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Musculoskeletal & Sarcoma

1. Demographics

Incidence

1789 cases were diagnosed with Sarcoma between 1 January 1987 and 31 December 1996. Incidence by gender and diagnosis year for the last 5 years of this ten-year interval is presented in the table.

Diagnosis Year

1992

1993

1994

1995

1996

1992-1996

1987-1996

Females

88

94

78

132

118

510

930

Males

80

101

88

86

104

459

859

Total

168

195

166

218

222

969

1789


​About 37.9% of all Sarcoma incidence is due to Soft tissue sarcoma (678 cases during the ten years), 14.2% is due to Sarcoma of Bone (254 cases), remaining 47.9% are found in other tissues.

Age

18 infants under 1 year of age were diagnosed in BC during this ten years, the oldest diagnosed person was 100 years old. Three quarters of diagnosed patients were 35 year old and older, median age at diagnosis was 57 years and the mean was 52.4. Age distribution is presented on the histogram below:

Survival

The plot indicates that the majority of patients diagnosed with Sarcoma died from causes other than Sarcoma (285 cases of death from Sarcoma), mostly from other cancers (373 cases); few died from non-cancer causes (70 cases). Median overall survival for these patients is 4.93 years, 95% confidence interval is from 4.4 to 5.94 years.

Estimated Probability of Surviving up to 1, 3, 5 and 7 Years after Diagnosis with Sarcoma

Estimated Probability

Years After Diagnosis

of Surviving

1 year

3 years

5 years

7 years

Sarcoma (only)

91%

82%

77%

76%

Overall Survival (all causes)

77%

59%

50%

44%

2. Predisposing Factors / Prevention

1 Bone Cancer

Risk Factors:

Bone cancers account for 0.5% of all malignant neoplasms in the human. There are three main types of bone cancer. Osteosarcoma, which arises most often in the growing ends of long bones; chondrosarcoma, which develops in the metaphysis; and Ewing’s sarcoma, which according to recent evidence may arise from primitive nervous tissue in the bones of the axial skeleton. Several additional types of bone cancer are much less common, and include chordoma, fibrous histiocytoma, and fibrosarcoma.

Osteosarcoma has a bi-modal distribution with peaks in adolescence and late in life. Early studies of incidence and mortality indicate that higher and sustained increased prevalence in young males might be related to the adolescent growth spurt. The adolescent peak for osteosarcoma appears to be related to the pubertal growth spurt, and the rising incidence after middle age has been linked to Paget’s disease.

A role for genetic susceptibility is suggested from the association of osteosarcoma with retinoblastoma and the Li-Fraumeni syndrome; and from the near-absence of Ewing’s sarcoma in Blacks and Asians. Further research is needed in this area.

Prevention:

No primary prevention measures are presently available. Bone cancer is rare in B.C., and no screening maneuvers have been identified to date to reduce mortality from the disease.

References:

  1. Miller RW, Boice JD Jr., Curtis RE, Bone cancer. In Schottenfeld D, Fraumeni JF Jr.. (Eds) Cancer Epidemiology and Prevention 2nd Ed. 1996. Oxford University Press, Oxford. Pp971-983.

2 Soft Tissue Sarcomas

Risk Factors:

Cancers of soft tissue account for about 1% of all malignant neoplasms and for about 1% of all cancer deaths. Generally speaking, the statistics in Canada indicate an upward trend in both incidence and mortality of soft tissue sarcomas.

Ionizing radiation at high doses is known to produce a variety of sarcomas, but accounts for only a small fraction of the cases. Thorotrast, vinyl chloride, inorganic arsenic, and androgenic steroids can induce hepatic angiosarcomas, and recent studies have linked soft tissue sarcomas with occupational exposures to herbicides, mainly phenoxyacetic acids and chlorophenols.

An excess of soft tissue sarcomas has been reported in patients receiving therapeutic immunosuppression for renal transplantation and other conditions, although risk is not as high as for non-Hodgkin’s lymphoma.

Prevention:

No recommendations regarding primary prevention can be made at this time. No screening maneuvers are available for soft tissue sarcomas.

References:​​

  1. Zahm SH, Tucker MA, Fraumeni JF Jr.. Soft tissue sarcomas. In: Schottenfeld D, Fraumeni JF Jr. (Eds) Cancer Epidemiology and Prevention 2nd Ed. 1996. Oxford University Press, Oxford, Pp984-999.

3. Screening / Early Detection

No specific screening procedures recommended for the general population.​

4. Diagnosis

​1 Clinico-pathologic Considerations

The diagnosis of musculoskeletal and soft tissue neoplasms involves a multidisciplinary approach between clinicians, radiologists and anatomical pathologists. Histologic examination remains the gold standard in the diagnosis of mesenchymal tumors. However, the adjuvant diagnostic techniques of electron microscopy, immunohistochemistry and more recently genetic evaluation of neoplasms via conventional cytogenetics or a variety of molecular genetic techniques are increasingly used in the diagnostic workup of patients’ tumors. Appropriate clinical information must be made available to all members of the diagnostic team since it forms an invaluable component of the diagnostic algorithm used in the work up of patients.

2 Classification Criteria

The World Health Organization’s International Histological Classification of Tumours is used to classify neoplasms of bone and soft tissue (Reference). Two points need to be emphasized regarding these neoplasms.

1.  Neoplasms of mesenchymal tissues are classified based on the microscopic resemblance of the neoplastic cells to known mature or immature mesenchymal cells. It is not based on the tissue site of origin of the neoplasm. For example, sarcomas that demonstrate skeletal muscle differentiation are classified as rhabdomyosarcomas because the individual neoplastic cells demonstrate cytoplasmic evidence of skeletal muscle differentiation. In fact, rhabdomyosarcomas rarely arise in the large skeletal muscles and commonly develop in regions which normally contain no or scant numbers of mature skeletal muscle cells (the lower genital tract).

This raises the question as to what is the "cell of origin" of the various neoplasms that constitute the mesenchymal tumors. In the vast majority of cases the answer to this is unknown. Current theories suggest that there are ubiquitously distributed mesenchymal cells throughout the skeleton and somatic soft tissues that have the capacity to differentiate into a variety of different mesenchymal cell types. These "pluripotential" cells likely represent the population that result in the majority of mesenchymal neoplasms. Most of the time the circumstances or signals that result in the development of the neoplastic phenotype are unknown. A proportion of mesenchymal neoplasms are composed of cells that do not resemble any known immature or mature mesenchymal cells. These latter neoplasms are typically designated in a descriptive manner (e.g. alveolar soft part sarcoma).

2.  Unlike epithelial neoplasms in which there is a clearly recognized and biologically understood pathway that explains the development of malignant neoplasms on the background of pre-existing benign neoplasms (the adenoma-carcinoma sequence), the development of a sarcoma in the setting of a pre-existing benign mesenchymal neoplasm is rare. There are a number of uncommon hereditary syndromes in which benign mesenchymal neoplasms have a recognizable risk of "malignant degeneration", (Neurofibromatosis type I, multiple hereditary osteochondromatoses, multiple enchondromatosis). However numerically the sarcomas arising in these conditions constitute a tiny fraction of all sarcomas. The more usual circumstance in sarcoma is for the malignancy to develop de novo. On occasion, low grade, slow growing sarcomas may transform into high grade, biologically aggressive sarcomas. This phenomenon is known as "dedifferentiation" and most characteristically arises in low grade osseous chondrosarcomas and low grade soft tissue liposarcomas. Under these circumstances the behavior of the neoplasm, and by extension, the management of the patient, will be significantly altered by the presence of the high grade component of the neoplasm.

3 Diagnostic Pathology

  • Histologic evaluation remains the gold standard in the classification of mesenchymal neoplasms. In the majority of instances this requires appropriately fixed biopsy tissue. 10% buffered Formalin is the fixative of choice for all tissue samples.
  • On occasion fresh tissue is preferable, particularly if cytogenetic or molecular genetic investigations are anticipated in the work up of a neoplasm (for example in the setting of "blue cell tumors" of children and young adults). Under these circumstances direct communication between the clinician and pathologist should occur to ensure appropriate "triage" of tissue samples.
  • Immunohistochemical techniques that allow specific recognition of nuclear, cytoplasmic and membranous antigens within neoplastic cells are a useful adjuvant to aid in the precise classification of mesenchymal neoplasms.
  • Ultrastructural examination using electron microscopy also may aid in defining specific lines of "differentiation". Recently cytogenetic evaluation of selected mesenchymal tumors has demonstrated consistent reproducible abnormalities that serve as markers for subgroups of these neoplasms. These include chromosomal translocations, deletions and acquisition of marker chromosomes. These "genetic abnormalities" are typically identifiable only within the neoplastic cells and are notpresent in patients’ germline. In addition to having diagnostic relevance these genetic abnormalities may help explain the acquisition of the neoplastic phenotype although presently the pathogenesis of this is not understood.
  • Grading of sarcomas: Histologic grading of sarcomas attempts to stratify specific neoplasms into groups of similar biologic behavior based upon their microscopic appearance. In general four parameters are evaluated in an attempt to apply a numerical grade (one to three) to individual neoplasms. These include the relative cellularity of the neoplasm, the presence or absence of necrosis, the degree of nuclear atypicality and the mitotic rate. Using these parameters it is considered that low grade sarcomas (histologic grade 1 of 3) have a low risk of metastasis whilst intermediate and high grade sarcomas (histologic grades 2 and 3 of 3) have significant metastatic capability.

4 Synoptic Report Form

The reporting of soft tissue sarcoma biopsy and/or resection specimens should include in addition to all of the patients demographic information the following points

  1. The tissue site, including a statement as to the relationship to fascia (i.e. whether the tumor is superficial or deep).
  2. The procedure (biopsy or resection).
  3. The histologic type of neoplasm.
  4. The (numerical) grade of tumor if it is a sarcoma.​
  5. The size of the tumor in centimeters.
  6. The status of the surgical margins including a measured distance to the closest margin. The microscopic composition of the tissue between the neoplasm and the margin should also be included (i.e., adipose tissue, skeletal muscle, pseudocapsule, fascia etc.)
  7. An estimate of the percentage of tumor necrosis.
  8. A statement as to the presence or absence of vascular invasion.
  9. The results of adjuvant diagnostic techniques including immunohistochemical staining panels, ultrastructural findings etc.

5. Staging

​1 Classification Criteria

Though morphological characteristics recognized in histopathologic grading of tumours generally correlate with biological behavior, a more complete assessment of the tumor and its spread(i.e., staging) is necessary for planning treatment and comparing results. No single clinical staging system for musculoskeletal tumours and sarcomas has been accepted.

At the present time two systems of staging are being used:

  • The TNM staging system that recognizes recognizing tumor type, grade (G), size (T) and presence of lymph nodes (N) or distant metastases (M). 
  • The Enneking staging system mainly used for musculoskeletal tumors is based on histologic subtype, grade and the anatomical setting (intra or extra compartmental).

Efforts are currently being made to consolidate these two systems into a more meaningful staging system.

2 Staging Diagram 

The Staging sheet includes a statement of the site of the primary, the final diagnosis and the staging using the Enneking staging system. It must be signed and dated by the attending physician.

3 Investigations for Staging

It is incumbent upon the primary care physician:

  • to recognize the organic basis of the patient's complaint of pain, swelling or dysfunction and 
  • to obtain accurate clinical information about the tumor by careful history and physical examination

A high index of suspicion of malignancy is essential, for example, in a teenager with knee pain unrelated to trauma or persisting longer than it should or in the patient over fifty years old with the same clinical presentation in whom metastatic disease to bone becomes increasingly common.

Similarly, when the complaint is a deeply located large soft tissue mass, soft tissue sarcoma must be considered in the differential diagnosis so that appropriate baseline investigations may be done.

The Musculoskeletal Tumor and Sarcoma Group have become increasingly aware of frequently encountered pitfalls in early management. These make the definitive treatment of these lesions more difficult, more complicated and less satisfactory. It has been our experience that nearly one in three patients have not received ideal oncologic management due to errors in investigation, diagnosis or treatment.

The major problem encountered is related to the biopsy which is discussed here prior to other considerations, ONLY to emphasize that it should NEVER be done before other appropriate staging procedures. Caution should be exercised in carrying out invasive procedures. Above all, a BIOPSY must not precede other investigations for fear of interfering with their results.

BIOPSY

The goal of biopsy is to harvest a representative sample of the tumor without compromise of the definitive management. Sarcomas are tumors that are known to be able to spread by implantation. It should be done only when

  • all anticipated investigations are completed and, 
  • in the case of musculoskeletal tumors, after full consultation with an orthopaedic oncologist so that the best site for biopsy can be chosen so that most informative specimen can be examined by pathology. 
  • For non-musculoskeletal sites, consultation with a surgical oncologist is important for biopsy planning. There are surgeons in various subspecialties area if general surgeon is not the most appropriate – see relevant site in CMM for Gynecology, Urology, central nervous system, thorax, and Head and Neck consultant surgeons. If any doubt who to call, you are encouraged to ring BCCA referral desk for contact initiation – (604)877-6066 or for out of area 1-800-877-6000, X 6066.

Investigations may include:

1. PLAIN RADIOGRAPHS
A plain X-ray is the most important initial investigation of a potential bone neoplasm. It is helpful in the investigation of soft tissue lesions particularly if the lesion is mineralized.

2. MAGNETIC RESONANCE SCAN (MR SCAN)
The MR scans have become vital in the management of musculoskeletal tumours and sarcomas because they:
a) provide detailed information that has increased our ability to safely excise lesions that formerly were felt to be inoperable.
b) are particularly helpful in evaluating the extent of soft tissue lesions and their relationships to surrounding vital structures
c) aid in the evaluation of the medullary canal of long bones valuable in the search for such things as skip metastases in osteosarcomas.
d) on occasion may lead to a diagnosis based only on the MR signal characteristics of the lesion, as is the case in intramuscular lipomas or low-grade liposarcomas (lipoma-like).

The MR scan is severely affected by the BIOPSY PROCEDURE and should be done BEFORE THE BIOPSY is performed. The scan is very sensitive to reactive edema and post-procedural scans can be difficult to interpret.

3. COMPUTERIZED TOMOGRAPHY (CT SCAN)
This examination has become an essential part of the staging studies necessary for planning treatment, particularly FOR:
a) STAGING the lungs (The chest CT scan is very sensitive and false positives are common and over interpretation is to be avoided. Plain chest radiographs are usually recommended for chest follow up.)
b) GUIDING core needle biopsies FOR most cases.

4. RADIONUCLEOTIDE SCAN ("BONE SCAN")
A total body technetium scan will give useful information:
a) not only about a presenting bone lesion
b) but also about possible multiple lesions and bone reaction to overlying sarcomas.

A bone scan is generally not indicated in soft tissue tumors.

5. TOMOGRAPHY - NO LONGER ROUTINELY USED.

6. ANGIOGRAPHY
a) has a limited place in investigation of musculoskeletal tumours and sarcomas
b) is useful in the investigation and treatment of hemangioma, arterio-venous malformation, and metastatic renal and thyroid carcinoma.

7. ULTRASOUND EXAMINATIONS
Ultrasound has no routine application in the pre-biopsy evaluation of solid soft tissue lesions occurring at any site. They maybe misleading, particularly when the radiologist attempts to make a diagnosis. The ultrasound scan simply serves to delay the diagnostic process, and should not be ordered. The single most important test for a bone or soft tissue sarcoma is the magnetic resonance scan (MR scan).

Referral Information

Prompt referral to a tertiary centre when suspicious of the diagnosis of sarcoma:

  • Evaluation by a member of the specialized multi-disciplinary team
  • Investigations as outlined below
  • Discussion in a multidisciplinary forum
  • Management as planned by TEAM

In general, the Sarcoma Group supports the following principles of referral:

  • Any patient with a bone lesion or soft tissue mass that on general history and physical examination is not diagnosed to be benign should be referred to or discussed with the Musculoskeletal Tumor and Sarcoma Group of the BC Cancer Agency.
  • Primary referral is preferable even before the appropriate investigations have been ordered. The working diagnosis of "mass" or "hole-in-bone" is sufficient for referral.
  • Some benign soft tissue and bone tumors are extremely difficult to treat. For this reason, the referral of benign disease is also encouraged.
  • If the patient requires surgical management, and the referring surgeon is comfortable performing with the recommended procedure, the patient will be referred back to that surgeon for surgery after a diagnosis is made. Generally clear communication between outside (referring) doctors and BCCA attending doctors is required so that the appropriate arrangements can be made for the individual patient.
  • If for any reason primary care is mandatory outside the Agency in the local community and the patient cannot be referred to the Agency, then strict adherence to first principles of investigation and biopsy are absolutely essential.

1) Adult Patients (>16 years) – After referral to BC Cancer Agency

Primary referral – untreated patients

  • Patients are generally seen within 5 –10 working days after referral. More urgent situations require personal contact with one of the oncologists on the Team. If any pertinent Xrays have been done it is very important that they be available for the New Patient Appointment. If there is any doubt that films will not be at BCCA, then arrangements for the patient to pick up and bring them should be made.
  • At the first visit, the patient is seen in consultation by an oncologist who will arrange all pertinent investigations usually for during the next 10 working days. These investigations might include MR and CT of the local area, CT-guided biopsy of lesion, if indicated, CT lungs and bonescan, if indicated.
  • Discussion at the Musculoskeletal Tumor and Sarcoma Conference (Mondays at 0800h) is planned for 10 to 15 working days after the new patient visit. At that time the specialized team of surgeons, radiation oncologists, medical oncologists, pathologists, and radiologists reviews all pertinent records, investigations and pathology with representation by Videolink from all FOUR Agency sites. The Team makes management decisions.
  • Referring physicians and surgeons are welcome to participate at the Conference.
  • Patients are generally informed of the plans within the next day or two. Recommendations are communicated to the referring doctor in a timely fashion by phone and/or formal Conference note.
  • Whenever possible the patient will be advised to return to his or her own community for subsequent treatment. However if care is required at a tertiary centre such a recommendation will be made to the primary physicians.

Secondary referral – after diagnosis and some management

Referral to the Agency after the diagnosis of musculoskeletal tumor or sarcoma, either recent or remote, should be accompanied by all available information on the patient at the time of referral. This information might include clinical and laboratory information, investigations and X-rays, surgical observations and pathologic material. Because of short intervals to new patient appointments –imaging is best carried to the appointment by the patient so it is available for the consulting doctor at the time of the appointment.

2) Children (<17 years)

Any patient less than seventeen years of age at PRESENTATION should be referred to the Paediatric Oncology Division of the Cancer Agency located at the BC Children's Hospital(BCCH) or the Paediatric orthopedic surgeon at the BCCH (Dr. Ken L. B. Brown, (604) 875-2642 ). The principles of treatment (particularly in regard to biopsy and surgical treatment) remain the same but there are certain unique characteristics of these tumours recognized in this age group.

3) Tertiary Triage Criteria

All patients should be referred to a tertiary cancer center either BC Cancer Agency or the BC Children's Hospital. Below are the numbers to contact if you are referring a new patient:

Organization

Clinic

Phone

FAX

BC Cancer Agency 

Vancouver Cancer Clinic

(604)877-6066

(604)708-2005

 

Fraser Valley Cancer Clinic

(604)930-4004

(604)675-7222

 

Cancer Clinic of the Southern Interior

(250)712-3969

(250)979-4001

 

Vancouver Island Cancer Clinic

(250)370-8228, Local 2439

(250)519-2001

BC Children's Hospital

Oncology clinic

(604)875-2116

 

01 Surgical Management of Sarcoma

​The guiding principle of surgical intervention is complete removal of the primary tumor with maximum retention of function and minimum possibility of local recurrence. Classically, in extremity tumours, this has been accomplished by ablative surgery (amputation). Today, the increasing use of limb salvage procedures has become possible because of effective adjuvant radiation therapy(see below). Neo- adjuvant chemotherapy may contribute in some instances by reducing tumor edema and size and by eradicating micrometastases. As a result, it becomes even more essential that a multi-disciplinary treatment team plan the overall management recommendations from the beginning.

Excision Type

Synonymous terms

Comments

Intralesional Excision*

curettage, debulking or piecemeal removal

This procedure may be appropriate for some benign tumors, but never for malignant tumors

Marginal excision*

'shell-out'

This procedure transgresses the pseudo-capsule (zone of reaction), microscopic tumor is left behind and opened tissue planes are contaminated.

Local recurrence is 100% in high-grade lesions and high in lower grade entities.

Wide excision*

intra-compartmental excision**

wide local excision

The neoplasm is removed outside its reactive zone, with an adequate but variable amount of "normal" tissue attached to it. In soft tissue sarcomas, unless the margin is extremely wide, there remains a likelihood of local recurrence.

Radical Excision*

extra-compartmental excision**

The tumor and surrounding tissues are removed by dissecting along planes that are separated from the tumor and its tissue of origin by at least one involved anatomical structure in both longitudinal and transverse planes.

*The procedure amputation may fit into any one of these four categories as inadequate (or adequate) surgical treatment.

** For musculoskeletal lesions

 

  • Surgery (PLANNED wide local excision) is the most important component of curative therapy, except in the rare case.
  • Inoperable tumors are incurable. Ewing's sarcoma and rhabdomyosarcoma may be possible exceptions with some patients who have had inoperable disease being cured with multi-modality therapy including chemotherapy and less local excision and/or radiation therapy.
  • Imaging and diagnostic procedures should precede PLANNED wide local excision.
  • Radical surgery does not imply adequate surgery. Very careful pre-operative assessment is required before attempting wide excision.
  • Even the presence of demonstrable pulmonary metastases need not preclude curative treatment - these can be resected surgically with the proper indications.
  • In the case of extensive lytic destruction of weight bearing bones with pain, fracture or impending fracture – rigid internal fixation may be considered as part of the management after considering the diagnosis and extent of disease. In patients over 40, the most common cause of a such a lesion is metastatic disease – BUT primary bone tumors do still occur. Curative management may be seriously compromised if hasty surgery is planned without consideration of the clinical setting.

02 Surgical Management of Metastatic Disease

Unresectable metastatic disease is not curable for the majority of patients a primary diagnosis of sarcoma. Most sarcoma patients require resection of the metastases to improve their chance of cure. Post resection, chemotherapy may not add to the curability of a patient with soft tissue sarcoma though some patients with metastatic Ewings sarcoma or rhabdomyosarcoma maybe cured by chemotherapy without operative intervention.

A patient will be considered for resection of skeletal or pulmonary metastasis if:

  • The primary disease is or can be controlled.
  • A complete metastectomy can be performed
  • The fewer the number of metastatic lesions the better. We can expect up to a 30% salvage rate in well selected cases.

Surgery is also considered to palliate pain or prevent fracture or debility when appropriate.

03 Special Surgical Considerations

​Revised 4 January 2012

1) Retroperitoneal Soft Tissue Sarcomas (RSTS)

  • RSTS are uncommon lesions constituting less than 10% of all soft tissue sarcomas.
  • The majority of retroperitoneal soft tissue tumours are malignant.
  • They tend to present late in their course as they can grow silently for many years. Presenting symptoms may be vague abdominal pain or abdominal protrusion or intestinal complaints due to massive tumour size. They may also be detected unexpectedly at the time of laparotomy.
  • General management is as described in the general sections on musculoskeletal and soft tissue sarcomas. Core biopsy should be used for tissue diagnosis after all investigations are completed. Because of the location of these lesions, it is usually not possible to excise the biopsy tract.
  • Early referral for consultation is extremely important.
  • Surgical excision, with clear margins, gives the best chance of cure. This often requires the en bloc removal of adjacent organs, most commonly the kidney, adrenal, small bowel and colon. As for musculoskeletal and non-retroperitoneal soft tissue sarcomas, "shell-out" procedures should be avoided as they leave microscopically positive margins. Mobilizing adjacent organs off the tumour is equivalent to "shelling-out" the tumour.
  • Patients found, unexpectedly, at the time of a laparotomy, to have a retroperitoneal tumour should not undergo incisional biopsy. This contaminates the peritoneal cavity and substantially decreases the cure rate. Core biopsy (Tru-cut needle) may be acceptable if hemostasis can be assured and contamination of the peritoneal cavity avoided. Tissues should not be mobilized to expose the tumour for biopsy purposes.
  • Recurrent retroperitoneal tumours may be suitable for re-excision. Re-operative surgery is generally considered palliative and should be offered for symptom control. Cures following re-excision of lesions that were not treated with primary wide local excision have been reported. Prolonged palliation can be achieved for low grade tumours.

2) Intra-abdominal Sarcomas Including Gastrointestinal Stromal Tumors (GIST)

Staging Diagram pdf icon

A. Intra-abdominal Sarcomas

  • Complete excision is essential if cure is to be achieved. Unlike for retroperitoneal tumours, preoperative tissue diagnosis is not recommended for intra-abdominal masses because of the risk of peritoneal dissemination.
  • For lesions arising from the stomach or rectum, diagnosis via endoscopic ultrasound is an option, particularly in cases where simple surgical resection is not feasible (proximal gastric tumours, low rectal tumours, metastatic tumours).
  • Nodal clearance is not essential, as dissemination tends to be by direct, intra-coelomic or hematogenous spread rather than by lymphatic spread.
  • Adjuvant therapies are not indicated.
  • Palliative radiotherapy may be of benefit in managing unresectable disease where bleeding or pain is problematic.

B. Gastrointestinal Stromal Tumours (GIST)

  • 85% of tumours of gastrointestinal tract are now known to be gastrointestinal stromal tumours (GIST's). The incidence is 14.5/106/year or about 50 cases per year in BC.
  • These tumors have staining characteristics similar to the cells responsible for bowel motility - the interstitial cells of Cajal staining for KIT, a receptor tyrosine kinase (RTK), which helps to distinguish them from smooth muscle cell tumors, true leiomyosarcomas. Targeting KIT with Imatinib has revolutionized the treatment of advanced GIST.
  • Most patients have an exon-11 mutation of KIT (70%) especially primary lesions in the stomach. The second most common mutation is exon-9, more commonly found in small bowel GIST. Platelet-derived factor alpha (PDGFRA) mutations occur in about 5% cases. This is a RTK in the same family as KIT and is blocked by Imatinib.
  • Mutation analysis is recommended at the time metastasis are diagnosed.  In high risk patients for whom adjuvant therapy is important – mutation analysis is also imporatant.  Young patients (less than 40) are more likely to have imatinib resistant disease or even hereditable conditions predisposing to GIST so their tumours should also have mutation analysis Requisition form. For the most current forms, see the BC Cancer Genetics Laboratory.
  • It is difficult to determine the malignant potential of these tumours. The most important considerations are mitotic index, size and non-gastric location of primary (likely related to Exon-9 mutation not being common in gastric GIST).

A recently published nomogram (Gold, Lancet Oncology 2009) assesses risk of recurrence based on those factors. The sarcoma systemic team are assigning risk categories using that nomogram as follows:

  • Complete excision is essential if cure is to be achieved
  • In some situations neoadjuvant (preoperative) Imatinib at standard dosing may be considered to downstage disease thus enabling curative surgery with less post surgical morbidity.  Neoadjuvant therapy should always be discussed with the surgical oncology team, if necessary at the Multidisciplinary Musculoskeletal Tumour and Sarcoma Conference. The patient should continue with imatinib after surgery for a total of three years of imatinib unless there is intolerance of the drug. Mitotic counts are not helpful in the post imatinb setting – so proper risk assessment is not possible for most patients starting Imatinib neoadjuvantly.
  • Nodal clearance is not essential, as dissemination tends to be by direct, intra-coelomic or hematogenous spread rather than by lymphatic spread.
  • Management patients with newly diagnosed operable non-metastatic GIST by risk category above:

Very low risk

Discharge – no recommended routine follow-up testing

Low risk

We recommend clinical evaluation, CBC, LFT’s, creatinine and CT scan at 6 months interval X 1yr; then yearly X 4 years.

These patients can be discharged if adequate follow-up care available in the community.

High risk

Adjuvant Imatinib 400 mg PO Daily (SAAJGI) X 3 yrs for all high risk patients (Joensuu J Clin Oncol 29: 2011 (suppl; abstr LBA1). Protocol code SAAJGI. No CAP required. Class 2 drug application required outside BCCA. http://www.bccancer.bc.ca/NR/rdonlyres/D2AED198-E2C7-4DBB-9490-7B6A332610C4/54957/Class2form_1Jan2012.pdf.

Eligibility: 

  • Unequivocal diagnosis of Gastrointestinal Stromal Tumour (GIST): Demonstration of c-kit protein using DOG1 confirmation of diagnosis
  • Diagnosisof c-kit negative GIST: Mutation analysis (if possible) should show one of hte mutations known to respond to Imatinib.
  • patient with completely resected GIST and high risk for recurrence:
    • 5-year relapse-free survival less than 60% as calculated using Gold Nomogram (Lancet Oncology 2009) (80 points or more)
  • Follow-up:  Clinical evealuation associated with imaging as below
    • Chest X-ray yearly
    • CT scan abdomen and pelvis
      • years 1-3 (on drug): every 4-6 months
      • yeasrs 4-5 (or 2 year off drug): every 3-4 months
      • Thereafter till 10 years: every 6 to 12 months at physicians discretion.

Adjuvant Imatinib -The ACOSOG study Z9001showed that adjuvant Imatinib (400 mg dose daily for 1 year) was beneficial, especially for subjects with tumours 10cm or greater who have a relapse rate of 50% at 1 year and 75% by 2 years vs 5% and 25% for the Imatinib treated groups. As yet overall survival improvement has not yet been seen. At ASCO 2011, Joensuu reported on the Finnish group’s randomized adjuvant study for high risk patients with resected GIST comparing taking standard dose Imatinib for 1-year versus 3-years. At a median follow-up of 4.5 years, there was significant relapse-free and overall survival benefit for the 3-year arm (Joensuu, J Clin Oncol 29: 2011 (suppl; abstr LBA1)). 

  • Treatment of advanced disease
    • Combination chemotherapy for advanced disease is of limited value; about 0-5% of patients have a response.
    • Imatinib (Gleevec, Glivec, STI571) inhibits autophosphorylation of the c-KIT receptor tyrosine kinase causing approximately a 55% response rate (complete or partial responses) and a 88% clinical benefit rate (includes all patients whose disease is smaller or stable) for patients with advanced disease. Median survival after Imatinib is 4.9 years compared with 8 – 10 months in the pre-Imatinib era. Standard dosing is 400 mg orally daily (SAAVGI). Patients with known exon-9 mutations may benefit from double dose Imatinib (800 mg daily) (SAAVGIDD) -- but shoudl be started off with the lwoer dose as 40% or more patients will respond to the lower more tolerable dose and crossing over to the higher dose is still effective.
    • Patients initially responding to 400 mg dose of Imatinib may respond to double dose as first therapy on progression (at 40% clinical benefit rate). RECIST criteria are not the best for assessing response to small molecules – especially GIST.  The increasing size of a solid lesion or a new solid lesion is generally safe to diagnose progressing disease. But enlarging cystic components or even new tiny cystic lesions in the liver maybe compatible with a good response – expert clinical review is required. Stability of disease is also considered a positive response and doses of drugs do not need to be increased. (Choi, E. J Clin Oncol 25:1753-1759. © 2007)
    • After progression on double dose Imatinib, second line Sunitinib (SAAVGS) (class II) is generally recommended. Improved progression-free survival and overall survival has been observed.
    • Regorafenib has recently been approved for use as third line therapy for patients with advanced GIST(USAAVGR).  CAP submission is required.
  • There is no GIST study ​open in BC at this time.
  • Palliative radiotherapy may be of benefit in managing unresectable disease where bleeding or pain is problematic.

3) Phyllodes Tumor of Breast – Low or High Grade (Cystosarcoma Phyllodes – benign or malignant)

  • Stromal tumor arising in breast tissue
  • a phyllodes tumor should be considered in the differential diagnosis of a 'recurrent fibroadenoma'
  • Even though phyllodes tumors are generally diagnosed at excisional biopsy, CT scan of chest wall and breast and lungs should be done for staging to clarify extent of disease and look for pulmonary metastases.
  • Subsequent planned wide local excision may be avoided only if margins are deemed adequate on review by a multi-disciplinary sarcoma team.
  • Unless the tumor is very superficial in a larger breast, fascia should always be taken.
  • Mastectomy is not a specific recommendation – but may be required to get adequate wide local excision.
  • If a planned wide excision is being performed then immediate reconstruction is an option.
  • Node dissection is NOT recommended unless there is also an invasive carcinoma seen in the specimen or the tumor is histologically felt to be an undifferentiated spindle cell tumor in which case final diagnosis may be invasive carcinoma.
  • Margins should be clear of tumor on histological examination. If close or worrisome further surgery is indicated.
  • Radiation therapy is generally avoided unless margins are compromised.
  • Adjuvant chemotherapy is NOT indicated in pure phyllodes tumor, low or high grade. However if there is associated invasive breast cancer, adjuvant chemotherapy would be recommended if appropriate.
  • Follow-up should be as for appropriate grade of sarcoma.
  • Recurrences of phyllodes tumors are generally associated with a worsening of the grade of the lesion
4) Dermatofibrosarcoma Protuberans (DFSP):
  • Malignant tumor which is locally aggressive but has low metastatic potential.
  • Requires very wide local excision to eradicate
  • Moh's surgery may be an option.

04 Radiotherapy

Radiation is used for both curative treatment and for palliation. It may be used alone or in conjunction with surgery and/or chemotherapy. The radiation oncologist is an integral part of the sarcoma management team that performs a preoperative assessment of patients with possible sarcomas.

Combined with surgery, radiation therapy has

  • improved local tumor control and
  • frequently allows for less radical and mutilating surgery (for example, limb salvage).

It is essential that there is good communication between the surgeon and radiation oncologist to ensure that these two modalities are combined to their best effect.

  • Radiation is indicated for most patients with high grade soft tissue sarcomas after limb sparing surgery or wide local excision
  • Patients who may be suitable for surgery alone are those who have tumours which are located superficially, are < 5 cm in size and are widely excised (e.g. underlying fascia removed and at least 1 cm in all other directions)
  • Inappropriate drain site placement or surgical exploration of the primary site may seriously compromise radiation therapy delivery.
  • Radiation therapy may be given either PRE or POST operatively. Both approaches have their advantages and disadvantages.

Pre-operative Radiation Therapy

Post-operative Radiation Therapy

Advantages:

  • Smaller treatment volume
  • Normal blood vessels in situ and so fewer hypoxic (radioresistant) cells present
  • Surgery facilitated (fibrosis of reactive zone)
  • Avoidance of delays due to operative complications

Advantages:

  • Full pathology report available
  • Avoids surgical delay due to complications from radiotherapy
  • Biopsy pathology may be inadequate
  • Lower risk of wound complications

Disadvantages:

  • higher chance of wound complications
  • Post surgical pathology may be more difficult to interpret
  • Patient may decide to refuse surgery after radiotherapy completed

Disadvantages:

* Larger radiation treatment volume required. If there is wide surgical disruption of tissues radiotherapy treatment will be severely compromised.

Primary, curative radiotherapy may be used alone to ablate local disease:

  • where surgical resection is not possible (for example the vertebral column),
  • with tumours such as Ewing's sarcoma, which have high local control rates with radiotherapy and chemotherapy without surgery,
  • or cases of medical unsuitability for surgery.

Adjuvant radiotherapy combined with wide or radical excision is the best means of achieving local control of disease or most patients. The radiotherapy course is fairly standardized. Doses can be modified depending on the treatment volume and the proximity and nature of surrounding normal structures. Planning may involve computerized tomography and specially made devices for immobilization. A radiotherapy treatment course will usually take 4 to 6.5 weeks and treatment will be given once daily on weekdays.

Early side effects include skin erythema and desquamation (especially in skin creases). Late side effects include fibrosis of subcutaneous tissue and skin atrophy. It is essential that one third of the circumference of a limb be kept out of the radiation field if at all possible. If not, circumferential scarring can occur resulting in an increased risk of subsequent lymphedema and loss of the vascular supply to the limb. Hence the importance of well placed scars.

Palliative Radiotherapy

Radiotherapy can be used to palliate symptoms from incurable sarcoma. It is usually possible to use standard short palliative courses. Sometimes higher doses are required to achieve local control.

05 Chemotherapy

Revised 17 May 2010 

1) Curative setting

Chemotherapy may be combined with surgery or radiation therapy in the curative management of some patients with sarcoma.

  • Routine post-operative adjuvant chemotherapy for the treatment of soft tissue sarcomas continues to be a controversial.
  • However, adjuvant chemotherapy is a routine component in treatment of many patients with primary bone tumors and some of the soft tissue sarcomas, which have been mainly associated with the Pediatric or late adolescent age groups, such as Ewings Sarcoma also known as peripheral neuroectodermal tumor(PNET), rhabdomyosarcoma – all subtypes, and intra-abdominal small round blue cell tumor.
  • Generally adjuvant chemotherapy programs are initiated before definitive surgery and/or radiation therapy and is known as neo-adjuvant or pre-operative chemotherapy.
  • Local management with surgery or radiation is generally undertaken after several cycles of chemotherapy and then the chemotherapy is completed. Therefore, the sarcoma team medical oncologist must remain an active member of the multi-disciplinary team approaching the new patient to facilitate prompt completion of investigations, initiation of chemotherapy and coordination of the patient management plan.
  • In specific clinical circumstances, some patients will be offered high dose chemotherapy with total body irradiation and stem cell rescue as the culmination of their treatment program.
  • See 2) Intra-abdominal Sarcomas Including Gastrointestinal Stromal Tumors (GIST)​ in 03 Special Surgical Considerations​
2) Palliative Setting

Chemotherapy can be helpful for palliation in selected patients with metastatic disease who have

  • symptomatic unresectable metastases
  • rapidly progressing metastases or
  • unresectable primary tumours.

Standard drug therapy is single agent Adriamycin (SAAVA) which despite a response rate of 25 - 30 % affords equivalent prolongation of survival as compared to more modern single agent protocols or combinations. There is no curative drug therapy for metastatic inoperable soft tissue sarcomas. In some patients with peripheral neuroectodermal tumours and rhabdomyosarcoma, cure can be achieved with chemotherapy. Occasionally high does chemotherapy with stem cell support may be offered in those instances.

New drug development remains a very high priority for oncologists treating metastatic sarcomas. BCCA oncologists participate in studies testing new chemotherapy drugs combinations and/or new drugs for the treatment of patients. Some of these new drugs are modifications of older drugs known to have some activity; others are new types of drugs, such as signal transduction inhibitors. The latter are very attractive for patients who have types of tumors with readily identifiable genetic markers, e.g. c-kit in GIST. Unfortunately not every patent is eligible for every study but available studies will be discussed with the individual eligible patient.

06 Combined Multi-modality Treatment for Specific Diseases

​1) Ewing's Sarcoma and Other Small Round Blue Cell Tumors:

  • In the group of tumours often referred to as "round cell" or "blue cell" tumours (Ewing's sarcoma, primitive neuroectodermal tumor, Askin's tumor, histiocytic lymphoma) a combination of chemotherapy and radiotherapy is recommended.
  • Ewing's sarcoma, relatively rare in the adult age group, is more often treated in the Paediatric setting.. Treatment of the adult population affected by these tumours generally parallels that recommended by the BC Children's' Hospital group.
  • A program consisting of alternating combinations of drugs both before and after local control measures (surgery and /or radiation therapy).
  • The role of surgery in the management of Ewing's sarcoma is still being defined except in cases of primary tumor involvement of an expendable bone where surgery avoids the use of radiation therapy(e.g. ribs or head fibula).
  • Debulking surgery is under considered for tumors in sites not amenable to complete resection.
  • Patients with metastatic Ewings are treated with curative intent as these tumors are very sensitive to chemotherapy. Occasionally high dose chemotherapy with total body radiation therapy and stem cell transplant may be offered.

2) Osteosarcoma /Malignant Fibrous Histiocytoma of Bone (MFH of Bone) / other High Grade or Spindle Cell Sarcomas of Bone

Adjuvant chemotherapy has now been established as an essential part of the management of osteogenic sarcoma. Randomized studies show a significantly improved overall survival for non-metastatic osteosarcoma patients treated with adjuvant chemotherapy (Link, Eilber). Spindle cell tumors of bone are also believed to benefit from adjuvant chemotherapy and are generally managed in the same osteosarcoma.

Once the staging studies have been completed and a biopsy diagnosis made, preoperative administration of a multi-drug program is preferred.

Lack of tumor necrosis seen in the final operative specimen in some instances may result in a change in the recommended post-operative regimen.

Patients with operable pulmonary metastatic disease at diagnosis or subsequently may be cured and therefore are treated aggressively with thoracotomy with or without chemotherapy.

3) Rhabdomyosarcomas

Rhabdomyosarcomas are tumors which occur primarily in the Pediatric age patient.

The primary management involves neoadjuvant chemotherapy, followed by surgery and radiation therapy.

In the adult setting, the protocols used are derived from the Paediatric group recommendations.

Adult patients are often treated in a manner similar to Ewings/PNET patients.

4) Adjuvant Chemotherapy for Other Soft Tissue Sarcomas

The role for routine adjuvant chemotherapy for soft tissue sarcoma patients remains controversial, but we recommend its discussion with patients in the following situations:

  • large primitive tumours
  • poor prognosis, high grade histologic subtypes that have been shown to be chemo-responsive, e.g. cellular myxoid liposarcoma
  • marginal local excision cases in which radiation cannot be delivered
  • bulky locally advanced disease with preoperative radiation therapy
  • in the setting of a controlled randomized trial

Follow-up

​Revised 15 June 2010

The broad ranging types of musculoskeletal tumours and sarcomas prohibit a rigid recommendation with respect to follow-up.

  • A follow-up program for the individual patient (frequency of examination and types of evaluation) would depend on the expected biological behavior of the tumor, an assessment of the treatment accomplished (whether it might result in cure or not)and the site of the primary lesion (tissue and anatomical).
  • In all cases, the follow-up visit should be a clinical examination of the patient with emphasis on the local site and the common foci of metastases. In most sarcomas, metastatic disease will involve the lungs so that periodic chest X-rays would be indicated.
  • For superficial and distal tumours, clinical examination is more reliable than imaging. For deeper, proximal and axial tumours, periodic CT scans or MR scans are preferable.
  • Bone scans are unreliable as an indicator of early local recurrence. In areas where bone has been surgically interfered with the scan will remain "hot" for two to three years after.

See 4) Summary of standard recommendations below.

1) Rationale for follow-up for patients whose disease has been treated for cure and for whom further interventions for cure may be possible

Follow-up is generally indicated where early detection of an abnormality may result in cure.

Areas of concern:

a) Curable recurrence at the site of the primary:

if a second wide excision is possible it may achieve a cure providing there is no sign of metastasis. Therefore intensive follow-up with examination of the primary site is recommended every 3 months and if superficial this may be sufficient. If the primary was deep the examination should be supplemented by scans (CT or MR) every 6 months.

if further surgery is not possible or can not achieve a cure follow to assess symptoms from treatment or disease at 6 monthly intervals. No imaging tests are indicated unless symptoms arise.

b) Development of curable lung metastases:​

In those with osteosarcoma, wedge excisions of the metastases can achieve long term survival. Quasi adjuvant chemotherapy may also be recommended. CXR of the lungs every 3 months for 2 years then every 6 months till 5 yrs of follow-up completed – then yearly.

For patients with soft tissue sarcomas, the role of metastasectomy is controversial as there has not been routine benefit noted at meta-analysis. Patients who would be fit enough to undergo thoracotomy and felt to be going to benefit from resection of metastases if detected are generally followed with routine CXR as above.

c) Complex treatment programs resulting in late complications

For example, complications from combined resection and radiotherapy of a limb, radiotherapy to abdominal organs compromising function of the bowel or kidneys.

    • Follow with special attention to the function of the relevant organ at routine visits 3 – 6 monthly.
    • Once blood counts have returned to normal following adjuvant chemotherapy, it is generally not necessary to follow these routinely.
    • Once serum biochemistry has recovered or stabilized, it is generally not necessary to follow these routinely.
    • Adriamycin cardiotoxicity may develop years after adjuvant therapy.

2) In those patients when any future recurrence, local or distant, is not amenable to curative therapy

Rigorous follow-up is less important for this small minority of patients. They should be followed as for other patients with incurable disease.

3) Those patients who were not curable at presentation (and 2 above)

  • Less rigorous follow up is indicated. No routine tests should be done. The patients are often be followed in their local community at 6 to 12 monthly intervals.
  • If there is recurrence in the future and symptoms arise then palliative measures specifically to control those symptoms can be instituted.
  • There is no evidence that finding such incurable recurrence earlier by testing asymptomatic patients allows any better or more effective treatment.

4) Summary of standard recommendations:

 

Adult Soft Tissue Sarcomas

Bone tumours, Ewing’s and Rhabdomyosaroma

Special situations (see below)

Clinical examination

Yr 1- 2 Every 4 months

Yr 3,4,5 Every 8 months

Yearly to continue

Yr 1- 2 Every 3 months

Yr 3,4,5 Every 6 months

Yearly to continue

 

Chest X-ray

& X-rays operative site if bone primary

Yr 1,2 Every 4 months

Yr 3,4,5 Every 8 months

CXR Yearly to 10 years

Yr 1,2 Every 3 months

Yr 3,4,5 Every 6 months

CXR Yearly to 10 years

If suspicious lesion(s) encountered, chest CT scan is indicated if surgery for cure is an option.

Local Imaging:

CT or MR

Baseline 3 – 6 months after treatment

Baseline 3 – 6 months after treatment

For patients with deeper, proximal or axial tumours:

  • Yr 1 – 2 Every 4 months
  • Yr 3 - 5 Every 8 months
  • Yearly thereafter

Bone scan

 

To be done at completion of treatment and again only at recurrence



 

SOURCE: Musculoskeletal & Sarcoma ( )
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