metastasis Used for other forms of sarcoma if MRI can not be used Approach to the patient : Ancillary procedures Magnetic Resonance Imaging Imaging modality of choice for evaluating sarcomas Accurately distinguishes and delineates between soft tissue, bone vascular structures and compartment Different views ( saggital, coronal ) allow 3D views Special techniques available ( MRAngiography) adjunct to cytologic analysis in distinguishing benign lesions Surveillance for monitoring tumor recurrence Approach to the patient : Ancillary procedures Pet SCANS ( POSITRON EMISSION TOMOGRAPHY) Functional Imaging Modality ◦ Uses F – D Glucose uptake of tissues and tumor ◦ In itself does not have a good anatomical correlation ◦ must be partnered with CT Scans Evaluation of the whole body Not used for the initial assessment and staging of the tumor Assess tumor grading Assess response to chemotherapy Approach to the Patient : Biopsy HISTOPATHOLOGIC DIAGNOSIS Biopsy – obtaining a sample from the mass in question for pathologic study Ø Fine Needle Aspiration Biopsy o able to provide cells which may be assessed as benign or malignant ØCore Needle Biopsy o provides a larger sample , tissue, includes extracelluar matrix. Shows relationship to other cells ØIncision biopsy o a larger sample of tissue. More invasive and may be more superficial ØExcision biopsy Removal of the entire tumor Ø Removal of the entire mass with margins Ø Not recommended for the initial management due to the high incidence of positive tumor margins ØEn bloc resection resection of the entire tumor including its lymphovascular structures Ø Not recommended since metastatic spread is by hematogenous route Approach to the Patient : BIOPSY BIOPSY : CLINICAL KEY POINTS ØAdequate tissue sample for histopathologic studies which may include regular stains, immunohistochemical stains, molecular testing, genetic testing ØHemostasis is of importance. : Hematogenous spread ØEntry puncture (for needle biopsy )and incision ( for incision biopsy) must be carefully planned for it to be included in excision or radiation ØImage guidance ( ultrasound or ct scan ) is recommended for needle biopsies so as to limit areas of capsule violation/puncture Approach to the Patient: Pathologic Assessment morphologic assessment Tumor Grade Supporting ancillary Techniques vImmunohistochemistry vCytogenetic testing vMolecular cytogenetic Testing vFlourecence In Situ Hybridization ( FISH ) vPCR Based methods PATHOLOGIC CLASSIFICATION and TUMOR GRADE are very important in PROGNOSTICATION  Approach to the Patient: Pathologic Assessment STANDARDIZED PATHOLOGY REPORT ØPrimary Diagnosis ØAnatomic site ØDepth of invasion ØSize ØHistologic grade ØMitotic figures ØNecrosis ØMargins ØVascular invasion ØLymph node status  Approach to the Patient: Pathologic Assessment LIMITED /LOW METASTATIC POTENTIAL Desmoid Atypical Lipomatous tumor (Well Differentiated liposarcoma) Dermatofibroma protuberans Solitary fibrous tumor INTERMEDIATE RISK FOR METASTATIC POTENTIAL Myxoid liposarcoma Myofibrosarcoma Extraaskeleal myxoid chondroma HIGH RISK METASTATIC POTENTIAL angiosarcoma clear cell sarcoma pleomorphic sarcoma Dediffrentiated liposarcoma Leimyosarcoma Rhabdomyosarcoma Synovial Sarcoma  Approach to the Patient: STAGING v Based on Universally accepted Tumor staging system vWorld Health Organization system vAmerican Joint Committee on Cancer ( AJCC ) 8th. edition vHISTOLOGIC GRADE of AGGRESIVENESS (TUMOR GRADE) is included in the Staging vAJCC Staging vAlso known as TNM staging T- size and depth N. Nodal Status M-Metastasis Histologic grade of aggressiveness  Approach to the Patient: STAGING HISTOLOGIC GRADE OF AGGRESSIVENESS v MOST IMPORTANT PROGNOSTIC FACTOR vDefining features vCellularity vCell differentiation vPleomorphism vNecrosis ( 50% ) vNumber of mitosis per high power field ( 10/hpf, 10-19 /hpf, >20/hpf ) vGood predictor of distant metastasis and overall survival (OS) v 5-10 % metastasis in low grade v25-30% intermediate grade v50-60% high grade  Approach to the Patient: STAGING HISTOLOGIC GRADE OF AGGRESSIVENESS vNational Cancer Institute vHistologic subtype, location and amount of necrosis vFrench Federation Cancer Center vTumor differentiation , Mitoses /HPF,and amount of tumor necroisthree vAJCC vThree tier group v Grade 1 Well differentiated v Grade 2 Moderately differentiated v Grade 3. Poorly differentiated  Approach to the Patient: STAGING American Joint Committee on cancer (AJCC) 8th edition T – Tumor Characteristics v size v Depth of iinvasion N- Nodal involvement ◦ Presence or absence of regional metastasis M – Distant Metastasis ◦ Presence or absence of distant metastasis ◦ Lung metastasis from extremity, Trunk and head and neck STS ◦ Liver and peritoneal metastasis for Intraabdominal, angiosarcoma, GIST Two types of staging 1. Clinical Staging ( preoperative staging ) 2. Pathological staging postoperative staging Approach to the Patient: STAGING Approach to the Patient: STAGING  Approach to the Patient: CLINICAL STAGING History and Physical Examination Histopathologic studies on the Primary Tumor Biopsies Lymph node evaluation Imaging Results  Approach to the Patient: TREATMENT PLANNING GOALS Ø Maximize long term Recurrence Free Survival (RFS) ØIncrease time of Overall Survival ( OS ) ØOverall 5 year survival rate with STS is about 50-60% 5 year survival rate ØMinimizing Morbidity ØMaximizing function and quality of life Approach to the patient : Treatment Planning MultiDisciplinary Team (MDT)oncology - Surgeon/ surgical oncologist -Anesthesiologist - Medical oncologist -Pain and Paliative Care Specialist -Rediation oncologist -Reconstructive Surgeon - Diagnostic Radiologist -Rehabilitation Medicine specialist - Pathologist - Intervetntional Radiologist --endoscopist ( Gastroenteroogist, otorhinolaryngologists ) -Nutritionist -Psychologists / Counselors -Geneticists -Nurse -Patient’s Relatives advocate  Approach to the Patient: TREATMENT MODALITIES SURGERY Ø Remove the entire tumor with a 1-2 cm margin ØMaybe used as lone treatment if tumor is resectable (R0) Resection or in combination with other treatment modality options if tumor is unresectable ØFactor affecting the resectability and type of surgical resection ØTumor location ØTumor size ØDepth of invasion ØInvolvement of nearby structures ØNeed for sking graftin or tissue reconstruction ØPatiet’s performance status  Approach to the Patient: TREATMENT MODALITIES SURGERY RESECTABILITY RO – no gross nor microscopic tumor left behind (negative Margins of resection ) This includes metastasis R1 – No gross tumor is left behind but there is evidence of microscopic malignant cells left ( Positive margins of Resection ) R2 – Gross tumor left behind The chances of RO are increased by observing recommended distance from the end of the gross tumor to the lines of resection (1-2 cm in STS)  Approach to the Patient: TREATMENT MODALITIES SURGERY v 1980s and earlier – extremely radical resection ( amputation for Limb Sarcoma) was the procedure of choice v1985 concensus statements have been made that limb sparing surgery coupled with radiation therapy +/- systemic chemotherapy will produce equivalent OS vRadical amputation is reserved as the treatment of choice for rare cases wherein tumor can not be resected and irradiated vSurgical reexcision is recommended for patients with a pathologically positive margin (R1 Resection )when possible vSurgery is also recommended to remove recurrent tumor when possible vAdequate margins of 1-2 cm is advocated except in cases where smaller margins are necessary to preserve vital functional structures v In clinical practice – metallic clips are best left on the margins which. Provide guide to reexcision or radiation treatment  Approach to the Patient: TREATMENT MODALITIES SURGERY v surgery resection lines should be carried out through normal tissue vSTS are generally surrounded by a pressed layer of tissue that forms a pseudocapsule but resection should be well beyond the capsule ( wide excision vs enucleation) vIf tumor abuts neurovascular structures, the adventitia or perineurium should be removed vFor bone involvement, resection of bone and reconstruction may be carried out but may increase risk for post-operative morbidity and decrease postoperative functional outcome vRadical lymphadenectomy is indicated for patients with biopsy proven Lymph node metastasis  Approach to the Patient: TREATMENT MODALITIES SURGERY – ISOLATED LIMB PERFUSION v Limb sparing technique using high perfusion rate of Tumor necrosis alpha and melphalan under hyperthermic condition v isolating the main artery and main vein of the affected limb vExternal iliac –thigh tumors vFemoral/popliteal – leg tumors vAxillary vessels – upper extremity tumors v Main artery and vein are connected to an infusor pump oxygenator. The limb circulation is occluded by a tourniquet and chemothereapeutic agents are pimped in and circulated for 90 minutes and hyperthermia at 40degrees Celsius is maintained vNot very commonly used as a lot of questions need to be answered for this technique  Approach to the Patient: TREATMENT MODALITIES RADIATION vPart of the standard of care of high grade extremity and trunk sarcoma vSmall , low risk and intermediate risk tumors that are amenable to wide excision may do away with surgery v high risk tumors will benefit from radiation vDifferent modes of radiation therapy are available vExternal Beam Radiotherapy (EBRT) vBrachytherapy vIntensity Modulated Radio Therapy ( IMRT ) vTiming of Radiotherapy vPreoperative Chemotherapy vIntraopertive Chemotherapy vPostoperative Chemotherapy  Approach to the Patient: TREATMENT MODALITIES RADIATION COMPLICATIONS vWound dehiscence vWould necrosis vInfection vSeroma formation vCellulitis vFibrosis vContractures  Approach to the Patient: TREATMENT MODALITIES SYSTEMIC THERAPY vAttempts to address systemic spread distant metastasis vIndicated for vwith high risk features STS vNon extremity sites vTIMING of CHEMOTHERAPY vNeoadjuvant v Downsize the tumor v Observe Response vAdjuvant vConcurrent Chemoradiation – chemotherapeutic agent as a radiosensitizer ( Synergistic effect) v Decreases treatment time v Quicker control of the local disease  Approach to the Patient: TREATMENT MODALITIES SYSTEMIC THERAPY STANDARD CHEMOTHERAPY ØPoor results results ØSensitivity varies by histologic type ØSynovial , myxoid liposarcoma uterineleiomyoma are chemosensitive ØPleomorphic liposarcoma, leiomyosarcoma, Desmoplastic round cell tumors have moderate sensitivity ØClear cell sarcoma, endometrial sarcoma, Alveolar soft part sarcoma chemo resistant Doxorubicin Iposphamide Complications : cardiotoxicity Newer agent : Gemcitabine, Taxanes and trabectedine – more promising results  Approach to the Patient: TREATMENT MODALITIES SYSTEMIC THERAPY TARGETED THERAPY vTarget a specific process in the cell cycle vTyrosine kinase inhibitor ( Imatinib, sunitinib, sorafenib) Targeting the CKIT receptor ( CD117) vGastrointestinal Stromal Tumors vAnti vascular endothelial growth factor ( bevacizumab ) vAngiosarcoma vPazopanib – angigogenesis inhibitor targeting vascular endothelial growth factor receptors vhemangioendothelioma  Approach to the Patient: TREATMENT PLANNING ü Multidisciplinary team approach üpatient’s stage üPrognosis =OS and RFS üfunctional outcome and expected quality of life üAvailable treatment options available to the patient  Approach to the Patient: TREATMENT PLANNING BASIC PRICIPLES of treatment LOCAL Disease RESECTABLE ØSurgery alone if tumor is completely resectable (RO) and with low grade /stage ØSurgery with Radiation if completely resectable (RO) with intermediate or high grade/stage ØSurgery with Radiation if resectable with close margins ØSurgery with chemotherapy for certain STS with intermediate or high risk for distant metastasis or recurrence Øe.g. Gastrointestinal stromal Tumor  RESECTABILITY RO – no gross nor microscopic tumor left behind (negative Margins of resection ) This includes metastasis R1 – No gross tumor is left behind but there is evidence of microscopic malignant cells left ( Positive margins of Resection ) R2 – Gross tumor left behind The chances of RO are increased by observing recommended distance from the end of the gross tumor to the lines of resection  Approach to the Patient: TREATMENT PLANNING BASIC PRICIPLES of treatment LOCAL Disease UNRESECTABLE Ø CONSIDER neoadjuvant treatment with intent of surgery ØSurgery (R1 /R2) resection with adjuvant chemo and radio therapy increases functional survial with a small increase in overall survival compared with no treatment ØExtremely radical surgery ( amputation ) is reserved as a last resort ØDefinitive Radiotherapy and Chemotherapy is reserved for the patients with poor performance status  Approach to the Patient: Surgical Treatment Assessment and Management Pathologic Study Ø more accurate stage/grade than preoperative stage Ø provide the resection margin status MANAGEMENT OF POSITIVE EXCISION MARGINS Ø Re excision of the tumor bed ØAdjuvant Radiation Therapy for tumors not amenable to reexcision Dissection of Lymph nodes D1 – removal of lymph nodes surrounding the organ D2 removal of lymph nodes in along the main blood supply of the tumor D3, removal of the lymph nodes associated with adjacent organs Both needed for staging, and cure  Approach to the Patient: TREATMENT PLANNING BASIC PRICIPLES of treatment METASTATIC Disease REGIONAL METASTASIS ØRegional lymph node metastasis is uncommon