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Musculoskeletal & Sarcoma

1. Overview

Sarcoma and Connective tissue tumors

This overview of the BC Cancer approach to the management of sarcoma and connective tissue tumors was developed by Dr. Ursula Lee in conjunction with members of the BC Cancer Sarcoma team and was last updated on June 1, 2018.

Scope, Purpose and Target Audience:

The purpose of this overview is to: 
  • Provide a summary of current knowledge with regards to staging, risk factors, and diagnostic techniques of sarcomas for health care professionals in British Columbia
  • Provide an overview of typical practice at BC Cancer.
Sarcomas are rare tumors and should be diagnosed and treated at a center with an experienced multidisciplinary sarcoma team which should include specialists from surgical oncology, radiation oncology, medical oncology, pathology and diagnostic imaging to ensure optimum management.

2. Referral Criteria

For optimal management, patients should be referred as soon as possible. Do not hesitate to contact BC Cancer for an opinion. It is much better to contact us before any surgery has been attempted. We are always happy to answer your questions and review cases with you.

Sarcomas should be considered in the differential diagnosis when patients present with the following symptoms and signs:
  • Any superficial mass which measures >5 cm
  • All deep-seated masses irrespective of size
  • Any painful mass
  • A mass that is increasing in size
  • Recurrence of a mass after excision
Children aged 17 years or less at presentation should be referred directly to BC Children’s hospital pediatric oncology service directly.

3. Classification

Sarcoma and connective tissue tumors arise from embryonic mesenchymal cells that have the capacity to mature into striated skeletal and smooth muscle, adipose and fibrous tissue, bone  and cartilage among other tissues.

Neoplasms arising from neuroectodermal tissue that give rise to malignant tumors affecting peripheral nerves are also included because of similarities in clinical behavior, management and outcome.

Soft tissue tumors may be benign or malignant. Malignant mesenchymal neoplasms comprise less than 1% of all adult malignancies and 15% of pediatric cancers. Approximately 80% of sarcomas originate from soft tissue and the rest originate from bone.

The group of soft tissue neoplasms includes more than 50 different histologic subtypes (more than 100 including benign neoplasms). WHO classifies most soft tissue neoplasms according to the presumptive tissue of origin.  

Some examples include:  
  • Leiomyosarcoma, Liposarcoma, Fibrosarcoma, Angiosarcoma, Rhabdomyosarcoma, Malignant peripheral nerve sheath tumor (MPNST)
Where histogenesis is uncertain, the designation reflects the architectural pattern.

Some examples include:
  • Alveolar soft part sarcoma, clear cell sarcoma, epithelioid sarcoma, Synovial sarcoma
Some connective tissue tumors do not (or rarely) metastasize but can be locally aggressive. Some examples include:
  • Desmoid fibromatosis, Giant cell tumor of bone (GCTB), diffuse-type pigmented villonodular synovitis (dtPVNS).
References

Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO classification of tumours of soft tissue and bone, 4th ed, IARC Press, Lyon 2013


4. Incidence and Etiology

Soft tissue sarcomas (STS) are rare tumors with an annual incidence of about 5 – 6 per 100,000 persons per year. They account for only 1% of all cancers. However, these tumors account for nearly 7% of cancer in children under 15.

The large majority of soft tissue sarcomas arise de novo, without an apparent causative factor, but some may be related to underlying inherited conditions or environmental factors. 

a) Inherited Conditions

Some inherited conditions are associated with an increased risk for the development of soft tissue sarcomas. Some examples include:

Syndrome
Pattern of Inheritance 
Gene
Associated Tumor(s)
Carney-Stratakis
AD
SDHB, SDHC, SDHD
Gastro-intestinal stromal tumor (GIST), paraganglioma
Learn more
Familial GIST
AD
KIT, PDGFRA
GIST
Li-Fraumeni
AD
TP53, CHEK2
Osteosarcoma, rhabdomyosarcoma and other tumors
Learn more
Neurofibromatosis type 1
AD
NF1
MPNST(malignant peripheral nerve sheath tumor), GIST, rhabdomyosarcoma
Learn more
Gardner syndrome (FAP variant)
AD
APC
Desmoid fibromatosis
Learn more
Retinoblastoma
AD
RB1
Osteosarcoma, rhabdomyosarcoma, leiomyosarcoma
Learn more

Young age at presentation and a personal and/or family history of cancer suggest an underlying germline mutation. It is important to identify these patients for genetic counselling and surveillance for other disease manifestations.

b) Radiation Exposure

Prior radiation treatment (for example in adjuvant treatment of breast cancer), is associated with increased risk of malignancy within the previous radiation field. The risk increases with the amount of radiation therapy given. The median latent interval (time between exposure and tumor diagnosis) is about 10 years. Chemotherapy given with radiation therapy may decrease the time to development of a radiation associated sarcoma.

c) Viral infection and immunodeficiency

Human immunodeficiency virus (HIV) and Human herpesvirus 8 have been implicated in the pathogenesis of Kaposi sarcoma. 

d) Chemical carcinogens

Due to rarity and difficulty in isolating a single agent, causal associations are difficult to prove. There have been documented associations between vinyl chloride or arsenic exposure with hepatic angiosarcoma.

References

  • Taghian A, Tubiana M, Long term risk of sarcoma following radiation treatment for breast cancer. Intl J of radiation Oncology Biology Physics. Vol 21, Jul1991.
  • Neglia et al. Second malignant neoplasms in 5 year survivors of childhood cancer: Childhood Cancer survivor study. JNCI 2001; 93 (9) 
  • Ferrari A, Sultan I, Huang TT, et al. Soft tissue sarcoma across the age spectrum: a population-based study from the Surveillance, Epidemiology, and End Results database. Pediatr Blood Cancer. 2011; 57:943–949.
  • Zhang AY, Judson I, Benson C, Wunder JS, Ray-Coquard I, Grimer RJ, Quek R, Wong E, Miah AB, Ferguson PC, Dufresne A, Teh JYH, Stockler M &  Tattersall MHN. Chemotherapy with radiotherapy influences time-to-development of radiation-induced sarcomas: a multicenter study. British Journal of Cancer volume117, pages326–331 (25 July 2017)

5. Staging System


The American Joint Committee on Cancer (AJCC)/International Union against Cancer (UICC) stage classification system stresses the importance of the malignancy grade in sarcoma. In general, in addition to grading, other prognostic factors are tumor size and tumor depth for limb sarcomas. Tumor site, resectability and presence of metastases are also important.

American Joint Committee on Cancer (AJCC)/International Union against Cancer (UICC) TNM staging system:

Primary tumour (T)
TX
Primary tumour cannot be assessed
T0
No evidence of primary tumour 
T1
Tumour 5 cm or less in greatest dimensiona
T1a
Superficial tumour
T1b
Deep tumour
T2
Tumour >5 cm in greatest dimensiona
T2a
Superficial tumour
T2b
Deep tumour 

Regional lymph nodes (N) 
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis 
N1b
Regional lymph node metastasis

Distant metastasis (M) 
M0
No distant metastasis
M1
Distant metastasis 

Anatomic stage/prognostic groups: 

Stage IA
T1a
N0
M0
G1, GX
T1b
N0 
M0
G1, GX

Stage IB
T2a
N0
M0
G1, GX
T2b
N0
M0
G1, GX

Stage IIA
T1a
N0
M0
G2, G3
T1b
N0
M0
G2, G3

Stage IIB
T2a
N0
M0
G2
T2b
N0
M0
G2

Stage III
T2a, T2b
N0
M0
G3
Any T
N1
M0
Any G

Stage IV
Any T
Any N
M1
Any G

American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Handbook, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com.

6. Diagnosis

a) History and Physical Examination
Presentation will depend largely on the type of sarcoma and location of the tumour.  The most common presenting complaint is that of a gradually enlarging, painless mass. The anatomic site of the primary disease represents an important factor influencing treatment and outcome. These tumors may occur anywhere, but the majority are in the extremities. They can become quite large especially in the thigh or retroperitoneum. There may be pain or symptoms associated with compression by the mass, such as paresthesias or edema. 

b) Imaging

Magnetic Resonance Imaging (MRI):
  • The modality of choice for detecting, characterizing and staging soft tissue tumors due to its ability to distinguish tumor tissue from adjacent muscle and fat, as well as to define relationships to key neurovascular structures.
  • The preferred imaging modality for evaluation of soft tissue masses of the extremities, trunk and head and neck. 
  • Provides better tissue discrimination between normal and abnormal tissues
  • Aids in guiding biopsy, planning surgery, evaluating response to treatment, and in the long term follow-up for local recurrence.
Computerized Tomography (CT):
  • The preferred imaging modality for primary chest, retroperitoneal and visceral sarcomas.
  • A baseline chest CT at the time of diagnosis is recommended for accurate staging, particularly for high-risk sarcomas (>5cm in diameter, deep and high grade).
PET-CT:
  • PET scanning is not routinely recommended for initial sarcoma staging workup, but is often used to stage tumors such as Ewing sarcoma and rhabdomyosarcoma.
  • There may be a role in selected cases for detecting extrapulmonary metastases.
Bone scan:
  • Is usually not helpful for initial staging of soft tissue sarcomas.
Plain radiographs:
  • Plain films of the primary site can be useful to rule out soft tissue masses that arise from bone and to detect intratumoral calcifications such as those that appear within soft tissue (extraskeletal) osteosarcoma and synovial sarcomas.
c) Biopsy: principles of biopsy

  • A biopsy is necessary to establish malignancy, to assess histologic grade and to determine the specific histologic type of sarcoma. This information is essential to ensure the best outcome for the patient.
  • A biopsy should be undertaken only after the tumor has been completely imaged and at the request of the treating surgeon. 
  • The biopsy should be performed after MRI has been done, as post procedural edema may make the MRI difficult to interpret.
  • In collaboration with the treating surgeon, the needle tract (which needs to be excised with the tumor) can be established in keeping with oncologic principles.
  • A poorly placed initial biopsy may compromise definitive surgery by affecting subsequent surgical resection, preparation of flaps, and/or cosmetic repair, or result in the need for more extensive surgery to encompass the biopsy site at the time of definitive resection.
  • Adequate tissue is required as this affect diagnostic accuracy. 
  • Contemporary diagnostic approaches to most malignancies, including sarcoma, combine initial morphologic evaluation with diagnostically relevant cytogenetic, molecular and immunohistochemical testing methods. Therefore, the initial biopsy sample should ideally obtain sufficient tissue for these ancillary diagnostic techniques.
Core biopsy
  • The preferred method of obtaining tissue is with a well-placed core needle biopsy if technically feasible, with resection of the entire needle tract at the time of definitive surgery.
  • CT or ultrasound-guided biopsy of deep lesions can improve the diagnostic accuracy in lesions with cystic areas and necrosis by allowing the operator to select the site to be biopsied.
  • In general, a core biopsy has low incidence of complications and high diagnostic accuracy.
Incisional biopsy
  • If needed, incisional biopsy should be performed by the surgeon planning the definitive resection.
  • Open biopsy incisions should be placed longitudinally along the extremity so that the scar can be resected along with the tumor at the time of definitive resection.
Excisional biopsy
  • Should be avoided, particularly for lesions greater than 2 cm on size, since such an approach will make definitive resection more extensive due to contamination of surrounding tissue planes. 
Fine needle biopsy
  • Is not recommended in the initial diagnostic evaluation of a suspicious soft tissue mass due to limited sampling leading to low diagnostic accuracy and lack of tissue for ancillary diagnostics (eg. Cytogenetics).
  • Can be useful in confirming disease recurrence.
d) Pathology

  • Pathology specimens of suspected soft tissue sarcoma should be reviewed by a pathologist who specializes in the evaluation of soft tissue sarcomas.
  • Diagnostic accuracy relies on a number of factors including appropriate and adequate sampling, quality of tissue obtained, the experience and expertise of the pathologist and the ability to collaborate closely with the treating surgeon to plan appropriate biopsies.
  • Histologically, the diagnosis of soft tissue sarcoma is made on the basis of morphologic pattern.
  • Novel insights into the molecular pathogenetic basis for sarcomas have reshaped contemporary diagnosis. 
  • Ancillary techniques are routinely used as an adjunct to morphologic diagnosis including immunohistochemistry and molecular genetic analysis. 
  • Molecular genetic analyses, such as fluorescence in situ hybridization, reverse transcription polymerase chain reaction, expression profiling and targeted sequencing have increasingly been incorporated into the routine diagnostic workup of these neoplasms. 
  • Some alterations with known protein correlates have resulted in the establishment of immunohistochemical markers with diagnostic, prognostic and/or predictive properties.
References

  • Sinha S, Peach AH. Diagnosis and management of soft tissue sarcoma. BMJ 2010; 341:c7170
  • Schaefer IM, Cote GM, Hormick JL. Contemporary diagnosis, genetics and genomics. JCO 2018;36(2):101-111

7. Management

Soft Tissue Sarcoma (STS) – Non-metastatic, Non-GIST, Non-Fibromatosis, non-angiosarcoma

Local control of extremity soft tissue sarcoma:
  • The tumor should be carefully assessed using physical examination and radiographic evaluation to assess the size, depth and location of the mass, along with signs of neurovascular involvement are essential for designing the best therapeutic approach.
  • Local control refers to the treatment approaches focusing on the primary site of disease. The therapeutic goals of local control are to improve patient survival and minimize or eliminate morbidity associated with the primary tumor. Individual patient and tumor factors will influence management. Risk features include a tumor size of  >5cm, deep lesion and high grade disease.
Surgery
  • Surgical resection remains the cornerstone of local control in STS.
  • The extent of surgical resection has increasingly become histology specific and has generally moved away from overly morbid operations, highlighting the importance of evaluation by a sarcoma surgeon.
  • Wide local excision (WLE) alone results in unacceptably high local recurrence rates of 30-50%.
  • The use of perioperative radiotherapy significantly reduces local recurrence rates.
  • Currently, limb-sparing WLE and Radiation are the standard of care for primary extremity STS. 
Radiation Therapy
  • Radiation therapy (RT) recommendations depend on a number of factors including histology, tumor size and grade, and the depth of lesion.
  • Local control can be improved with peri-operative RT in selected patients with extremity STS.
  • Radiotherapy may be administered pre- or post-operatively. Both result in similar local control efficacy. There are advantages and disadvantages with either approach.
  • Pre-operative radiotherapy allows for a smaller treatment volume and results in lower rates of long-term fibrosis and lymphedema, and improved joint mobility. However, rates of early wound complications are higher.
  • With post-operative radiotherapy, definitive surgery is not delayed and there are fewer wound complications. However, a larger treatment volume is required, with potential attendant subsequent long-term radiation associated side effects. 
Chemotherapy
  • There is currently no consensus on the role of adjuvant chemotherapy. Available evidence from meta-analyses and randomized clinical trials suggest that post-operative chemotherapy improves relapse free survival in patients with extremity sarcoma. However, individual studies of adjuvant chemotherapy have produced mixed results for overall survival benefit. The Sarcoma Meta-analysis collaboration (SMAC) showed a trend in favor of OS advantage for doxorubicin-based adjuvant chemotherapy in patients with extremity sarcoma, which was not statistically significant. An updated meta-analysis reported marginal efficacy in terms of RFS and OS. Thus, while postoperative adjuvant chemotherapy is not routine, it may be considered in selected patients based on a number of factors including age, comorbidities, histologic subtype, size, grade, depth of lesion and resection margin.
Advanced or metastatic soft tissue sarcoma (STS)
  • STS most commonly metastasize to the lungs. Tumors arising in the abdominal cavity more commonly metastasize to the liver and peritoneum.
  • The decision making in the management of advanced or metastatic STS is complex, depending on diverse presentations and histologies, and should always be multidisciplinary.
  • In general, presentation with metastatic disease is considered incurable, and treatment is considered palliative. Chemotherapy usually plays a primary role in the management of metastatic sarcoma. However, there may also be a role for surgery or radiation therapy for palliation to control symptoms and improve quality of life.
  • Where lung metastases are synchronous, in the absence of extrapulmonary disease, standard treatment is chemotherapy. Surgery of completely resectable residual lung metastases may be considered as an option, especially when a tumor response is achieved. 
  • Metachronous resectable lung metastases without extrapulmonary disease are managed with surgery as standard treatment, if complete excision of all lesions is feasible.
  • Appropriate imaging should be utilized to exclude extrapulmonary disease. These can include CT or PET scans. The role of chemotherapy in this setting is individualized.  Where chemotherapy is added to surgery as an option, it is preferable to give the chemotherapy prior to surgery to assess tumor response and modulate treatment as needed.  
  • Extrapulmonary metastatic disease is treated with chemotherapy. 
  • In highly selected cases, surgery of responding metastases may be offered as an option following multidisciplinary evaluation, taking into consideration their site and natural history of the disease in the individual patient.
  • Chemotherapy for metastatic /advanced disease: Standard first-line chemotherapy consists of anthracycline-based therapy. Multi-agent chemotherapy has not been found to be superior to Doxorubicin alone in terms of overall survival. However, a higher response rate can be expected, especially in chemo-sensitive subtypes. Thus, in selected patients, the combination of doxorubicin with Ifosfamide could be considered. 
  • After failure of anthracycline-based chemotherapy, other agents have been shown to be active. been shown to be active (but without high-level evidence) include:
    • Gemcitabine with or without docetaxel (leiomyosarcoma, undifferentiated pleomorphic sarcoma, angiosarcoma).
    • Taxanes (angiosarcoma)

References

  • Crompton, et al. Local control of soft tissue and bone sarcomas. JCO 2018;36(2):111-117.
  • 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
  • Haas RL, Gronchi A, Van de Sande MAJ, etl: Perioperative management of extremity soft tissue sarcoma. JCO 2018:36(2): 118-124
  • Soft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and followup. The ESMO/European sarcoma network working group. Annals of onc 2014;25 (Suppl. 3): iii102-iii12
  • Judson I, Gelderblom H, Schoffsji P, t al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomized controlled phase 3 trial.  Lancer Oncol 2014;14: 415-423
  • Adjuvant chemotherapy for localised resectable soft tissue sarcoma of adults: Meta-analysis of individual data. Sarcoma Meta-analysis collaboration. Lancet 1997, 350:1647-1654, Pervaiz N, Colterjohn N, Farrkhyar F etal. A systematic meta-analysis of randomized controlled trial of adjuvant chemotherapy for adult soft tissue sarcoma. Cancer 2008; 113:573-581.

8. Retroperitoneal Sarcoma

  • Given the rarity of RPS, there isn’t high level evidence based on large randomized controlled trials to guide management. The recommendations and statements below are based on smaller prospective and retrospective cohort and case-controlled studies and expert consensus opinions.
  • Retroperitoneal sarcomas (RPS) are rare, comprising 10-15% of all STS. Patients usually present in their 50’s, although the age range is broad. These tumors affect men and women equally. 
  • Approximately 80% of retroperitoneal tumors are malignant. 
  • The majority of patients who present with a primary retroperitoneal, extra-visceral, unifocal soft tissue mass will be found to have a sarcoma.
  • The most common histologic subtypes in adults are:
    • liposarcoma, leiomyosarcoma and undifferentiated pleomorphic sarcoma.
  • Differential diagnosis: other entities that may present as retroperitoneal masses and need to be ruled out include metastatic adenocarcinoma, lymphoma, germ cell tumor and paraganglioma.
Presentation
  • RPS typically do not cause many symptoms until they are large enough to compress or invade surrounding structures. Thus, most tumors are already large (>15cm) and advanced at the time of diagnosis.
  • Local invasion or compression can lead to lower extremity edema, gastrointestinal symptoms and ascites.
  • Distant metastases (most commonly to lung and liver) can be present in about 10% of cases at the time of diagnosis.
Staging and preoperative assessment
  • CT scan of chest, abdomen and pelvis with IV contrast.
  • MRI is an option for patients with IV contrast allergy or other contraindications, or pelvic tumors, and for assessing the extent of tumors to specific sites (ie. Vertebral foramina, sciatic notch) that is not clear on CT scan. 
  • Functional assessment of the contralateral kidney is necessary for planning treatment of the ipsilateral RPS.
  • Bone scan and PET scanning do not usually add useful information to staging assessment. 
Biopsy
  • Image-guided percutaneous coaxial core needle biopsy is strongly recommended (unless the imaging is pathognomonic and no pre-operative treatment is planned.
  • Multiple needle cores should be obtained to allow for histologic and molecular subtyping. 
  • Sampling of the more solid, dedifferentiated tumor component represented by well-perfused areas in contrast (enhanced CT or MRI is strongly encouraged). 
  • The risk of needle track seeding is minimal and should not be a reason to avoid a biopsy.
  • Fine needle aspiration should be avoided as it rarely yields diagnostic information and can delay treatment.
  • Laparotomy with open biopsy and/or laparoscopic biopsy should be avoided as this exposes the peritoneal cavity to contamination by sarcoma, distorts subsequent planes of dissection, may put vital neurovascular structures at risk and may still not provide diagnostic material due to lack of 3-dimensional image guidance.
  • Patients found unexpectedly to have a retroperitoneal mass at the time of laparotomy, laparoscopy or other abdominal procedure should not undergo biopsy. Nothing further should be done at that time. The patient should undergo dedicated imaging and workup of the retroperitoneal mass. 
Surgery
  • The best chance for resection with curative intent is at the time of primary presentation. 
  • The individual management plan will take into account tumor factors (histologic subtype which determines biologic behavior, response to treatment) and patient factors (performance status, nutritional status, comorbidities).
  • Complete gross resection is the cornerstone of management.  Surgery should aim to achieve a macroscopically complete resection, with a single specimen encompassing the tumor and involved contiguous organs, and at minimizing microscopically positive margins. This is best achieved by resecting the tumor en bloc with adherent structures even if not overtly infiltrated. 
  • Surgical expertise in RPS requires specific anatomic knowledge of the retroperitoneal space to minimize the risk of intra- and peri-operative morbidity.
Adjuvant/Neoadjuvant therapy
  • Although no randomized trials of neoadjuvant therapy versus resection alone for RPS have been reported to date, neoadjuvant therapy in the form of chemotherapy, external beam radiation or combined radiation and chemotherapy is safe for well-selected patients and may be considered after careful review by a multidisciplinary sarcoma tumor board. This is particularly relevant in the case of technically unresectable/borderline resectable RPS that could potentially be rendered resectable by downsizing, and for chemo-sensitive histologies.
  • There is no study-proven value for post-operative adjuvant treatment after complete gross resection of RPS with either radiotherapy or systemic therapy.
Follow-up evaluation
  • Risk of recurrence after grossly complete resection does not plateau. Patients should be followed indefinitely.
  • The median time to recurrence of high-grade RPS is less than 5 years after definitive treatment.
  • Follow-up assessment should include cross-sectional imaging.
  • In years 1-5, follow-up evaluations should be at intervals of 3-6 months, extending to annually after year 5. 
Recurrent retroperitoneal sarcoma
  • The decision to pursue curative resection with complete gross resection is multifactorial. 
  • Histopathologic subtype should factor into the decision to pursue re-resection as response to treatment varies by histologic subtype. For example, well-differentiated liposarcoma would be favored for re-resection.
  • Other factors to consider which predict for favorable outcome are: no history of tumor rupture, low grade, long disease-free interval, and solitary recurrence. 
  • The chance of long-term disease free survival is limited despite complete gross resection of recurrent RPS.
  • For isolated locoregional recurrence, the goal of resection should be curative.
  • Multifocal intra-abdominal disease is difficult to resect completely and will almost certainly recur. 
  • In general, synchronous abdominal and distant recurrence should not be resected, and the patient should be considered for systemic therapy.
  • Neoadjuvant systemic therapy may be of benefit in downsizing recurrent disease and assessing tumor biology. 
  • Pre-operative radiotherapy should be considered if not previously given and if recurrence is isolated.
  • There is no proven role for post-operative adjuvant systemic or radiotherapy after complete resection of recurrent RPS.
  • There is no proven role for intraperitoneal chemotherapy with regional hyperthermia.
  • The management of patients who are not eligible for resection should be individualized and can include palliative systemic therapy, radiation or surgery with the intent of relieving symptoms and improving quality of life.
  • In select patients, survival with recurrent RPS may be prolonged (eg, well-differentiated liposarcoma).  The potential to live many years despite ongoing presence of disease should be recognized and adequately communicated with the patient.
References

  • Management of primary retroperitoneal sarcoma (RPS) in the adult: a consensus approach from the Trans-Atlantic RPS working group.  Ann Surg Onc 2015; 22:256-263
  • Management of recurrent retroperitoneal sarcoma (RPS) in the adult: A consensus approach from the Trans-Atlantic RPS working group. Ann Surg Onc 2016; 23:3531-3540

9. Gastrointestinal Stromal Tumor (GIST)

Presentation
  • GISTs are the most common STS of the GI tract, and can arise anywhere in the GI tract, but stomach (60%) and small intestine (30%) are the most common primary sites. Other much less common sites include duodenum, rectum, colon, appendix and rarely, esophagus.
  • Presenting symptoms include early satiety, abdominal pain, intraperitoneal hemorrhage, GI bleeding, or fatigue related to anemia. 
  • Some patients may present with an acute abdomen due to rupture or obstruction. Up to 20% of patients have overt metastases at diagnosis, typically within the abdominal cavity or liver.
  • Lymph node metastases are rare except when arising in pediatric GISTs, pediatric-type GISTs in young adults and syndromic GISTs.
  • Lung and extra-abdominal disease are seen usually in advanced disease. 
  • Most GISTs are sporadic.
  • Rare tumor syndromes predisposing to GIST include: neurofibromatosis 1, Carney-Stratakis syndrome and Carney triad.
Imaging
  • Contrast-enhanced CT is the imaging modality of choice for diagnosis, initial staging, restaging, monitoring response to therapy and surveillance. 
  • PET scan helps to differentiate active tumor from necrotic, inactive scar or benign tissue, and can be used to clarify ambiguous findings on CT or MRI scans, but it is not a substitute for CT.
Biopsy
  • GISTs are soft and fragile tumors mostly arising from the muscularis propria and sometimes muscularis mucosa, seen as smooth submucosal masses.
  • Endoscopic biopsies using standard techniques usually do not obtain sufficient tissue for a definite diagnosis.
  • Pre-operative biopsy is not generally recommended for a resectable lesion in which there is a high suspicion for GIST and the patient is otherwise operable.
  • EUS-guided FNA biopsy of primary site is preferred over percutaneous biopsy due to the risk of tumor hemorrhage and intra-abdominal tumor dissemination.
  • Biopsy is necessary to confirm the diagnosis of primary GIST before initiating preoperative therapy.
  • Percutaneous image-guided biopsy may be appropriate for confirmation of metastatic disease.
Pathologic assessment
  • Pathology report should include: anatomic location, size, mitotic rate.
  • GISTs arise most commonly from KIT and PDGFRA activating mutations.
  • Mutation analysis of KIT and PDGFRA is mandatory for optimal care of GIST.
  • Most GISTs express KIT (CD117) and DOG1.
  • Approximately 80% of GISTs have a mutation in the gene encoding the KIT tyrosine receptor kinase; another 5-10% have a mutation in the gene encoding the PDGFRA receptor tyrosine kinase.
  • About 10-15% are wild-type with no detectable KIT or PDGRFA mutations.
  • Most KIT mutations occur in exon 11 (90%) or exon 9 (8%). Other rare KIT mutations are found in exon 13 and exon 17.
  • PDGFRA mutations usually affect exons 12,14 and 18.
  • KIT exon 11 mutations are common in GISTs of all sites, whereas KIT exon 9 mutations are specific for intestinal GISTs. PDGFRA exon 18 mutations are common in gastric GISTs.
  • Immunohistochemical (IHC) staining for CD117, DOG1 and /or CD34 and molecular genetic testing to identify KIT and/or PDGFRA mutations are important in the diagnosis of GIST.
  • However, the absence of KIT and/or PDGFRA does not exclude GIST.
  • Tumors lacking KIT or PDGFRA mutations should be considered for further evaluation with SDHB immunostaining, BRAF mutation analysis and SDH gene mutation analysis.
  • Loss-of-function mutations in succinate dehydrogenase (SDH) gene subunits or loss of SDHB protein expression by IHC have been identified in a majority of wild-type GISTs lacking KIT ad PDGFRA mutations.
  • SDH-deficient tumors should prompt germline testing for SDH mutations. Carney-Stratakis syndrome is a rare heritable condition with a germline mutation in SDH complex genes SDHA, SDHB, SDHC or SDHD.
  • Cancer genetics Solid tumor requisition 
Prognostic and Predictive factors
  • Tumor size
  • Location of primary
  • Mitotic rate
  • Tumor rupture
  • Incomplete resection
  • The presence of KIT or PDGFRA mutation status are predictive of response to TKI therapy in patients with advanced or metastatic GIST.  Conversely, GISTs that do not contain KIT or PDGFRA mutations are unlikely to benefit from imatinib therapy. GISTS harboring the PDGFRA mutation D842V (about 8% of G ISTs) do not respond to imatinib or other approved Tyrosine kinase inhibitors (TKIs), but most respond to BLU-285.
  • SDH-deficient and NF-1 –related  GISTs are less sensitive to TKIs.
  • Factors associated with poorer DFS include: KIT exon 9 duplication, KIT exon 11 deletion, non-gastric primary site, larger tumor size, and high mitotic index.
Risk stratification

Table 1: Three commonly used schemes for estimating the risk of GIST recurrence after surgery

Nomogram to predict probabilities of 2- and 5-year recurrence-free survival

Figure 2: Nomogram to predict probabilities of 2- and 5-year recurrence-free survival
  • Memorial Sloan Kettering (MSK) Cancer Center calculator tool to predict 2 and 5 year recurrence free survival after surgery for GIST

Treatment

Surgery
  • GISTs are fragile and should be handled with care to avoid tumor rupture. 
  • Surgery is the primary treatment for localized and potentially resectable GIST lesions with a goal of complete gross resection with intact pseudocapsule.
  • Lymph node dissection is usually not indicated in adults.
  • All localized GISTs >= 2cm should be resected.
  • Management of smaller gastric GISTs <2cm should be individualized. 
Neoadjuvant therapy
  • Preoperative therapy with imatinib, an inhibitor of KIT and PDGFRA, can be considered in patients with unresectable or borderline resectable locally advanced tumor, or a potentially resectable tumor that requires extensive organ disruption.
  • In patients with GIST arising in the esophagus, esophagogastric junction, duodenum or distal rectum, preoperative imatinib may shrink the tumor to allow a more conservative excision  and increase the likelihood of a complete (R0) surgical resection.
  • Typically neoadjuvant imatinib is administered for 6-12 months, with frequent imaging and periodic surgical re-assessment to determine when to operate (ie, at first resectability versus best tumor response).
  • Patients whose tumors are known to be unresponsive to imatinib  eg.  PDGFRA D842V mutation or SDH-deficient or Neurofibromatosis  (NF-1) related GIST should proceed directly to surgery.
  • The usual dose of imatinib is 400 mg daily.
Adjuvant therapy
  • Imatinib is a selective inhibitor of the KIT protein tyrosine kinase.
  • The optimum duration of post-operative adjuvant therapy is not yet established.
  • Based on the Scandinavian Sarcoma Group (SSG) XVIII trial, the current standard is to treat patients with high risk GIST for 3 years postoperatively at a dose of imatinib 400 mg once daily.
  • At the BC Cancer centres provincially(or agency - leaving this with just BC Cancer is not grammatically correct), patients with nomogram scores of 80 or higher (estimated 5 year RFS 65% or less) are considered high risk and are offered adjuvant Imatinib for 3 years. 
  • Tumors with exon 9 mutation are less sensitive to Imatinib, but in the adjuvant setting it is unknown whether a higher dose of 800mg imatinib daily would be beneficial. This will require further prospective study. 

Follow-up

NCCN guidelines:
  • For completely resected GIST:
  • History and physical exam every 3-6 months for 5 years then annually.
  • CT scan every 3-6 months for 3-5 years, then annually.
ESMO guidelines:
  • Very low risk GIST: routine follow-up likely not warranted although recurrence risk is not nil.
  • Low-risk GIST: benefit of routine follow-up is unknown. Could consider CT or MRI every 6-12 months for 5 years.
  • High risk GST: CT or MRI every 3 -6 months for 3 years during adjuvant therapy, then imaging every 3 months for 2 years, then every 6 months until 5 years from stopping adjuvant imatinib, then annually for another 5 years. 

Advanced or Metastaric or Recurrent GIST

Diagnosis
  • Baseline imaging is recommended prior to initiation of treatment.
  • Patients with unresectable or widely metastatic disease should have diagnosis confirmed with biopsy.

Systemic therapy

Imatinib
  • Most GISTs are characterized by activating mutations in the KIT or PDGFRA proto-oncogenes affecting membrane tyrosine kinase (TK) receptors.
  • Systemic therapy in the form of small molecules targeting receptor tyrosine kinases (tyrosine kinase inhibitors or TKI) have induced rapid and sustained clinical benefit in GISTs. 
  • Imatinib is the primary treatment for patients with advanced, unresectable or metastatic GIST at a standard does of 400mg daily. 
  • If there is poor response or tumor progression on 400 mg daily then imatiniib should be escalated to 800 mg daily (given as 400 mg twice daily).
  • Poor initial response to imatinib at 400 mg daily is more frequent in patients with exon 9 mutations. These patients should be closely observed and dose escalated quickly.
  • Continuous use of imatinib is recommended for metastatic GIST until progression.
  • Common side-effects of imatinib include edema, diarrhea, nausea, fatigue, muscle cramps, abdominal pain and rash. 
  • Serious side effects such as lever enzyme abnormalities, lung toxicity, low blood conts and GI bleeding have rarely been reported and often improve after imatinib is withheld.
  • The side-effect profile may improve with prolonged therapy.
  • Imatinib is a rare of cardiotoxicity such as congestive heart failure, arrhythmias or acute coronary syndromes, occurring in less than 1% of treated patients.
Sunitinib
  • Sunitinib is a multi-targeted TKI with activity agsinst KIT, PDGFR, VEGFR, and FLT-1/KDR.
  • Second-line therapy with Sunitinib should be initiated when the majority of disease is no longer controlled on imatinib. 
  • The usual dose of sunitinib is 50 mg daily for 28 days with 14 off in a 42-day cycle.
  • To avoid recurrent tumor symptoms during the 2 week break and to manage adverse effects, it would not be unreasonable to use a continuous daily dose of 37.5 mg, which provides similar safety, tolerability and response rates to the 4 weeks on/2 weeks off regimen.
  • Sunitinib-related toxicities can often be managed with dose interruptions or reductions.
  • Side effects include fatigue, nausea, vomiting, cytopenias, diarrhea, abdominal pain, mucositis, anorexia, skin discoloration and hypertension.
  • Sunitinib is associated with cardiotoxicity and hypothyroidism.  Therefore patients should be closely monitored for hypertension, LVEF and TSH.
  • If hypothyroidism is detected, patients should receive thyroid hormone replacement therapy.
  • Hypertension should be treated with antihypertensive agents. 
Regorafenib
  • Regorafenib is a multi-targeted TKI targeting VEGFRI-3, TEK, KIT, RET, RAF1,BRAF, PDGFR and FGFR.
  • Regorafenib has been approved for treatment of patients with GIST previously treated with imatinib and sunitinib.
  • The dose is 160 mg daily for 21 days with 7 days off, repeated every 28 days.
  • The phase 3 GIST-Regorafenib in progressive disease (GRID) trial demonstrated  4 month improvement in PFS but no difference in OS (probably due to cross-over).
Surgical management of advanced /metastatic GIST
  • The role of metastasectomy in patients whose disease is controlled with imatinib is controversial. 
  • It is possible that debulking of metastatic disease after an initial stabilization or response to imatinib may help in prolonging disease control by preventing the emergence of resistant clones.
  • Resection of a focal progressing lesion may allow the use imatinib to be prolonged, whereas surgery for diffuse progression would not. 
  • The role of metastasis surgery in patients on sunitinib or regorafenib is unclear, except for patients who require emergency surgery. Patients with progressive disease on sunitinib and regorafenib likely have multiple resistant clones and greater tumor bulk , and therefore the potential benefits versus risks of surgery need to be carefully considered.
Other palliative approaches
  • Radiotherapy can be effective in stabilizing progressing liver or intra-abdominal lesions.
  • Local interventional modalities such as embolization and radiofrequency ablation can potentially be considered for liver metastases.
  • For patients with progressive GIST after all standard therapies, discontinuing TKI therapy is not recommended given the rapid rate of progression documented after discontinuation.
  • Restarting imatinib after progression on at least prior imatinib and sunitinib increased PFS slightly form 0.9-1.8 months compared with best supportive care.
  • Pazopanib plus best supportive care was shown to improve PFS compared to best supportive care alone, in a small randomized trial of patients whose GIST was resistant to imatinib and sunitinib.

References

  • Von Mehren M, Joensuu H. Gastrointestinal stroma tumors. JCO 2018; 36(2):136-43.
  • Gold J, Gonen M, Gutierrez A, et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localized primary gastrointestinal stromal tumor:  retrospective analysis. Lancet Oncol 2009; 10:1045-52
  • Wozniak A, Rutkowski P, Schoffski P, et al. Tumor genotype is an independent prognostic factor in primary gastrointestinal stromal tumors of gastric origin: a european multicenter analysis based on ConticaGIST. Clin Cancer Res 2014;20:6105-6116.
  • Rose S. BLU-285, DCC-2618 show activity against GIST. Cancer Discov 2017; 7:121-122.
  • Joensuu H, Eriksson M, Sundby Hall K, et al. One versus three years of adjuvant imatinib for operable gastrointestinal tumor: a randomized trial.  JAMA 2012; 307 (12):1265-72
  • Demetri G, van Oosteram AT, Garrett CR, et al. Efficacy and safety of sunitinib in patietns with advanced gastrointestinal stromal tumor after failure of imatinib: A randomized controlled trial. Lancet 2006;368:1329-1338
  • George S, Blay JY, Casali OPG, et al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumor after imatinib failure. Eur J Caner 2009; 45:1959-1968.
  • Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumors after failure of imatinib and sunitinib (GRID): An international, multicenter, randomized , placebo-controlled phase 3 trial. Lancet 2013; 381:295-302.
  • Du CY, Zhou Y, Song C, et al. Is there a role of surgery in patients with recurrent or metastatic gastrointestinal stromal tumors responding to imatinib: A prospective randomized trial in China. Eur J Cancer 2014; 50: 1772-1778.
  • Bauer S, Rutkowski P, Hohenberger P, et al. Long-term followup of patients with GIST indergoing metasttectomy in the era of imatinib: Analysis of prognostic factors (EORTC-STBSG collaborative study). Eur J Surg Oncol 2014;40:412-419.
  • Kang YK, Ryu MH, Yoo C, et al. Resumption of imatinib to control metatatic or unresectabe gastrointestinal stromal tumors after failure of imatinib and sunitinib (RIGHT): A randomized, placebo-controlled phase 3 trial. Lancet Oncol 2013; 14:1175-1182.
  • Mir O, Cropet C, Toulemonde M, et al. Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumors resistant to imatinib and sunitinib (PAZOGIST): A randomized, nulticentre, open-label phase 2 trial. Lancet Oncol 2016;17:632-641
  • Trent C, Patel SS, Zhang J, et al. Cancer 2010;116(1):184-92.


10. Desmoid Fibromatosis

Presentation
  • Desmoid tumors (DTs) are rare, accounting for 0.03% of all neoplasms and < 3% of all soft tissue tumors.
  • Desmoid tumors or aggressive fibromatosis are classified as benign tumors because of their lack of metastatic potential and low risk of mortality.
  • DTs are locally infiltrative and may result in significant morbidity and, very rarely, death.
  • DTs can occur in any anatomic location, but frequently arise in the abdominal wall, neurovascular bundle of the limb and shoulder girdle, root of the mesentery, and head and neck structures.
  • Depending on location, presentation can vary from asymptomatic to severe pain, deformity, swelling, loss of function, bowel obstruction or perforation, and/or threat to vital organs.
  • DTs usually affect individuals between 15-60 years of age.
  • There is a slight female preponderance.
  • DTs are characterized by variable clinical behavior. Some desmoids may grow progressively larger over time, while others may experience indolent growth or periods of growth arrest and spontaneous regression.
  • There is also variability in the propensity to recur after definitive therapy.

Risk Factors

FAP and Gardner syndrome
  • Most DTs are sporadic.
  • About 5-15% are associated with familial adenomatous polyposis (FAP), while 10-20% of patients with FAP will develop desmoids.
  • FAP is caused by mutations in the APC gene on chromosome 5q21-q22.
  • Gardner syndrome is a variant of FAP, characterized by intestinal polyposis and various bone and soft tissue lesions, including osteomas, epidermal inclusion cysts, lipomas, fibromas and desmoid fibromatoses.
  • Most DTs associated with FAP are abdominal (intra-abdominal or abdominal). 
  • Screening colonoscopy can be considered in patients with newly diagnosed DTs especially if they are a young, have intra-abdominal or abdominal wall desmoid, or multiple desmoids.
  • With the increasing use of prophylactic colectomy in patients with FAP, DTs have become an important cause of morbidity and mortality.
Pregnancy
  • DTs have been associated with high estrogen states.
  • Extra-abdominal and abdominal desmoids can occur in women during or following pregnancy. Trauma related to the pregnancy (including scar from prior Cesarean section) and exposure to elevated hormone levels may both be contributory.
  • Pregnancy-associated desmoids are associated with good outcomes overall.
Antecedent trauma
  • Desmoid tumors have been associated with antecedent trauma, particularly surgical intervention, as noted in patients with FAP and pregnancy-associated desmoids, but also with sporadically occurring desmoids.
  • There may be a molecular connection between wound healing processes and fibroproliferative disorders of mesenchymal tissue. 
Molecular pathogenesis
  • The molecular events leading to desmoid formation are incompletely understood.
  • Virtually all patients with DTs harbor inactivating mutations in either CTNNB1 (90% somatic - sporadic ) or APC (9% germline - hereditary).
  • Desmoids in FAP arise from APC inactivation and subsequent beta-catenin accumulation in cells.
  • Sporadic desmoids arise from mutations in gene for beta-catenin, CTNNB1, while APC mutations are uncommon.

Diagnostic workup

Imaging
  • MRI is preferred for truncal and extremity DTs for defining relationship of the tumor to adjacent structures to assess resectability and need for treatment.
  • CT can also adequately evaluate DTs.
Biopsy
  • Core needle biopsy is usually sufficient to make a diagnosis in the hands of an experienced pathologist.
Pathology
  • Positive immunohistochemistry for nuclear beta-catenin supports the diagnosis of desmoid tumor, although it should be noted that nuclear beta-catenin is not completely specific, being occasionally seen in other entities (eg. Solitary fibrous tumor and synovial sarcoma) and not all desmoid tumors will stain for nuclear beta-catenin (cytoplasmic staining is more sensitive, but less specific). 
  • Genomic sequencing reveals a very low mutational burden with no consistent genetic changes, except in Gardner syndrome cases.
Endoscopy
  • Given the association of desmoids with FAP, it is important to obtain an accurate family history, especially of colon cancer. 
  • Colonoscopy may be recommended for all patients diagnosed with desmoid tumor especially an intra-abdominal desmoid.

Treatment

Active surveillance
  • Desmoids have an unpredictable clinical course, encompassing progression, stability or even spontaneous regression. 
  • Close observation, in consultation with the sarcoma team, is an acceptable strategy for stable, asymptomatic primary or recurrent desmoids.
  • Active surveillance may not be appropriate if progression could be life-threatening or pose a risk to  critical adjacent structures (eg. nerves or vessels)
  • Patients should be monitored clinically and with imaging every 3-6 months. If disease is stable, then monitoring intervals can be extended.
Surgery
  • Surgery, when medically and technically feasible with negative margins, is an acceptable treatment option for patients who are symptomatic or experiencing rapid or life-threatening progression.
  • Tumor location and size, and patient’s age are factors associated with recurrence risk.
  • The relationship between surgical margin status and local recurrence rate is unclear. 
  • Thus, aggressive attempts at achieving widely negative margins are not warranted, especially if they result in increased risk of morbidity.
  • Intra-abdominal/mesenteric desmoids that develop in patients with FAP are often unresectable as they tend to be large, infiltrative and/or multiple in nature. Attempted resections can result in substantial morbidity. For these patients, a multidisciplinary approach, which may include initial medical therapy, is recommended. 
Radiation Therapy
  • Radiation therapy is an effective and reasonable primary therapeutic option for symptomatic patients who are not candidates for surgical or systemic therapies. 
  • Given the unclear relationship between margin status and local recurrence risk, the role of post-operative radiation is also unclear and tends to be avoided in this generally younger patient population.
  • Radiation therapy is not usually recommended for retroperitoneal or intra-abdominal desmoid tumors.

Other local therapies:

Cryoablation
  • Cryosurgery/cryoablation may be considered as an adjunct or stand-alone treatment for local control or palliation of musculoskeletal neoplasms.
  • Patients presenting with aggressive or symptomatic benign bone or soft tissue neoplasm may benefit from cryoablation while minimizing morbidity compared for eg, with surgery or radiation.
  • An advantage of cryoablation for desmoids is that it allows conservative treatment of a benign process and the ability to re-treat if necessary with decreased chance of significant morbidity.
  • Cryotherapy should only be attempted in a specialized setting in experienced hands. There is local experience with cryotherapy at Vancouver General Hospital under Dr. Peter Munk.
Systemic therapy
  • There are a variety of options for systemic therapy depending on patient and disease factors such as resectability, disease indolence, symptomatic disease, urgency to induce response, prior local therapy and potential morbidity of local therapy. 
  • A wide class of drugs has shown variable degrees of activity.
  • Initial treatment with hormonal agents (tamoxifen) with or without NSAIDs (sulindac or celecoxib) may be suitable for patients with less aggressive, minimally symptomatic disease in whom an urgent response is not required. 
  • The risk of cardiovascular events may be increased in patients receiving celecoxib, and this information should be considered when prescribing celecoxib to individual patients, weighing risks versus benefits, especially in patients with risk factors for cardiovascular disease. 
  • Tyrosine kinase inhibitors (Imatinib, Sorafenib) have demonstrated activity in the treatment of desmoid tumors.
  • Chemotherapy is generally reserved for slowly progressing, symptomatic disease that have failed prior therapies or, rapidly progressing, unresectable disease.
  • Doxorubicin-based chemotherapy, including single agent liposomal doxorubicin, has been effective in patients with recurrent and unresectable tumors.
  • The combination of  low dose methotrexate with vinorelbine or vinblastine has also shown activity with durable clinical benefit 
Duration of therapy: 
  • There is no strong evidence to guide duration of therapy.
  • Duration of therapy should be based on toxicity and response. 
  • Response to systemic therapy can be slow to manifest, sometimes taking 6 to 8 moths or more. 
  • Imaging every 2 -3 cycles (or every 2-3 months) to monitor response or disease stability, and ensure non-progression is reasonable.
  • Non-cytotoxic therapies could be continued in the absence of toxicity and based on the patient’s response and wishes for treatment breaks.
  • Doxorubicin-based therapies are limited by cumulative cardiotoxicity and myelosuppression.
  • The weekly Methotrexate plus vinblastine combination tends to be less toxic and often administered for one year.
Surveillance
  • Consensus-based guidelines from NCCN suggest history and physical with imaging (CT or MRI) every 3-6 months for 2-3 years then annually.

References

  • Gounder MM, Thomas DM, Tap WD. Locally aggressive connective tissue tumors. J CLin Oncol 2018;36(2):202-209.
  • Fletcher JA, Bridge JA, Hogendoorn PCW et al. Desmoid-type fibromatoses.
  • WHO Classification of Tumors of Soft Tissue and Bone. Lyon: IARC Press 2013; 72–73.
  • Alberta Health Services Clinical Practice guidelines. Desmoid tumors. July 2017. https://www.albertahealthservices.ca/assets/info/hp/cancer/if-hp-cancer-guide-sar004-desmoid.pdf
  • Gronchi A, Casali PG, Mariani L, et al. Quality of surgery and outcome in extra-abdominal aggressive fibromatosis: a series of patients surgically treated at a single institution. J Clin Oncol 2003: 21:1390-1397.
  • Skapek SX, Anderson JR, Hill DA, et al: Safety and efficacy of high-dose tamoxifen and sulindac for desmoid tumor in children: Results of a Children’s Oncology Group (COG) phase II study. Pediatr Blood Cancer 60:1108-1112, 2013
  • Kasper B, Baumgarten C, Bonvalot S, et al: Management of sporadic desmoid-type fibromatosis: A European consensus approach based on patients’ and professionals’ expertise—A sarcoma patients EuroNet and European Organisation for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group initiative. Eur J Cancer 51:127-136, 2015
  • Fiore M, Colombo C, Radaelli S, et al: Hormonal manipulation with toremifene in sporadic desmoid-type fibromatosis. Eur J Cancer 51: 2800-2807, 2015
  • Tsukada K, Church JM, Jagelman DG, et al. Noncytotoxic drug therapy for intra-abdominal desmoid tumor in patients with familial adenomatous polyposis. Dis Colon Rectum. 1992;35(1):29.
  • Chugh R, Wathen JK, Patel SR, et al. Efficacy of imatinib in aggressive 37. Chugh R, Wathen JK, Patel SR, et al. Efficacy of imatinib in aggressive fibromatosis: Results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial. Clin Cancer Res. 2010;16(19):4884. Epub 2010 Aug 19.
  • Gounder MM, Lefkowitz RA, Keohan ML, et al. Activity of Sorafenib against desmoid tumor/deep fibromatosis. Clin Cancer Res. 2011;17(12):4082. Epub 2011 Mar 29.
  • Garbay D, Le Cesne A, Penel N, et al. Chemotherapy in patients with desmoid tumors: a study from the French Sarcoma Group (FSG). Ann Oncol 2012;23:182-186. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21444357.
  • Constantinidou A, Jones RL, Scurr M, et al. Pegylated liposomal doxorubicin, an effective, well-tolerated treatment for refractory aggressive fibromatosis. Eur J Cancer 2009;45:2930-2934. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19767198.
  • Azzarelli A, Gronchi A, Bertulli R, et al. Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis. Cancer. 2001;92(5):1259.
  • Rose PS, Morris JM. Cryosurgery/cryoablation in musculoskeletal neolams: history and state of the art. Curr Rev Muskuloskelet Med 2015;8:353-360.




11. Bone Sarcoma

Primary bone cancers are rare neoplasms accounting for <0.2% of all cancers. They demonstrate wide clinical heterogeneity, and are often curable with appropriate treatment. 

Osteosarcoma, Chondrosarcoma and Ewing sarcoma are the three most common forms of bone cancer. Other rarer forms of malignant bone tumors include high grade undifferentiated pleomorphic sarcoma of bone, chordoma and giant cell tumor of bone (GCTB).  GCTB has both benign and malignant forms, with the benign form being the most common subtype. 

Patients with primary bone sarcoma should be diagnosed and treated at a center with an experienced multidisciplinary sarcoma team including Surgical Oncology, Radiation Oncology, Medical Oncology, Pathology and Diagnostic imaging to ensure the best outcome for the patient.

Given that most of the patients presenting with primary bone tumors are young, long-term surveillance and follow-up will be needed to monitor for recurrence and morbidities associated with chemotherapy and radiation therapy. Fertility issues (especially in patients treated as adolescents and young adults) should be discussed when appropriate.

Diagnostic workup of a bone tumor
All patients with suspected bone sarcoma should undergo complete staging prior to biopsy.

Imaging
  • Plain radiographs of primary site.
  • MRI of the entire length of the involved long bone
  • CT chest
  • Bone scan and/or
  • PET/CT scan
Biopsy
  • The placement of biopsy is critical to the planning of potential limb-sparing surgery.
  • Biopsy should be performed at the surgical centre that will provide definitive treatment for patients with suspected malignant primary bone tumor.
  • Either core needle biopsy or open biopsy may be recommended to confirm the diagnosis prior to any surgical procedure or fixation of the primary site, with the decision ideally made at a multidisciplinary meeting including orthopaedics, radiology and pathology.
  • If a core needle biopsy is planned, the interventional radiologist and orthopedic surgeon should communicate about the placement of the biopsy tract.
  • If an open biopsy is chosen, it should ideally be done by an orthopedic surgeon who will perform the definitive surgery.

Osteosarcoma

Presentation
  • Osteosarcoma (OS) is the most common primary malignant bone tumor in children and young adults.
  • OS incidence is bimodal, with a peak in boys between ages 15-19 and in girls  at ages 10-14, corresponding with puberty. There is a second incidence peak in the elderly, age >59 years. 
  • Most patients complain of localized pain with a tender soft tissue mass most commonly involving the metaphyseal region of long bones especially  the distal femur.
  • 10-20% of patients have demonstrable macro-metastatic disease at the time of presentation.
  • Occult micrometastases are presumed to be present in the majority of patients who appear to have localized disease.
Risk factors
The majority of OS in children are sporadic whereas in older adults, about one third of OS cases are associated with Paget’s disease of bone or arise as a secondary malignancy.
Risk factors include:
  • Radiation exposure
    • The average interval between irradiation and secondary OS is about 12-16 years, although can be shorter in childhood cancer survivors
  • Chemotherapy
    • Prior exposure to chemotherapy, especially alkylating agents can be associated with secondary OS and may potentiate the effect of prior radiation.
  • Paget disease and other benign bone lesion
  • Inherited conditions
    • Hereditary retinoblastoma (mutations in RB1) and Li-Fraumeni syndrome (TP53 mutation) are associated with increased risk of OS.
Histologic subtypes
  • Conventional High grade Osteosarcoma
    • Most common subtype accounting for 90% of all OS.
    • Subclassified as osteoblastic, fibroblastic or chondroblastic histological variants, depending on the predominant cellular component, although their clinical behavior are similar and are all managed the same way.
  • Rarer histologic variants of osteosarcoma: their clinical behavior may carry a somewhat worse prognosis, but management is similar to conventional high grade OS
    • Small cell
    • Telangiectatic
    • Multifocal
    • Undifferentiated high-grade pleomorphic sarcoma of bone
  • Parosteal Osteosarcoma and low grade intramedullary (fibrous dysplasia-like) osteosarcoma
    • Low grade surface (parosteal) or medullary lesions that typically require close radiology-pathology correlation for diagnosis.
    • Treatment consists of surgical resection alone in most cases as the risk of metastasis is very small
  • Periosteal Osteosarcoma
    • Intermediate grade surface lesion with  greater likelihood of metastases compared with parosteal OS, but  lower than classic intramedullary OS.
    • Role of adjuvant chemotherapy is controversial but is often recommended because of the estimated 20% metastatic rate. However, the benefit of adjuvant chemotherapy is unproven.

Treatment

Chemotherapy
  • Chemotherapy is essential for the treatment of OS (other than the rare low grade subtypes) to achieve cure as most patients are suspected of harboring micrometastatic disease at the time of diagnosis.
  • Short, intensive chemotherapy regimens containing cisplatin and doxorubicin with or without high-dose methotrexate and ifosfamide have been demonstrated to produce excellent long-term result similar to those achieved with multiagent chemotherapy.
  • Appropriate growth factor support is indicated in this curative treatment regimen.
  • While pathologic response to chemotherapy is a prognostic indicator of outcome, there is no evidence that changing chemotherapy on the basis of histologic response results in improved outcome. Therefore it is recommended that postoperative chemotherapy be completed with the same pre-operative regimen. 
  • FERTILITY ISSUES should be discussed with patients prior to commencing chemotherapy.
Surgery
  • Re-staging with pretreatment imaging modalities is usually obtained  prior to surgery to assess response. These include:
    • CT chest
    • MRI and/or CT of primary site
    • Radiographs of primary site
    • Consider PET-CT if done pre-chemotherapy
    • Repeat other abnormal tests
  • Surgery remains an essential component for curative treatment for OS.
  • Wherever possible, limb-sparing surgery is preferred.
  • Amputation is generally reserved for patients with tumors in unfavorable anatomic locations not amenable to limb-sparing surgery with adequate surgical margins.
  • Conventionally, chemotherapy is given peri-operatively, with surgery being undertaken usually after 3 cycles of chemotherapy. This allows for rapid symptom improvement, assessment of chemo-responsiveness of the tumor and time for surgical planning.
Radiation therapy
  • Conventional OS is considered to be relatively radioresistant. 
  • Currently there is no role for adjuvant radiation therapy in the first-line curative setting.
  • Palliative radiation can be helpful in treating painful metastases or lesions with impending complications such as fracture.
  • In patients with unresectable tumors or when surgery would be highly morbid, radiation with or without concurrent chemotherapy can be considered. 
Patients with metastatic disease at diagnosis
  • Patients presenting with metastatic disease at diagnosis have a poor prognosis, although long-term survival and cure may still be achievable, depending on the site(s) of metastatic disease.
  • 60-70% will have lung only metastases, while 20-30% will have bone metastases, either skip or distant. 
  • The survival of patients with bone metastases is dismal.
  • The ability to control all foci of disease using a combination of surgery, chemotherapy and sometimes radiation therapy is important for long-term survival.
  • In the absence of bone metastases, cure is achievable in some patients with resectable metastases.
  • Patients with lung-only metastases at initial presentation should be treated aggressively with surgery and chemotherapy, and pulmonary metastasectomy should be considered. 
  • Patients who develop lung metastases after completing first-line therapy should also be considered for potential metastasectomy.
Surveillance and follow-up
  • The purpose of post treatment surveillance is to monitor for recurrence and chronic morbidities associated with chemotherapy and radiation therapy, particularly in long-term survivors.
  • Consensus-based NCCN guidelines recommend post treatment surveillance consisting of physical exam, chest imaging and imaging of primary site every 3 months for 2 years, then every 4 months in year 3 then every 6 months  in year 4 and 5, then annually 

References

  • Whelan JS, Davis LE. Osteosarcoma, Chondrosarcoma, and Chordoma. J  Clin Oncol. 2018; 36(2): 188-193.
  • NCCN Clinical Practice Guidelines in Oncology: Bone Cancer, v1.2018. 2017. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp
  • Mirabello L, Troisi RJ, Savage SA: International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons. Int J Cancer 125:229-234, 2009
  • Mialou V, Philip T, Kalifa C, et al. Metastatic osteosarcoma at diagnosis: prognostic factors and long-term outcome--the French pediatric experience. Cancer 2005;104(5):1100nt
  • Cesari M, Alberghini M, Vanel D, et al. Periosteal osteosarcoma: a single-institution experience. Cancer. 2011;117(8):1731.
  • Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314:1600-1606, 1986.
  • Bielack SS, Smeland S, Whelan JS, et al: Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 GoodResponse Randomized Controlled Trial. J Clin Oncol 33:2279-2287, 2015
  • Bramwell V, Burgers M, Sneath R, et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol 1992;10:1579-1591. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1403038.
  • Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet 1997;350:911-917. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9314869.
  • Fuchs N, Bielack SS, Epler D, et al. Long-term results of the co- operative German-Austrian-Swiss osteosarcoma study group's protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol 1998;9:893-899. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9789613.
  • Anninga JK, Gelderblom H, Fiocco M, et al. Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? Eur J Cancer. 2011 Nov;47(16):2431-45. Epub 2011 Jun 22.
  • Mahajan A, Woo SY, Kornguth DG, et al: Multimodality treatment of osteosarcoma: Radiation in a high-risk cohort. Pediatr Blood Cancer 50:976-982,2008


Ewing Sarcoma

Ewing sarcoma (ES) comprises a group of small round cell sarcomas with characteristic molecular findings consisting of non-random chromosomal translocations between the EWSR1 gene on chromosome 22 (or its FUS homolog) and one of several genes belonging to the ETS family of transcription factors (most commonly FLI1).

The diagnosis of ES encompasses lesions previously classified as Askin’s tumors, peripheral neuroectodermal tumors (PNET) and other names that are no longer part of the WHO classification.

Presentation
  • Ewing sarcoma can develop form almost any soft tissue or bone, but the most common site is in the long bones of the extremities and pelvic bones. Only a minority arise in soft tissue. 
  • ES is mainly seen in children and young adults, and occurs rarely in patients over 40 years of age.
  • Patients typically present with localized pain and swelling.
  • While overt metastatic disease is seen only in about 25% of patients at initial diagnosis, it is assumed that subclinical metastases are present in nearly all patients because of the 80-90% relapse rate with local therapy alone. Hence chemotherapy is an important component of treatment of ES.
  • Lung and bone/bone marrow are the most common sites of metastases, with lung metastases representing the first site of distant spread in the majority of patients.
Differential diagnosis and Pathology
  • The morphologic appearance of ES is somewhat generic, similar to that of other small round blue cell tumors including lymphoma, small cell osteosarcoma, mesenchymal chondrosarcoma, undifferentiated neuroblastoma, poorly differentiated synovial sarcoma, desmoplastic small round cell tumors, and rhabdomyosarcoma, as well as germ cell tumors, small cell carcinoma and melanoma variants. Immunohistochemistry and often molecular testing is often required to sort out among these possibilities, which can lead to delays in diagnosis.
  • The majority of ES express CD99, a cell surface glycoprotein encoded by the CD99 or MIC2X gene. However this is not specific for ES as many other tumors (eg. Rhabdomyosarcoma) and normal tissues are also immunoreactive with anti-MIC2 antibodies.
  • Molecular genetic studies are usually required to secure the diagnosis and are considered a standard of care for Ewing sarcoma given the major treatment implications of this diagnosis versus other small blue round cell tumors.
Molecular genetics
  • The main driver of ES is the reciprocal translocation between EWSR1 on chromosome 22 and FLI1 genes on chromosome 11 (EWSR1-FLI1).  This recurrent chromosomal translocation t (11;22)(q24;q12), can be detected by fluorescence in situ hybridization (FISH). The resultant fusion transcript can be detected by RT-PCR, NanoString or RNA-Seq technologies.
  • 85-90% of ES harbor the t(22;11) EWSR1-FLI1 translocation.
  • A smaller percentage of ES harbor translocations of EWSR1 with other genes in the ES family that share structural homology with FLI1 such as ERG, ETV1, ETV4, or FEV.
  • Finally, rare cases of ES are associated with translocations involving FUS, a gene related to EWSR1. 
  • These translocations are thought to function primarily as transcriptional regulators altering the epigenetic state of the cell, blocking differentiation and increasing cell division.
Prognostic factors
  • Presence or absence of metastases at diagnosis and extent of metastatic disease.  Patients presenting with lung-only metastases generally do better than lung and bone or bone only metastases and may enjoy a prolonged survival.  Patients with lung only metastases that can be ultimately resected may have an opportunity for cure.
  • Tumor location: Patients with extremity primary lesions do better than those with axial primaries (pelvis, rib, spine, scapula, skull, sternum, clavicle). Patients with primary pelvic tumors are more likely to present with metastatic disease.
  • It is also more difficult to achieve widely negative margins in large axial lesions  and those involving pelvis and spine.
  • Response to induction therapy and completeness of surgical resection are prognostic factors for survival.
  • Currently there are no prospectively validated biomarkers, although studies are ongoing.
Diagnostic and Staging workup

Imaging studies
  • Plain radiographs
  • CT scan of primary site delineates the extent of cortical destruction and soft tissue disease.
  • CT chest
  • MRI is preferred in most cases because of its superior definition of tumor size, intraosseous and extraosseous extent, and the relationship of the tumor to fascial planes, vessels, nerves and organs.
  • The involved bone should be completely images to exclude the presence of skip lesions.
  • Bone scan is recommended to assess the entire skeleton
  • The role of PET or PET-CT scans for diagnostic workup is unclear.  However, PET-CT is increasingly being used in the initial staging workup and can be very useful for monitoring response to chemotherapy and/or radiation therapy.
Bone marrow biopsy and aspirate
  • Bone marrow biopsy (at least unilateral) is often recommended because of the predilection for ES to metastasize to bone marrow. This may also provide useful information in the event the patient goes on to treatment with high dose chemotherapy with stem cell transplant. 
Tumor biopsy
  • Biopsy should ideally be done after completion of imaging studies.
  • The surgeon should be consulted before biopsy to plan the biopsy route carefully and avoid compromising a later operation, especially with the opportunity for limb salvage.
  • Adequate amounts of tissue will be required to provide sufficient diagnostic material for the various studies necessary to make a correct diagnosis, including sufficient material for special studies including molecular genetics. Nevertheless, the sensitivity of current molecular techniques means that 
  • CT-guided core needle biopsy is usually sufficient. 
  • However, if only necrotic material is obtained then an open biopsy may be necessary. Fine needle aspirate is not generally sufficient to establish an initial diagnosis, although may be adequate to establish a diagnosis of recurrent or metastatic disease. 
Treatment for Localized Disease
  • Treatment of localized disease with curative intent involves multimodal therapy including chemotherapy, radiation and surgery. 
  • Fertility consultation should be considered prior to commencement of chemotherapy if possible.
Chemotherapy
  • Chemotherapy is critical for treating the primary tumor and eradicating subclinical metastases that are presumed to be present in most patients who present with apparently localized disease. 
  • The current standard chemotherapy for ES includes alternating regimens of multiagent chemotherapy using Vincristine, Doxorubicin and Cyclophosphamide  (VDC) alternating with Ifosfamide and Etoposide (IE). 
  • Typically, 4 to 6 cycles of alternating chemotherapy are given initially  as induction therapy followed by local treatment which can include radiation and /or surgery, followed by more chemotherapy to complete a total of 14 -17 cycles.
  • Dose intense chemotherapy with interval compression to 14 day cycles has been shown to be superior to the same chemotherapy regimens cycling every 21 days. Thus currently the preferred regimen for children and young adults is interval compressed chemotherapy with VDC alternating with IE and with growth factor support.
Local treatment
  • Re-staging workup prior to local treatment to include:
    • CT chest
    • MRI and/or CT of primary site
    • PET -CT scan if pre-treatment PET -CT scan done.
    • Repeat other abnormal studies.
  • Local control can be achieved with surgery, radiation therapy or both. The choice of local treatment to achieve control should be individualized, depending on factors such as  tumor location and size, response to chemotherapy, age, anticipated morbidities and patient preference.
Surgery
  • Surgery is preferred for potentially resectable lesions.
  • Surgical options include wide excision versus amputation. Where possible , limb salvage is preferred. 
Radiation Therapy (RT)
  • ES are radiosensitive tumors. The decision to treat with RT should be individualized.
  • The benefits of adjuvant RT should be balanced with the risk of chronic RT induced toxicities including radiation-induced malignancy.
  • Post-operative RT is recommended for patients with positive or close margins.
Treatment for metastatic disease
  • Patients with metastatic disease at diagnosis generally respond well to the same chemotherapy as is used for localized disease. 
  • Alternating multiagent chemotherapy using VDC /IE is given similar to treatment of localized disease.
  • Patients with limited lung only metastases may achieve long term survival.
  • Optimal local therapy including surgery and radiation therapy should be considered in addition to chemotherapy where feasible.
  • For patients with pulmonary metastases, bilateral, low-dose whole lung radiotherapy can provide added disease control without significant lung toxicity.
  • Resection of limited lung nodules may be undertaken in consultation with the multidisciplinary care team.
High dose chemotherapy with stem cell support
  • The benefit of high-dose chemotherapy with stem cell support is unknown; studies in this area have yielded conflicting results.
  • Whenever possible, patient should be enrolled in open clinical trials evaluating novel approaches.
Post -treatment surveillance 
  • The majority of relapses occur within 2 years of initial diagnosis, although late relapse is not uncommon.
  • Long-term survivors may develop late treatment related complications such as second malignancy, pathologic fractures and other radiation-related complications (eg. wound complications, pulmonary fibrosis, limb leg discrepancy, femoral head necrosis). 
  • Late chemotherapy -related complications include second malignancy, reduced fertility, renal insufficiency, cardiomyopathy and neuropathy.
Suggested Follow-up regimen 
Every 3 months for 2 years then every 6 months in years 3-5, then annually:
  • Physical examination
  • CBC
  • Plain radiograph of primary site
  • MRI or CT of primary site
  • CT chest

References 

  • Pappo AS, Dirksen U. Rhabdomyosarcoma, Ewing sarcoma and other round cell sarcoma. J of Clin Oncol 2018; 36(2):168-179.
  • Womer R, West DC, Krailo MD, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewinoma : A report form the Children’s oncology group. J of Clin Oncol 2012; 30(33): 4148. Epub 2012Oct22.
  • Dirksen U, Le Deley M-C, Brennan B, et al. Efficacy of busulfan-melphalan high dose chemotherapy consolidation (BuMel) compared to conventional chemotherapy combined with lung irradiation in ewing sarcoma (ES) with primary lung metastases: Results of EURO-EWING 99-R2pulm randomized trial (EE99R2pul) (abstr). J Clin Oncol 34, 2016 (suppl. abstr 11001). Abstract available online at: http://meetinglibrary.asco.org/content/166982-176.
  • Laurence V, Pierga JY, Barthier S, et aal. Long-term follow up of high-dose chemotherapy with autologous stem cell rescue in adults with Ewing tumor. Am J Clin Oncol. 2005;28(3):301. 



12. Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a small round blue cell tumor more commonly seen in children and adolescents and only rarely in adults. There is limited data available regarding the management of RMS in adults. The treatment approaches for adult RMS have been extrapolated from the multimodality treatment guidelines for childhood RMS. In comparison, disease outcome is less favorable for adults than for children. 

Histologic classification
RMS is thought to arise from immature cells destined to form striated muscle, although tumors can arise in any part of the body, including in locations where skeletal muscle is not typically found.

The different subtypes include:
  • Embryonal RMS
    • Most common subtype, of intermediate prognosis
    • Includes botryoid and spindle cell variants
  • Alveolar RMS
    • Defined by FOXO1 rearrangement by FISH or RT-PCR, with resultant fusion genes:  PAX7-FOXO1 ;t(1;13) or PAX3-FOXO1; t(2;13) , found exclusively in alveolar RMS.
    • Additional rare translocations have been described in alveolar RMS.
    • This type of RMS has a relatively poorer prognosis
  • Pleomorphic
    • More common in adults
Clinical Presentation
  • Tumors usually present as a non-tender enlarging mass.
  • Locations include head and neck (including orbital and parameningeal tumors), genitourinary tract, trunk and extremities.
  • Regional lymph nodes involvement can be seen in RMS, unlike other soft tissue sarcomas. 
  • It is presumed that the majority of patients who present with apparently localized disease have subclinical metastases. 
  • Sites of metastases include lung, bone marrow, bone, omentum/ascites, and pleura. Visceral and brain metastases are rare. 
Diagnostic and staging evaluation

Biopsy
  • Biopsy should be performed at a facility with expertise in evaluation of bone and soft tissue sarcoma  to ensure that the tissue is processed properly and to allow for the special studies needed for accurate diagnosis  and histologic classification. 
  • Adequate tissue for routine light microscopy, immunohistochemistry, cytogenetic and molecular genetic studies should be obtained .
Imaging studies
Imaging the primary site:
  • Plain radiograph
  • CT and or MRI
    • In certain sites such as head and neck, extremity and pelvic tumors, MRI is preferred for its ability to attenuate bone artifact and its superior soft tissue contrast.
    • MR scan of the craniospinal axis should be explored for parameningeal RMS to exclude leptomeningeal spread.
Metastatic workup:
  • CT chest, abdomen and pelvis
  • PET-CT scan: the role of PET-CT is unclear in the initial staging evaluation, but RMS is an FDG avid tumor and PET-CT effectively demonstrates lymphatic and distant metastases missed by conventional imaging methods. 
  • Bone scan: has been traditionally been included in staging workup of RMS in adult patients, but is no longer used for pediatric patients.
  • Bone Marrow biopsy
    • Bone marrow biopsy has traditionally been included in the staging workup of RMS. 
  • Whether bone scans and bone marrow biopsies may be avoided in selected patients with favorable characteristics remains unknown and will require confirmation in prospective studies. 
  • Lumbar puncture
    • Generally not necessary in most patients. The 2 exceptions are:
      • Patients with parameningeal primary RMS, including middle ear, nasal cavity, paranasal sinus, nasopharynx and infratemporal fossa sites. 
      • Patients with evidence of meningeal invasion by imaging studies.
Pathology
Diagnostic material should be reviewed by a pathologist with expertise in bone and soft tissue sarcoma to confirm the diagnosis.

Immunohistochemistry (IHC)
  • IHC is used to identify muscle-specific proteins such as actin, myosin, myoglobin, Z-band protein and myogenic differentiation (MyoD1 and myogenin – these two are the most sensitive and specific stains for RMS).
  • Other IHC stains may be useful in the differential diagnosis of tumors that present as small round blue cell tumors.
Molecular studies
  • FISH, RT-PCR, NanoString or NGS to identify FOXO1 rearrangements creating PAX-FOXO1 fusion transcripts in alveolar RMS.
Therapy
The current standard of care for RMS is multimodality approach to therapy, which has resulted in significant improvement in overall survival of RMS patients. Treatment includes chemotherapy, and definitive local therapy consisting of surgery (if feasible) and radiation therapy.

For the most current approach to pediatric RMS please contact the oncologists at BC Children’s Hospital. 

Treatment is individualized based on presentation and site(s) of disease. 

Chemotherapy
  • Chemotherapy is used for primary cytoreduction and eradication of both macroscopic and microscopic metastatic disease. 
  • RMS is a very sensitive disease to chemotherapy. Provided patients are fit, intensive multiagent chemotherapy is initiated despite the presence of metastatic disease. (However, the presence of metastatic disease is a poor prognostic factor). 
  • In various retrospective studies of multidrug chemotherapy regimens in adult RMS, overall response rates have ranged  from 82-86%,  while 5 year overall survival  ranged from 35%-47% (as compared to 5y OS of greater than 70% in children with non-metastatic RMS). 
  • Due to lack of data in adults, chemotherapy protocols for adult RMS are derived from pediatric studies.
  • The current approach at BC Cancer is to recommend alternating cycles of vincristine/doxorubicin/cyclophosphamide with ifosfamide/etoposide for a total of 14 cycles. 
Surgery
  • Where feasible, complete excision for localized disease is recommended, provided that functional and/or cosmetic results are acceptable. Given the varied potential sites of origin, surgery may not be feasible in some cases, for eg. in tumors arising in the head and neck.
Radiation therapy (RT)
  • Radiation therapy is usually an essential treatment modality to enhance local control in patients with RMS. 
  • At BC Cancer, RT is usually introduced after the patient has received 4-5 cycles of multiagent induction chemotherapy. 
  • If leptomeningeal dissemination is demonstrated, then craniospinal radiation therapy is indicated for curative therapy.
Post-treatment surveillance 
  • The majority of relapses occur within 2 years of initial diagnosis, with relapses generally being fatal. Late relapses (>5 years) are uncommon.
  • Long-term survivors may develop late treatment related complications such as second malignancy, pathologic fractures and other radiation-related complications (eg. wound complications, pulmonary fibrosis, limb leg discrepancy, femoral head necrosis). 
  • Late chemotherapy-related complications include second malignancy, reduced fertility, renal insufficiency, cardiomyopathy and neuropathy.
Suggested follow-up regimen 
Every 3 months for 2 years then every 6 months in years 3-5, then annually:
  • Clinical and physical exam
  • CBC
  • MRI or CT of primary site
  • CT chest

References

  • Little DJ, Ballo MT, Zagars GK, et al. Adult Rhabdomyosarcoma Outcome following multimodality treatment. Cancer 2002;95(2):377-388. Available at: http://www.ncbi/nlm.nih.gov/pubmeb/12124838
  • Womer RB, Daller RT, Fenton JG, et al. Granulocyte colony stimulating factor permits dose intensification by interval compression in the treatment of Ewing’s sarcoma and soft tissue sarcomas in children. Eu J Cancer 2000; 36 (2000): 87-94.
  • Weigel BJ, Lyden E, Anderson JR, et l. Intensive multiagent therapy including dose-compressed cycles of Ifosfamide/Etoposide and Vincristine/Doxorubicin/Cyclophosphamide, Irinotecan, and Radiation, in patients with high-risk Rhabdomyosarcoma: A report from the Chidlren’s Oncology Group. J of Clin Oncol 2015;34:117-122.
  • Arndt CAS, Hawkins DS, Meyer EH, et al. Comparison of results of a pilot study of alternating vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide with IRS-IV in intermediate risk rhabdomyosarcoma: a report form the Children’s Oncology Group. Pediatr Blood Cancer 2008; 50:33-36.
  • Rodeberg DA, Garcia-Henriquez N, Lyden ER, et al. Prognostic significance and tumor biology of regional lymph node disease in patients with rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2011;29(10):1304. Epub 2011 Feb 28.
  • Weiss AR, Lyden ER, Anderson JR, et al. Histologic and clinical characteristics can guide staging evaluations for children and adolescents with rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee. J Clin Oncol. 2013 Sep;31(26):3226-32. Epub 2013 Aug 12.
  • Hawkins WG, Hoos A, Antonescu CR, et al. Clinicopathologic analysis of patients with adult rhabdomyosarcoma. Cancer 2001; 19:794-803. Available at: http://www.ncbi.nlm.nih.gov/pubmed/112241248
  • Sultan I, Qaddoumi I, Yaser S etal. Comparing adult and pediatric rhbdomyosarcoma in the surveillance, epidemiology and end results program, 1975-2005: an analysisnof 20600 patients. J ClinOncol 2009;27:3391-3397. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18973919
  • Ferrari A, Dileo P, Casanova M, et al. Rhabdomyosarcoma in adults. Retrospective analysis of 171 patietns treated at a single institution. Cancer 2003;98:571-580. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12879475
  • Simon JH, Paulino AC, Ritchie JM, et al. Presentation, prognostic factors and patterns of failure in ault rhabdomyosarcoma. Sarcoma 2003;7:1-7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/185211362
  • Esnaola NF, Rubin BP, Baldini EH, et al. Response to chemotherapy and predictors of survival in adult rhabdomyosarcoma. Ann Surg 2001;234:214-223. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11505068
  • Ogilvie CM, Craword EA, Slotcavage RL, et al. Treatment of adult rhabdomyosarcoma. Am J Clin Oncol 2010;33:128-131. AVAILABEL AT: http://www.ncbi.nlm.nih.gov/pubmed/19225939


13. Follow-up

Follow-up after treatment for sarcoma

The purpose of surveillance is to detect recurrences that might still be potentially curable.

High risk patients generally relapse within 2-3 years, while low-risk patients may relapse later, although it is less likely. Relapses most commonly occur in the lungs. Early detection of local or metastatic recurrence to the lungs may have prognostic implications when these are early enough to be resected. 

Therefore, patients who are suitable for further surgery can undergo routine surveillance to detect early recurrence. There is limited data on effective surveillance strategies. 

Examples of guidelines include:

European Society for Medical Oncology (ESMO) guidelines:
High risk patients are followed: every 3 to 4 months in first 2-3 years then twice a year to year 5, then annually.

Low grade sarcoma: local relapse surveillance every 4 to 6 months and CXR or CT at longer intervals in first 3-5 years, then annually.

For more details:
https://www.esmo.org/Guidelines/Sarcoma-and-GIST/Soft-Tissue-and-Visceral-Sarcomas

National Comprehensive Cancer Network (NCCN) guidelines:
History and Physical examination, chest imaging (CT preferred) and imaging of surgical site: every 3 to 6 months  in first 2-3 years, every 6 months during years 4-5 and then annually

14. Resources

For patients: 

NCCN Guidelines for patients:

The Liddy Shriver Sarcoma Initiative

National Cancer Institute Adult Soft Tissue Sarcoma Treatment

For Health Care Professionals:

National Cancer Institute Adult Soft Tissue Sarcoma Treatment

SOURCE: Musculoskeletal & Sarcoma ( )
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