Soft Tissue Sarcomas


Overview

  1. Incidence
    • Rare tumors comprising < 1% of adult malignancies and 12% of pediatric malignancies
    • 60% occur in an extremity; 25% on the trunk; 15% in the pelvis/retroperitoneum

  2. Etiology
    • No specific etiologic agent is found in most patients
    • Several predisposing factors have been identified

    1. Genetic Predisposition
      • Neurofibromatosis → malignant peripheral nerve sheath tumors
      • Li-Fraumeni syndrome
      • Gardner’s syndrome and familial adenomatous polyposis → desmoid tumors

    2. Radiation Exposure
      • Angiosarcoma
      • Pleomorphic sarcoma

    3. Lymphedema
      • Angiosarcoma

    4. Infection
      • HIV and herpes virus 8 have been implicated in Kaposi’s sarcoma

  3. Pathology
    1. Histologic Subtypes
      • More than 60 recognized histologies
      • Most common histologic subtypes in adults are undifferentiated pleomorphic sarcoma, liposarcoma, and leiomyosarcoma
      • In childhood, embryonal rhabdomyosarcoma and Ewing’s sarcoma are most common

    2. Prognostic Factors
      • Tumor-related factors predictive of recurrence or survival include grade, size, and depth (superficial or deep)
      • Histology and site of origin are also important prognostic criteria
      • Nodal spread is rare

      1. Grade
        • Best indicator of biologic behavior
        • Graded from 1 to 3 (1 represents low-grade tumor, 3 represents high-grade tumor)
        • Determined by mitotic index, degree of differentiation, and amount of necrosis present
        • Low-grade tumors tend to recur locally and rarely metastasize; high-grade tumors have a much greater risk of metastasis

      2. Size
        • Less important than grade
        • T1, ≤ 5 cm; T2, > 5 cm and ≤ 10 cm; T3, > 10 and ≤ 15 cm; T4, > 15 cm

      3. Depth
        • Related to the investing fascia
        • Superficial lesions have a better prognosis than deep lesions

      4. Surgical Margins
        • Positive surgical margin is the most important treatment-related factor predictive of local and distant failure

Extremity Sarcomas

  1. Presentation and Evaluation
    • Typically present with a large, deep, immobile, painless mass
    • Thigh is the most common site
    • Commonly mistaken for a hematoma or lipoma
    • Physical exam should include a detailed neurovascular exam
    • MRI is the preferred imaging technique
    • Core-needle biopsy should be performed on any mass that is enlarging, symptomatic, deep, or > 5 cm in size
    • FNA is unable to distinguish between the different sarcoma histologies
    • Incisional biopsies should be orientated in the longitudinal direction to facilitate subsequent wide local excision
    • Undifferentiated pleiomorphic sarcoma is the most common subtype
    • Metastatic workup consists of a chest CT
    • Lymph node metastases are very rare

    Extremity Sarcoma
  2. Treatment of Primary Disease
    1. Surgery
      • Function-sparing and limb-sparing operations are standard
      • No role for complete compartment or muscle group resection
      • Tumor should be excised with a 1 to 2 cm margin of normal tissue, without violating or rupturing the pseudocapsule
      • Previous incisional biopsy site should be excised en bloc with the specimen
      • Tumors close to the skin should have an adequate skin margin excised
      • Tumors that abut bone, but do not invade bone, should include periosteum in the margin
      • If sacrifice of major vascular and neural structures is oncologically necessary (radical resection), vascular and nerve reconstruction should be considered

    2. Radiation
      • Postoperative radiation combined with limb-sparing surgery gives overall control rates equal to amputation
      • Reduces risk of local recurrence from 30% to < 10%, but does not impact metastasis or overall survival
      • Delivered preoperatively or postoperatively
      • Postoperative radiation can be delivered as external beam or brachytherapy
      • Brachytherapy allows additional radiation to a close margin (neurovascular structures) with minimal treatment to surrounding tissues
      • Preoperative radiation is associated with more wound complications, but has a better functional outcome
      • Small, low-grade tumors with an adequate resection margin do not need radiation

    3. Chemotherapy
      • Patients with large, deep, high-grade tumors may be considered for neoadjuvant or adjuvant chemotherapy
      • Active agents include adriamycin and ifosfamide
      • No evidence that chemotherapy improves overall survival

  3. Treatment of Recurrent Disease
    1. Local Recurrence
      • Patients with isolated local recurrences should undergo re-resection
      • 20% - 30% will require amputation
      • Adjuvant radiation should be administered if possible
      • Long-term survival is possible in two-thirds of patients

    2. Lung Metastases
      • Most common site of metastasis
      • Curative metastasectomy is possible if:
        • Primary tumor is controlled
        • No extrapulmonary disease
        • Patient can tolerate a thoracotomy
        • All lung disease is resectable
      • Patients with resected pulmonary metastases have a 20% - 30% 3-year survival rate

Retroperitoneal Sarcomas

  1. Pathology
    • Most common histologies are liposarcoma and leiomyosarcoma
    • Lymphoma and metastatic testicular cancer should be considered in the differential diagnosis of a large retroperitoneal mass

  2. Clinical Presentation
    • Often present with nonspecific abdominal complaints: early satiety, vague discomfort, weight loss, back or flank pain
    • Physical exam may be normal or may reveal a large flank or abdominal mass
    • Median size at diagnosis is 15 cm

    Retroperitoneal Sarcoma
  3. Diagnosis
    • CT scan confirms the presence of the mass
    • CT-guided biopsy is indicated if lymphoma is part of the differential diagnosis, or if neoadjuvant therapy is being considered

  4. Management
    1. Criteria for Unresectability
      • Vascular involvement of the aorta, vena cava, SMA, or iliac vessels
      • Peritoneal implants
      • Distant metastases that are not resectable for cure
      • Involvement of the root of the mesentery and the mesenteric vessels
      • Spinal cord involvement

    2. Surgery
      • Microscopically negative (R0) resection is the goal, but is rarely feasible due to large tumor size and anatomic constraints of the retroperitoneum
      • Most resections are microscopically positive (R1)
      • Kidney, colon, pancreatic tail, spleen, and psoas muscle often must be resected to achieve a complete resection (R0/R1)
      • No survival benefit to a debulking procedure (R2)

    3. Radiation
      • Post op radiation does not reduce local recurrence
      • Usually impossible to treat the entire tumor bed because surrounding structures do not tolerate high-dose radiation well
      • Neoadjuvant XRT is used in some centers for large high-grade or locally advanced tumors to optimize local control

    4. Chemotherapy
      • No proven benefit
      • Patients with high-grade lesions may be considered for treatment

  5. Outcomes
    • Most important prognostic factor is complete resection (R0/R1), followed by tumor grade and histologic subtype
    • Majority of recurrences are local
    • Most common sites of distant metastases are the liver and lungs

Desmoid Tumors

  1. Etiology
    • Locally aggressive tumors with no potential for metastasis or malignant degeneration
    • High rate of local recurrence even after complete resection
    • Death may occur from local invasion of vital blood vessels or organs
    • Most occur sporadically, but there are associations with familial adenomatous polyposis, pregnancy, and trauma

    1. Familial Adenomatous Polyposis (FAP)
      • desmoid tumors occur in 10% - 20% of patients with FAP (Gardner's syndrome)
      • ~50% are intraabdominal and ~ 50% involve the abdominal wall
      • In FAP, complications from desmoids are the second most common cause of death (after colon cancer)
      • Intraabdominal desmoids are often unresectable because they diffusely infiltrate the mesentery and encase the mesenteric vessels

    2. Pregnancy
      • Desmoid tumors are associated with high estrogen states
      • Many tumors stop growing or even regress without intervention after delivery

    3. Trauma
      • 30% of patients have a history of previous trauma or surgery at the tumor site

  2. Natural History
    • Highly variable and unpredictable clinical course
    • Most grow slowly and indolently over time
    • Periods of growth arrest or spontaneous regression are common
    • Rapid, progressive growth is less frequently seen
    • Local recurrences are common, even after a complete resection

  3. Etiology
    • Overactivation of the Wnt/beta-catenin signaling pathway appears to play a key role
    • APC gene tightly regulates levels of beta-catenin in the cell
    • Inactivation of the APC gene, or activating mutations in the beta-catenin gene, leads to increased levels of beta-catenin
    • Beta-catenin acts as a nuclear transcription factor which promotes cell proliferation and survival

  4. Clinical Presentation
    • Occurs in one of three sites: trunk/extremity, abdominal wall, or intraabdominal (bowel and mesentery)
    • In FAP patients, intraabdominal or abdominal wall desmoids predominate
    • In sporadic cases, the shoulder girdle, hip and buttocks, and extremities are most common
    • Extremity desmoids are usually located deep in the muscles

  5. Diagnosis
    1. Imaging
      • Defines the relationship of the desmoid to adjacent structures in order to assess resectability
      • MRI is preferred for trunk or extremity desmoids
      • CT is preferred for intraabdominal lesions
      • Imaging cannot reliably distinguish desmoids from soft tissue sarcomas

      Abdominal Wall Desmoid Tumor
    2. Histologic Diagnosis
      • Core biopsy is usually sufficient to make the diagnosis, although occasionally an incisional biopsy will be required
      • Desmoids lack the nuclear and cytoplasmic features of malignancy, necrosis is absent, and mitotic figures are rare

  6. Treatment
    1. Trunk and Abdominal Wall Desmoids
      1. Observation
        • Acceptable strategy for stable, asymptomatic lesions, especially if resection would cause major morbidity
        • Indicated in recurrent asymptomatic desmoids

      2. Surgery
        • Indicated in symptomatic patients, or for those with progressively enlarging tumors
        • Goal is complete resection with a negative microscopic margin (R0), but this is often not possible because of anatomic constraints and the infiltrative nature of desmoids
        • Skin grafts or flap reconstructions may be required for extremity desmoids
        • Abdominal wall desmoids require reconstruction with mesh to minimize the risk of hernias

        1. Resection Margins
          • Relationship between surgical margin status and local recurrence rates is unclear
          • Patients with widely negative margins (R0) have recurrence rates of 16% - 39%
          • Patients with microscopically positive margins (R1) have recurrence rates equivalent to patients with R0 resections
          • Patients with grossly positive margins (R2) have much higher local recurrence rates

      3. Radiation Therapy
        • Desmoids are radiosensitive tumors
        • Definitive treatment in patients who are poor surgical candidates, in patients who refuse surgery, or in patients for whom surgical morbidity would be excessive

        1. Postoperative XRT
          • Not recommended after an R0 resection
          • Unclear whether XRT is of benefit in patients with an R1 resection
          • Generally recommended after an R2 resection

    2. Intraabdominal Desmoids

      3. IntraAbdominal Desmoid Tumor
      1. Surgery vs Medical Management
        • Majority are unresectable because of diffuse involvement of the mesentery or encasement of the mesenteric vessels
        • Rate of recurrence is high after resection, as is the operative morbidity
        • Multimodality medical therapy is preferred
        • Medical treatments include NSAIDs (Sulindac), tamoxifen, targeted therapy (imatinib), or chemotherapy
        • Resection with small bowel transplant has been performed in several patients

Dermatofibrosarcoma Protuberans

  1. Etiology
    • Superficial cutaneous tumor that infiltrates tissue centimeters beyond the obvious margins
    • Recurs locally but rarely metastasizes

  2. Clinical Presentation
    • Initially presents as an asymptomatic plaque that slowly enlarges
    • Later on, the tumor becomes raised, firm and nodular
    • Most common location is on the chest and shoulders

    Dermatofibrosarcoma Protuberans
  3. Treatment
    • Wide excision with negative margins
    • May require plastic surgical reconstruction
    • Radiation is not generally helpful in reducing local recurrence







References

  1. Sabiston, 20th ed., pgs 754 - 770
  2. Cameron, 13th ed., pgs 825 - 839
  3. UpToDate. Clinical Features, Evaluation, and Treatment of Retroperitoneal Soft Tissue Sarcoma. Mullen, John, and Delaney, Thomas. April 2018. Pgs 1 – 40.
  4. UpToDate. Desmoid Tumors: Epidemiology, Risk Factors, Molecular Pathogenesis, Clinical Presentation, Diagnosis, and Local Therapy. Ravi, Vinod. March 2019. Pgs 1 – 30.
  5. UpToDate. Dermatofibrosarcoma Protuberans. Mendenhall, William. January 2019. Pgs 1 - 28.