SOFT TISSUE SARCOMA

Detailed Description about soft tissue sarcoma.
Deals with topics including etiology, histopathology,clinical presentation ,staging and prognostic factors and management methods including surgery and adjuvent therapy .

Soft tissue sarcomas are a heterogeneous group of malignant tumours derived from primitive mesenchymal cells.
They are aggressive tumours which are locally invasive and recurrent.
They are named based on the cell of origin .
They require multimodal treatment including surgery and certain adjuvent therapies

1. SOFT TISSUE   SARCOMA S5 UNIT

2. History 1 st referred in Papyrus Eberus in 1500 BC which recommends treatment with knife. Later Hippocrates , Celsus and Galen contributed Rudolf Virchow, Samuel Gross and Samuel Wilks laid the foundation of our modern day understanding of STS

3. Soft Tissue Sarcoma Soft tissue Connects,surrounds & support  skeletal system  Non-epithelial &            extra-skeletal Derived from mesoderm with neuroectoderm contributions Sarcoma Greek ‘Sarcos’ =fleshy Malignant tumours arising from  mesenchymal tissue younger age group  Fish flesh gross look with hemorrhage and necrosis Rapid growth ,early blood spread

4. Sarcoma Tumours of mesenchymal origin  Rare - < 1% of all cancers Arise from   bone - Osteosarcoma  soft tissue -Soft Tissue Sarcoma STS to bone sarcoma - 3:1 Sporadic- Origin is unknown. arise from pluripotent mesenchymal stem cells  somatic "driver" mutations in oncogenes/ suppressor genes

5. More common Older age group Arise from Sarcoma  Carcinoma  Origin  Mesenchymal(connective) tissue Epithelial tissue  Incidence  Less common  More common Age  Younger age  Older age  Vascularity  More vascular  Less vascular  Rate of growth  More rapid  Less rapid  Spread  Hematogenous spread  Lymphatic spread  Prognosis  More worse  Less worse

6. Soft Tissue Tumours Benign soft tissue tumors are 100 times more common than STS  Most of the sarcomas arise de novo . Benign tumour will not turn into malignancy

7. Soft Tissue Sarcomas  STS constitute heterogeneous group of malignant tumors derived from primitive mesenchymal cells. Aggressive tumours-locally invasive and recurrent Require multimodality therapeutic approach .

8. STS are named based on tissue which it resemble  Liposarcoma-Fat  Fibrosarcoma-fibroblast  Malignant fibrous histiocytoma-histiocyte              (Undifferentiated Pleomorphic Sarcoma-UPS )  Leiomyosarcoma- smooth muscle  Rhabdomyosarcoma-skeletal muscle  Chondrosarcoma-chondroblast  Angiosarcoma-blood vessels

9. Incidence   Soft-tissue sarcomas are relatively uncommon cancers.    1% of adults malignancy    15% of pediatric malignancies This may be because cells in soft tissue are not continuously dividing cells.  However they cause 2% of all cancer mortality -> aggressive behavior-life threatening 

10. Epidemiology   GENDER -males : females -> 4:1   AGE – older age group  Bimodal distribution - 5th and 8th decades. Median age of diagnosis is 59 yrs .  

11. Mortality   40% of the newly diagnosed sarcomas eventually die   In Surveillance, Epidemiology and End Results Program (SEER) data -> median age of death- 65yr Overall 5-year survival rate - 50% to 60%  Most will succumb within 2-3yrs of diagnosis.

12. Distribution Sarcoma has  > 50 histologic subtypes In adults UPS(MFH) and liposarcoma-15-45%   Rhabdomyosarcoma-10% Leiomyosarcoma 9-15% Synovial sarcoma-7% Malignant peripheral nerve sheath  tumour  (MPNST)-6%  Fibrosarcoma -5% In children Rhabdomyosarcoma  ,neuroblastoma 

13. RETROPERITONEUM LIPOSARCOMA VISCERAL (GIT)SARCOMA  LEIOMYOSARCOMA GENITOURINARY SYSTEM  LEIOMYOSARCOMA UTERUS LEIOMYOSARCOMA MYOCARDIUM ANGIOSARCOMA  HAND AND FOOT SYNOVIAL SARCOMA SKIN KAPOSI'S SARCOMA  HEAD AND NECK REGION ANGIOSARCOMA  SITE   COMMON TYPE  EXTREMITIES  MFH & LIPOSARCOMA

14. Anatomical location  Connective tissues seen throughout body so STS can occur anywhere  Extremities -  40%  (thigh-MC) Visceral - 19% Retroperitoneal - 15% Trunk/thoracic - 10%   Other- 13%

15. Distribution by location for adult patients with soft tissue sarcoma

16. AETIOLOGY By R i s h i ke s h  T h a m p i   

17. Aetiology Genetic factors Exposure to radiation Chemicals Viral infection Others

18.       Genetic Disorders                       Disorder                          Cause Neurofibromatosis Gardner syndrome Mutation in gene NF1 Defect in gene APC Li- Fraumeni syndrome Werners Syndrome Defect in gene TP53 Defect in gene  RECQL2 Gorlin syndrome  Retinoblastoma Defect in PTC gene Defect in gene  RB1

19. 1.Ne u r o fi b r o m a t o s i s Benign tumors under the skin and in other parts of the body Also known as von Recklinghausen disease. 5% have risk of developing nerve sheath tumour

20. 2 . Gardner syndrome Syndrome get many polyps in the colon and have a high risk of getting colon cancer. It also causes desmoid  tumors

21. 3. Li-Fraumeni syndrome  H igh risk cancer, such breast   cancer, brain tumors, and sarcomas

22. 4. Werner syndrome These include clogged heart arteries (arteriosclerosis) which can lead  to heart attacks, cataracts , and skin changes.  R isk of soft tissue   sarcomas.

23. 5. Gorlin syndrome Also called nevoid basal cell carcinoma syndrome

24. 6 .Retinoblastoma  R isk of developing bone           or soft tissue sarcomas

25.   Effects of  R adiation 8 to 50-fold increase in the incidence of STS is reported in patients who are treated for cancer of the breast, cervix and ovary by radiation.

26. C hem icals PVC T etrachlorodibenzodioxin   Arsen ic Thoratrast Pesticides Thorium oxide

27. Viral HIV in Kaposi's sarcoma    C           ytomegalovirus

28. Osteogenic sarcoma in Paget's disease of bone/exposure to radium Lymphangiosarcoma in post-mastectomy Lymphodema - Stewart   Treves syndrome.    Others

29. Histopathological classification  By Rishla  Sherin V.P 

30. Classification A) Tumour and tumour like lesions of fibrous tissu e           Fibrosarcoma B) Fibrohistiocytic tumors                 Dermatofibrosarcoma protuberance           Pleomorphic sarcoma       C) Tumours of adipose tissue                  Atypical lipoma                 Liposarcoma     D) Smooth muscle tumours                 Leiomyosarcoma                 Epitheloid leiomyosarcoma

31. E) Skeletal muscle tumours            Rhabdomyosarcoma            Rhabdomyosarcoma with ganglionic differentiation F) Tumour of blood vessels & lymphatics            Hemangiopericytoma            Angiosarcoma & lymphangiosarcoma            Kaposi’s sarcoma G) Tumours of peripheral nerves           Malignant peripheral nerve sheath tumour H)  Tumours of uncertain histiogenesis           Synovial sarcoma           Alveolar soft part sarcoma           Clear cell sarcoma

32. Topics for discussion Pleomorphic sarcoma  Leiomyosarcoma Liposarcoma Synovial sarcoma Fibrosarcoma Malignant peripheral nerve sheath tumor 

33. High grade undifferentiated pleomorphic sarcoma Malignant fibrous histiocytoma Grossly,         multilobulated         well circumscribed          firm,fleshy mass.

34. WHO categories:      a)Storiform        b)Inflammatory      c)Giant cell      d)Myxoid Histologically ,               Admixture of  Spindle shaped fibroblast like cells              & mononuclear histiocyte like cells.

35. Leiomyosarcoma Grossly,     diffuse,bulky,soft & fleshy mass      or a polypoid mass projecting into lumen

36. Histologically,      Whorled arrangement of Spindle shaped smooth muscle cell             With large & hyperchromic nuclei. Diagnostic criteria,     more than 10 mitosis per HPF

37. Liposarcoma Grossly,            Nodular circumscribed mass             But it is infiltrative 

38. Histologically ,           Variable number of lipoblasts- univacuolated  /                                 multivacuolated - Hallmark  of diagnosis .               4 Major histologic varieties are          1.Well differentiated             2.Myxoid.          3.Round cell                              4.Pleomorphic Click to add text

39. Synovial sarcoma Grossly , Variable size Multilobulated       Encapsulated.   Fish flesh like sarcomatous appearance  with foci of                          calcification                          cystic spaces  areas of hemorrhage necrosis.

40. Histologically , Biphasic cellular pattern Clefts or gland like structure cuboidal to columnar epithelial like cells           & spindle cells. Myxoid matrix, calcification,hyalination are present in stroma.

41. Fibrosarcoma Grossly ,           Lobulated & circumscribed            soft , fish flesh like ,with foci of necrosis &                  hemorrhage

42. Histologically ,         uniform spindle shaped fibroblast arranged in   intersecting    fascicles. In well differentiated tumour produce herring bone pattern

43. Malignant peripheral nerve sheath tumour Grossly , an unencapsulated fusiform enlargement of a nerve. Histologically , It resemble fibrosarcoma. Triton tumor :Rhabdomyosarcoma, cartilage, bone

44. CLINICAL FEATURES & DIAGNOSIS By Rose Tom

45. CLINICAL FEATURES Depends on anatomical site and depth of tumor Asymptomatic swelling – short duration – progressive increase in size 33% may complain of pain Occasionally may affect function

46. Extremity STS  Small painless mass Retroperitonial  sarcoma Large mass – compress/invade contiguous structures

47. CLINICAL EVALUATION Assess the size Plane Relation to neurovascular structures and bone Look for LNs and visceral  mets DDs : hematoma, pulled up muscle

48. Warning Signs Larger than 5 cm Increasing in size Painful Deep to the fascia Recurrence after previous excision Each factor has a 25% risk of malignancy

49. METASTASIS / SPREAD Alveolar soft part sarcoma Advanced extremity myxoid liposarcoma Retroperitoneal Overall + Extremity STS Malignant fibrous histiocytoma Angiosarcoma Rhabdomyosarcoma Clear cell sarcoma Epithelial Synovial sarcoma HEMATOGENOUS SPREAD LYMPHATIC SPREAD

50. DIAGNOSIS Evaluation begins with a comprehensive history and physical examination

51. INVESTIGATIONS DIAGNOSTIC METASTATIC PRE-OPERATIVE BLOOD INVESTIGATION Blood routine Urine routine RFT LFT IMAGING MRI CT Abdomen Chest X-Ray CT Chest CT Abdomen PATHOLOGICAL EVALUATION Core/Trucut biopsy Incision biopsy Excision biopsy

52. RADIOLOGICAL INVESTIGATIONS Goals - accurately define the local extent of a tumor & exclude metastatic disease. Major Modalities: MRI CT

53. MRI Imaging technique of choice for soft-tissue sarcomas of the extremities, except in patients in whom MRI is contraindicated. Accurately delineates muscle groups and distinguishes between bone, vascular structures, neurologic structures and tumor. Sagittal and coronal views allow three-dimensional evaluation of anatomical compartments.

54. CT CT remains the imaging technique of choice for RPSs.  Only complementary role in extremity STS Help to detect calcification within the lesion or bone involvement better than MRI. In addition to giving invaluable information about: anatomic considerations radiologic subtleties between the various histologic types  

55. PATHOLOGICAL EVALUATION In an adult any symptomatic and enlarging mass, any superficial mass >5cm, any deep mass-  should be biopsied 3 methods : Core needle biopsy Incision biopsy Excision biopsy FNAC has no significance in STS

56. RULES FOR BIOPSY Use a biopsy track that can be excised at the time of definitive surgery Plan the incision very well Most superficial part of the mass Along the long axis of the limb Without raising flaps Avoiding hematoma

57. Core needle Biopsy Biopsy of Choice 83% of initial biopsy is adequate for diagnosis 95% of these correlated well with final histology Repeat under image guidance

58. Incision Biopsy Performed as a last resort when core biopsy specimens are nondiagnostic. If core needle biopsy fails 2 times , plan incision biopsy Incisional biopsy is indicated for deep tumors or for superficial soft tissue tumors larger than 3cm Open biopsy is a reliable diagnostic method that allows adequate tissue to be sampled for definitive and specific histologic identification 

59. Excision Biopsy Recommended only for superficial tumors, <5 cm

60. Metastatic Investigations Chest X Ray & CT Chest  R/o  Blood born metastasis to lungs in extremity STS All patients with soft-tissue sarcoma should have a CXR Chest CT reserved for patients with a suspicious lesion on CXR or for patients with a high-risk tumor (large tumor size [>5 cm], deep tumor location, or intermediate/high-grade histology) CT Abdomen  Done along with primary R/o liver metastasis in retroperitoneal & visceral STS Extremity myxoid liposarcoma – mets to fatty tissue of abdomen & retroperitoneum

61. STAGING & PROGNOSTIC FACTORS By S Surya Sujith

62. Soft tissue sarcoma is an aggressive, Invasive  destructive tumour high recurrence and distant metastases rate. Grade is the single most important factor in staging  It denotes the “biological aggressiveness” and likelihood of metastasis

63.        AJCC STAGING   SYSTEM It includes: Histopathologic grade (G) Tumor size (T) Nodal involvement (N) Distant metastases (M)

64. Changes in AJCC 8 th edition soft-tissue sarcomas are divided into the different staging systems by anatomical site head and neck, extremity and trunk, abdomen/thoracic visceral organs retroperitoneum

65. 2. This staging system is applied to all extremity and trunk STS except desmoid and Kaposi sarcoma  3.  Superficial and deep location has been removed 4. T categories have increased from 2 to 4 5.  The term NX should not be used

6. N1 and M1 are stage 4

66. desmoid tumors /deep fibromatosis and Kaposi sarcoma are excluded from the sarcoma staging system GIST continues to have a unique staging system which is now classified under the soft-tissue sarcoma section

67. T-TUMOUR(T) TX -Primary tumor cannot be assessed TO - No evidence of primary tumor T1 – Tumor  </= 5cm  T2 -Tumor > 5 cm and </=10 cm  T3 -Tumor >10 cm and </=15 cm  T4 -Tumor >15 cm 

68. N-NODES (N) N0 - No regional lymph node metastases or unknown lymph node status  N1  -Regional lymph node metastasis Presence of positive nodes is considered Stage IV

69. Soft tissue sarcomas with nodal metastasis (< 3% of adult STS) Synovial sarcoma Ewing’s sarcoma Embryonal rhabdomyosarcoma Epithelioid sarcoma  Alveolar rhabdomyosarcoma Clear cell sarcoma  Angiosarcoma Malignant fibrous histiocytoma (MFH) It has poor prognosis

70. M-Distant Metastasis (M) M0: No distant metastasis  M1: Presence of distant metastasis Sites of metastasis 70% of extremity sarcomas metastasize to lung Retroperitoneal or visceral lesions metastasize to liver parenchyma Brain metastasis is seen in leiomyosarcoma,alveolar sarcoma and angiosarcoma

71. G-Histological Grading (G) GX -Grade cannot be assessed G1 -low grade (Tumour differentiation, mitotic count and necrosis score of 2 or 3 ) G2 - intermediate grade (score of 4 or 5 ) G3 -high grade (score of 6, 7, or 8 )

72. FNCLCC GRADE FNCLCC (Federation Nationale des Centres de Lutte contre le Cancer)grade is determined by three parameters 1. Differentiation(1-3) 2. Mitotic activity(1-3) 3. Extent of necrosis(0-2)  The scores are added to determine the grade

73. 1. Tumor Differentiation score 1 - closely resembling normal adult mesenchymal tissue  2-  histologic typing is certain  3-Embryonal and undifferentiated sarcomas, sarcomas of doubtful type

74. 2. Mitotic Count Score 1: 0-9 mitoses per 10 HPF  2: 10-19 mitoses per 10 HPF  3: >=20 mitoses per 10 HPF  

75. 3. Tumor  Necrosis Score 0-No necrosis 1-50%  tumor  necrosis 2- >=50%  tumor  necrosis.

76. STAGING STAGE T N  M GRADE I A T1 N0 M0 G1/Gx I B T2,T3,T4 N0 M0 G1/Gx II T1 N0 M0 G2/G3 IIIA T2 N0 M0 G2/G3 IIIB T3,T4 N0 M0 G2/G3 IV Any T N1 / Any N M0/ M1 Any G

77. Memorial Sloan Kettering Cancer Centre(MSKCC) Staging Based on three POOR prognostic factors : 1.High grade - 1 point 2. Tumor size >5 cm - 1 point  3. Deep tumor - 1 point 

78. MSKCC Staging Stage 0: no poor prognostic feature Stage  1 :  1  poor prognostic feature  Stage  2 :  2  poor prognostic feature  Stage  3 :  3  poor prognostic feature  Stage 4: Metastatic carcinoma 

79. PROGNOSTIC FACTORS Prognostic factors for overall survival include: tumor size >5cm Location (head/neck or deep tumors ) Age > 65 years Histologic subtype and higher grade of tumor Inadequate clearance margin Multifocality Lung secondaries, nodal metastasis More than one compartment involvement Click to add text Click to add text

80. SURGICAL MANAGEMENT Sabarinath s SURGICAL MANAGEMENT                                              By Sabarinath S

81.         SURGICAL TREATMENT Surgery - main treatment modality.  Amputation rate for STS has reduced from 50% in 1960 to 5% at present.  Also due to proper adjuvant radio therapy following function/limb sparing complete excision, application of microvascular surgeries. Neoadjuvant chemotherapy, perioperative /postoperative RT also play a major role.

82. Enneking classification 1.INTRALESIONAL EXCISION 2.MARGINAL EXCISION 3.WIDE EXCISION 4.RADICAL EXCISION

83. Intralesional excision It is done inside the pseudocapsule   Very high recurrence – upto 100% Not done  

84. Marginal excision En bloc resection through the reactive zone High recurrence rate-70%

85. Wide excision Wide excision means en bloc resection done through normal tissues beyond the reactive zone  it has local recurrence rate of 30%.

86. Radical excision If the margin is more than 5 cm outside the reactive zone.

87. Defines a curative margin as a margin of more than 5 cm outside the reactive zone   A  wide margin as a margin of 1-4 cm Wide margins classified into 2 subgroups:  1)Adequate    - Margin of 2 cm or more  2)Inadequate - Margin of 1–2 cm  Kawaguchi  Rule

88. Other procedures 1.Compartmental excision 2.Vascular resection with Vascular reconstruction 3.Amputation

89. Compartment Excision Radical limb saving procedure. Muscle group of 1 compartment resected from origin to insertion with tumour   Done only when tumour is intracompartmental . Not suitable when  extracompartmental  /many compartments involved / Encased to major neurovascular bundle.

90. Amputation Done in large tumours of upper or lower limbs. Radical amputation is done as disease has not spread systemically  In metastatic disease-no need for amputation as long-term survival is not possible

91. Indications for amputation 1)Major neurovascular encasement 2)Bone involvement 3)Multiple compartment involvement 4)Limb itself is diseased like lymphoedema 5)Recurrence with multicentricity

92. RETROPERITONEAL SARCOMA In retroperitoneal sarcoma,  Debulking surgery followed by radiation therapy  is used

93. CONSIDERATIONS IN SURGERY Do not raise flaps  Include previous biopsy site in area of surgery Minimum manipulation to avoid seeding Do not use drain ,If used ,the area should be included under radiation

94. RADIOTHERAPY AND CHEMOTHERAPY By Sachin Sanu

95. Radiotherapy External beam radiotherapy        IMRT - Intensity modulated radiotherapy       3- Dimension conformal radiotherapy Brachytherapy     Temporary-  loading  catheter                                                       iridium 192  Permanent - radio active seeds and deposited in the tumor (iridium 192)                                                        

96. Radiotherapy approaches Neoadjuvant (preoperatively) Intraoperative radiotherapy Adjuvant (postoperatively) Primary (radiotherapy alone)

97. Neoadjuvant radiotherapy Indication If the tumor is >5cm If tumor <5cm –not given    unless     a clearance margin of <1cm is expected                    close proximity to neurovascular bundle     Dose 45-50.4 Gy EQD2(Equivalent dose in 2 Gray fraction

98. Merits   of Neoadjuvant radiotherapy Vascularised tumor so outcome more Better peripheral sterilization Reduce the seeding of tumor during surgical manipulation Pseudocapsule may thicken and become acellular easing resection Tumor itself displaces the normal structures and protect them from radiation exposure

99. Demerits of Neoadjuvant Radiotherapy wound complication  -acute toxicity ( post operatively) delay the surgery (3-6week after surgery) Mark probable scar area and give reduced dose there to minimize wound complication

100. Adjuvant radiotherapy  Indications If tumor >5cm If tumor <5cm Not given unless margins are positive Within 1-2month after surgery Dose 60-66Gy in EQD2

101. Merits   Can tailor the shape of radiation based on the kind of tumor it is Get idea about the tumor shape, extend, & histologic subtype                    Demerits   greater area and dose  Lymphedema Joint stiffness Cutaneous fibrosis

102. Neoadjuant radiotherapy Prefered

103.   Retroperitonial sarcomas If margin positive after wide excision following post operative radiotherapy In non operable lung metastasis Stereotactic Body Radiation Therapy (SBRT) Intraoperative Radiotherapy Primary Radiotherapy

104. Chemotherapy   Indications      High grade liposarcoma       High grade synovial sarcoma      Ewing’s sarcoma      Rhabdomyosarcoma

105. Single agent Doxorubicin Ifosfamide Dacarbazine   Ifosfamide - hemorrhagic cystitis   Mesna (2mercapto ethane sulfonate NA) is used along ifosfamide to reduce side effect  Combination Agents   Gemcitabine and docetaxel     MIAD regimen ( mesna , adriamycin , ifosfamide , dacarbazine)

106. ISOLATED LIMB PERFUSION   To deliver high dose of chemotherapy directly to the affected limb gives a much more targeted and higher dose of chemotherapy uses cytotoxic drugs and tumour necrosis factor with hyperthermia

107. RECURRENT DISEASE For extremity sarcomas lung - only site of recurrence(50%).  If  resectable  -> thoracotomy and resection If unresectable palliative CT is given Local recurrence in extremity sarcoma –> 6-20 % Median interval for local recurrence -> 18 months 80% local recurrence can be treated by limb salvage WLE

108. Follow up History and clinical examination every 3-6month for 1 st 2 years 6 monthly for 3 rd to 5 th year  Later on annually   CT/MRI of primary site  CT chest  Evaluations for Rehabilitation