Soft tissue sarcoma

Can arise from anywhere in the body with a majority occurring in the limb or limb girdle or within the abdominal retroperitoneum, viscera or peritoneum.

Originate from mesenchymal tissues with some neuroectodermal contribution including muscle, fat, and fibrous supporting structures throughout the body.

The anatomic site of the primary disease is an important variable that influences treatment and outcome: extremities 43%, the trunk 10%, viscera 19%, retroperitoneum 15%, or head and neck 9%, are the most common primary sites.

Occur in fat, joints, muscles, blood vessels, nerves, and deep skin tissue.

Most common sarcomas metastasize to the lungs; tumors arising in the abdominal cavity more commonly metastasize to the liver and peritoneum.

Soft tissue sarcomas account for 1% of all adult malignancies.

Historically amputation was the treatment of choice for extremity soft tissue tumor, however advancements in surgery and radiation now provide limb salvage in place of amputation as the standard of care.

STS has an incidence of less than one per million per year.

In 2019, an estimated 13,500 persons were diagnosed with an STS.

Accounts for approximately 7%-15% of childhood cancers.

Rare tumors with 3.4 new cases per 100,00 persons.

In 2022 and estimated 13,190 people were diagnosed with soft tissue sarcoma in the US with 5130 deaths.

Survival rates are poor and have not changed in 40 years.

Most cases are sporadic in nature.

A small number of cases arise after radiotherapy.

Patients with localized STS are managed with surgery with or without radiation.
Guidelines for STS treatment is that in patients with large. greater than 5 cm tumors,  and high-grade histology should undergo RT in addition to surgical resection.
Management of soft tissue sarcoma in adults relates to disease subtypes:
STS of extremity, superficial/trunk, or head and neck
Retroperitoneal or intra-abdominal STS
Desmoid tumors, are a unique soft tissue tumor subtype characterized by local infiltration rather than distant metastases.
Rhabdomyosarcoma is the most common STS of children and adolescents and is less common in adults.

Despite aggressive local therapy, up to 50% of patients with high risk tumors of 5 cm or greater, and high-grade, primary STS lesions develop metastases.

Genetic syndromes predisposed to STSs and include Li-Fraumeni syndrome, characterized by TP53 oncogene mutation or deletion and increased lifetime risk.

Patients with loss of retinoblastoma tumor suppressor gene (RB) have a propensity for osteosarcomas and other sarcomas.

Patients with neurofibromatosis type one have an associated increased risk for malignant peripheral nerve sheath tumors among other sarcomas.

More than 100 histologic subtypes.

Affects approximately 200,000 individuals worldwide each year.

Most common types include: gastrointestinal stromal tumor, malignant fibrous histiocytoma (undifferentiate pleomorphic sarcoma), liposarcoma, leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma and angiosarcoma.

Despite adequate locoregional treatment up to 40% of patients will develop metastatic disease.
The Median and Overall survival for the treatment of advanced disease is poor, ranging from 12-18 months, with only modest improvement within the past 20 years.

Tumors are categorized as adipocytic, fibroblastic, myofibroblastic, smooth muscle, pericutic, skeletal muscle, vascular, chondro-osseous and of uncertain differentiation.

Liposarcoma is one of the most common subtypes, accounting for 20% of all STSs.

Rhabdomyosarcoma is the most common STS of childhood.

Exposure to radiation and vinyl chloride identified as risk factors.

Known risk factors include: genetic syndromes, radiation, and chemical exposure.

It is estimated that about 3% of STS are related to radiation induced lesions.

The time till radiation-induced soft tissue sarcomas is approximately 10 years.

Neurofibromatosis is an inherited syndrome that increases the cumulative lifetime risk for nerve sheath tumors to 10%.

Li-Fraumeni syndrome and hereditary retinoblastoma are genetic syndromes that are associated with STS and result from germline mutations of tumor suppressor genes specifically TP53 and RB1, respectively.

From a molecular genetics perspective, STS is classified into 2  broad categories: sarcomas with specific genetic alterations and relatively simple karotypes, most of them being translocation related sarcomas; and sarcomas with complex unbalanced karyotypes representing 2/3 of STS.
immunologically quiescent tumors because of low mutational burden.
Only 2.3% of sarcomas have mismatch repair deficiency.
Approximately 20% of sarcomas are related to translocation abnormalities characterized by oncogenic fusion proteins.

Actionable genomics alterations using next generation sequencing can identify up to 41% of cases.

Only 12% of cases are found to have PD-L1 activity.

75% of biopsy samples have FOXP3 positive cells, a hallmark of immuno suppressive CD4 positive T regulatory cells and 76% had a low density of CD8 positive cells.

Most common subtype of STS associated with hereditary retinoblastoma is leiomyosarcoma followed by fibrosarcoma.

1% of adult malignancies, and approximately 15% of pediatric malignancies.

Tumor spread patterns primarily dictated by this site of the lesion rather than to the specific subtype.

Nearly half of all patients with STSs die of metastatic disease.

Median survival of patients with advanced STSs is 15-18 months.

Soft tissue sarcomas of the extremities have a predilection to spread to the lungs, while soft tissue sarcomas originating in the retroperitoneum often relapse locally.

Most commonly metastasize to the lungs and for tumors arising in the abdominal cavity, liver and peritoneum metastases are common.

Selected patients with isolated resectable lesions can have a long-term disease free intervals and cure with surgery.

Size at presentation depends on the location with larger tumors in the proximal extremities and retroperitoneum and smaller lesions in the distal extremities.

Abdominal STS may cause bowel obstruction, GI bleeding or abdominal pain.

Accounts for 1-2% of malignancies.

Accounts for 0.7% of all new cancer cases.

5-year survival rate 50-66%.

When localized five year survival rate can be greater than 80% or less than 20% in the presence of metastases.

Prognosis is usually better when the primary lesion is located in the extremities compared with the retroperitoneum.

Dermatofibrosarcoma of STS subtypes has the highest 5 year survival rate of 92%.

Well differentiated liposarcoma has a high five year survival rate of approximately 84%.

Dedifferentiated chondrosarcoma has the lowest rate of 5 year survival at 19%.

Aveolar rhabdomyosarcoma has a low rate of 5-year survival of 20%.

More than 50 different types that vary in location of presentation with about 50% from extremities, 40% from trunk, abdomen, and retroperitoneum, and 10% from neck region.

Divided into 2 major genetic groups: 1-lesions with specific genetic alterations, such as chromosomal translocations or point mutations, and 2-sarcomas with nonspecific genetic alterations and unbalanced karyotypes.

Can be divided by molecular events into four types: Group 1-nonpleomorphic histologic subtypes and pathonogomic molecular events-GIST, dermatofibrosarcoma protuberans and pigmented villonodular synovitis where translocations fuse collagen promoters to growth factors, and sarcomas bearing fusion transcription factor translocations including Ewing family tumors: Group 2 -affect younger patients nonpleomorphic histology and karyotypes of limited complexity: group 3-adult tumors with pleomorphic histology and include dedifferentiated liposarcoma with CDK4/MDM2 amplifications, malignnt peripheral nerve sheath tumors with NF1 deletions, myxoinflammatory fibroblastic sarcoma: Group 4-most common n adults with complex karyotypes, pleomorphic histology and lack of consistent molecular events and include undifferentiated pleomorphic sarcoma, malignant fibrous histiocytoma, leimyodarcoma, pleomorphic lipo and rhabdomyosarcomas, angiosarcomas, osteosarcomas, myxofibrosarcoma, and myofibroblastic sarcoma.

Prior radiation therapy to the affected area, given some years before the development of the sarcoma, is a risk factor for soft tissue sarcomas.

Risk factors include genetic syndromes, radiation, and chemical exposure with herbicides, such as agent orange.

Neurofibromatosis increases the cumulative lifetime risk of nerve sheath tumors to 10%-resulting from dysfunction of NF1 gene.

Li-Fraumeni syndrome and hereditary retinoblastoma are genetic syndromes associated with STS and result from germ line mutations of suppressive genes specifically TP53 and RB1, respectively.

Leiomyosarcoma is the most common subtype associated with hereditary retinoblastoma, followed by fibrosarcomas.

More than 3% of patients have had radiation-induced disease.

Time from primary cancer to secondary radiation-induced STS averages 10 years.

Metastatic disease associated with a median survival of close to 12 months with fewer than 10% of patients alive and disease free at 5 years.

Treatment of metastatic disease is frustrating with few active agents and response rates of less than 20%.

The most common primary sites on the extremities (60%), trunk (19%), retroperitoneum (15%), and head and neck(9%).

Less than 10% of cases occur in the foot and ankle.

Approximately 10-20% located in the retroperitoneum.

Males have a slightly higher risk with a 1.23:1.0 ratio.

Diagnosis more common in individuals greater than 55 years with a mean age at diagnosis of 59 years.

Patients usually present with solid tumors with a new or growing lump.

The presenting masses are usually painless and most common sites are the extremities 33%, followed by the trunk 14%, and retroperitoneum 19%.

8% percent of STS can occur in the head and neck region

Half of patients with soft tissue sarcomas will die of their disease.

STS most commonly metastasize to the lungs.

Tumors arising in the abdominal cavity commonly metastasize to the liver and peritoneum.

MRI is distended modality of imaging for STS of the extremities, pelvis, and trunk.

CT imaging of the retroperitoneum and chest is useful in determining metastases.

PET scan an effective imaging modality.

Core needle biopsy preferred diagnostic technique required for grading.

Fine-needle aspiration does not usually provide sufficient tissue for accurate diagnosis.

When the lesion is superficial and smaller than 3 cm, removal of the entire tumor during the biopsy procedure is practical.

Pathologists specializing in sarcoma are required because of the associated high error rate by less experienced individuals.

Overall incidence has been increasing.

Differential diagnosis includes other malignant lesions, desmoid and benign lesions.

Histologically, the diagnosis is usually made by immunohistochemistry staining, aided with molecular testing, such as florescence in situ hybridization or reverse transcriptase-polymerase chain reaction, which can detect translocations, mutations, and recurrent gene amplifications present in certain sarcoma subtypes.
Highly experienced surgeons in treating sarcomas are required in the management of such patients.

Patients with soft tissue sarcomas treated at high-volume centers have significant better survival rates than those at facilities with low volume surgeries.

Molecular genetic testing can identify abnormalities associated with STS subtypes: the expression of PAX7-FKHR in alveolar rhabdomyosarcoma is associated with a four year survival rate of 75%, much higher than the 3% survival associated with PAX3-FKHR.

Two systems are used for grading: French Federation of Cancer Centers and the National Cancer Institute.

Grading includes tumor differentiation, histology, location, presence of necrosis, mitosis counts, and necrosis.

The French Federation of Cancer Centers grading better predicts tumor mortality and metastases.

Open and excisional biopsies provide a greater amount of tissue for analysis than needle biopsies.


Surgical principles include: excision of the biopsy site en bloc, dissection through grossly normal tissue planes uncontaminated by tumor.

In general radical excision or entire anatomical compartments is not necessary.

Surgical resection with negative margins is the mainstay of treatment for operable disease.

Staging is based on the American Joint committee on Cancer classification system.

Positive margins at surgery are marked with surgical clips to guide postoperative radiation.

Surgical margins of extremity sarcomas can be close as long as the resected tumor has no ink in it and it does not compromise the prognosis (Harati K).

In the event positive margins additional surgery should be performed long as tissue function is not compromised, and local control rates are better among patients who undergo reresection with rates of 85%, 85%, and 82% at 5,10 and 15 years, respectively.

Local control in patients who do not undergo reresection the rates are 78%, 73%, and 73%, respectively.

Amputation may be necessary in soft tissue sarcomas, but is avoided whenever possible.

Close margins may be necessary to preserve uninvolved critical neurovascular structures.

Microscopically positive surgical margins are associated with higher risk of local recurrence and lower rate of disease free survival in extremity sarcomas.

Negative surgical margins are recommended, but close margins may be effectve in patients undergoing RT.

Radiotherapy and chemotherapy are used for high grade lesions, deep lesions, and lesions greater than 5 centimeters.

The combination treatments can be used concurrently or independently before surgery to shrink the tumor and or after surgery to kill remaining cells.

Radiotherapy dose is to a total of 50 Gy in 1.8 – 2 Gy fractions.

Radiation techniques include external beam radiation, brachytherapy, and proton beam radiation.

Adjuvant radiation is considered with close soft tissue margins of less than 1 cm, or microscopically positive margin on bone, blood vessels or nerves.

Limb sparing surgery is recommended for most extremity STS to obtain local control with minimal disruption in function.

In general, tumors regress slowly with radiation therapy but on a size by size basis require similar dosages to maintain control as do carcinomas.

Appropriate patients for adjuvant chemotherapy or chemoradiotherapy are patients with stage III extremity or trunk sarcomas (greater than 5 cm), grade ¾ lesions deep to superficial fascia since 5-year survival and overall survival rates for such lesions after definitive local treatment are 52% and 56%, respectively.

First-line chemotherapy includes doxorubicin or gemcitabine and docetaxel, with a response rate of approximately 255 and overall survival of 12-18 months.

Doxorubicin single agent response rate of 20-35%.

Doxorubicin response related to dose intensification.

Dacarbazine has an overall response rate of 17% in adults with metastatic disease.

Dacarbazine has minor activity in leiomyosarcoma and fibrous tumors.

Ifosphamide-response rates 18-23% in soft tissue sarcomas.

Gemcitabine phase II studies reveal response rates of 4-18%.

Gemcitabine plus DTIC provides significant improved survival compared with DTIC alone in patients who have failed standard treatment for metastatic disease (Garcia-del-Muro X et al).

A combination of gemcitabine and docetaxel improves progression free survival, overall response rate, and overall survival compared with gemcitabine monotherapy therapy for the treatment of STSs.

In a phase 3 trial compared to placebo. As a second line or later treatment in metastatic soft tissue sarcoma. There was a significant improvement in progression free survival of 20 vs. seven weeks compared to placebo, without a significant improvement in overall survival (PALLETTE-Pazopanib Explored in Soft Tissue Sarcoma).

The addition of Pazopanib to neoadjuvant chemo radiotherapy results in increased rates of pathological near complete response, suggesting this agent in combination with chemotherapy in children and adults is efficacious with advanced soft tissue sarcomas.

In children lesions more often respond to chemotherapy than do adults

Eribulin improves overall survival in patients with advanced leiomyosarcoma and liposarcoma.

Trabectedin used in combination with specified radiotherapy Increased response rates in soft tissue sarcomas.

Olaratumab (Lartruvo) plus doxorubicin significantly extended overall survival in patients with a subset of soft tissue sarcomas compared to doxorubicin alone.

A phase III study of Olaratumab subsequently, did not show improvement in survival (Tap W).

Regorafenib is a treatment option.

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