What are the factors influencing the extent of surgery in BSTTs?

From Cancer Guidelines Wiki

Introduction

The objective of surgery in the management of malignant bone and soft tissue tumours (BSTTs) is to achieve adequate oncologic margins and to provide an acceptable functional reconstruction if possible. Amputation was previously the mainstay of surgical management. This has changed due to the advancement in chemotherapy and radiotherapy, improvements in implants and bone and soft tissue reconstruction techniques, and imaging modalities that has allowed accurate assessment of the extent of the tumour and surgical margins. Limb salvage surgery is now the goal and is achievable in over 90% of patients. This is, however, technically challenging and should be performed by surgeons who are proficient in the technique in the setting of a multidisciplinary team and in a specialist tumour centre.

BSTTs are characterised by the development of a mass, which causes symptoms or signs that lead to the diagnosis of the tumour. The nature of this mass will determine the extent of surgery required to achieve lasting local control of disease.

Benign tumours may be treated by surgery alone, whereas malignant tumours (primary and secondary) often require modern multimodal care, which includes radiotherapy, chemotherapy or a combination of the two in addition to surgery. This review will be confined to the management of malignant primary tumours.

Before planning surgery the following steps are highly recommended:

  • History and examination to determine the behaviour and characteristics of the mass, which will aid the determination of aggressiveness.
    • Any lump greater than 5 cm or deep to the deep fascia should be considered a sarcoma until proven otherwise.
    • Persistent and unremitting pain, unresponsive to oral analgesia and nocturnal in occurrence should be investigated and bone tumour excluded.
  • Local staging of the mass with anatomic imaging including plain radiographs, computed tomography, magnetic resonance imaging, bone scans, thallium scan, positron emission tomography. Local staging allows an assessment of the anatomic location, size, relationship to important visceral, neurovascular and musculoskeletal or joint structures. This information will be important for determining the surgical margin that is best suited for local control of disease.
  • Systemic staging of the patient including chest computed tomography, and positron emission tomography. Systemic staging allows an assessment of the extent to which the tumour has spread before or after primary treatment, as this will impact on treatment strategies.
  • Pathological staging of the mass through examination of tumour tissue by histological, immuno-histochemical, molecular pathological and cytogenetic methods. This information will be important for grading the tumour and providing a histologic diagnosis, which may be relevant to specific treatment strategies and prognosis.
  • Biopsy of the tumour is a critical part of planning because it provides tissue for assessing the malignancy or benignity of the tumour, and the histologic diagnosis. The manner by which the biopsy is performed will also have an impact on how subsequent treatment is undertaken. An inappropriately placed biopsy incision, complications of biopsy such as infection and haemorrhage or obtaining unrepresentative tissue may result in amputation, or a lost opportunity for limb sparing surgery. Groups who have the expertise in managing bone and soft tissue sarcomas should perform the biopsy.

Principles of limb sparing surgery

As our understanding and management of these patients have improved, the indications for limb salvage surgery have also expanded. When considering the feasibility of limb preservation, the following principles should be taken into account. Firstly, the outcome of surgery with regards to local recurrence, distant metastasis and survival outcome should be comparable to that of ablative surgery. The planned reconstruction should be associated with acceptable risk of complications, possible re-operations and secondary amputation and be reasonably durable. Finally, the functional outcome should be equivalent or better than amputation and should be acceptable to the patient.

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Factors that influence the extent of surgery

The extent of surgery is determined by the margins required to achieve local control of disease. Oncologically sound margins are those that give rise to the highest rates of local control of disease. The extent of the margins is multifactorial and include:

  • Tumour histology
  • Tumour size
  • Tumour grade
  • Nature of adjacent structures
  • Invasion of adjacent structures
  • Adjuvant therapies
  • Previous surgical manipulation of tumour
  • Biopsy
  • Fitness of patient
  • Potential for limb sparing surgery

Prior to a final decision as to the extent of surgery, full and informed consent must be provided by the patient who may agree with or object to the recommendation of the treating team. Some patients may elect for greater or lesser extents of surgery.

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Principles of surgical margins in sarcoma surgery

Surgery with adequate oncologic margins is critical for minimising the risk for local recurrence of disease. Adequate margins are those that remove the tumour in its entirety together with surrounding tissue that may contain microscopic tumour extension or satellites. The manner in which sarcomas grow and, the nature of surrounding tissue abutting the tumour may have a bearing on the planning of surgical margins.

The pseudo-capsule

Most sarcomas have a period of rapid growth. The compression of adjacent tissue produces a pseudo-capsule, which may be visible on anatomic imaging and also at the time of surgery. An inflammatory “reactive” zone caused by the release of tumour related cytokines also surrounds the tumour and includes the pseudo-capsule.[1] This reactive zone is known to contain micro-extensions or satellites of tumour. The pseudo-capsule is unreliable for containing tumour cells and may be mistaken for a more oncologically resilient structure and inadvertently used as a margin for resection.

Surgical margins

Enneking proposed the concept of surgical margins in the management of bone and soft tissue sarcomas. He demonstrated in a retrospective cohort series, that the incidence of local recurrence was 1/45 when the margins were adequate, while in patients where the margins were inadequate, the incidence of local recurrence was 8/8. In that series, he defined adequate margins as following surgery where the entire tumour-bearing compartment was resected.

The modern application of the Enneking system[2] describes four types of surgical margins:

Type of margin Plane of dissection
Intralesional Passes through the tumour or pseudo capsule.
Marginal Passes through the reactive zone just beyond the pseudo-capsule
Wide Passes beyond the inflammatory zone, and includes a cuff of normal tissue around the tumour, which is 2-5 cm thick in the longitudinal axis or includes a named anatomic layer in the radial axis
Radical Includes the entire tumour-bearing compartment including the origin and insertion of musculo-tendinous structures within the compartment.

The incidence of local recurrence increases as the surgical margin moves closer to the tumour. Radical margins are associated with a local recurrence rate of <5%. Wide margins are associated with a local recurrence rate of 5-15%. Marginal margins are associated with a local recurrence rate of 30-60%. Intralesional margins are associated with a local recurrence rate of 60-100%.

Quality of surgical margins

Following a retrospective cohort study of 503 patients, Kawaguchi et al.[3] proposed a modification of the Enneking system and recommended the following classification:

Type of margin Plane of dissection
Intralesional Curettage or debulking
Marginal Peri-capsular reactive zone
Wide A) Inadequate Normal cuff of tissue 1cm
Wide B) Adequate Normal cuff of tissue >1 to <5cm
Curative Normal cuff of tissue >5cm

In this study, they reported a local control rate of 90% for curative margins, 89% for Wide B margins, 82% for Wide A margins, 60% for marginal margins, and 21% for intralsesional margins. This system was based on the margin distance as measured from the reactive zone.

In designing this classification, they also took into consideration the quality of the surgical margin by the barrier of tissue that was included with the tumour. The authors defined barriers as any tissue, which has resistance to tumour invasion. These included:

  • Muscle fascia
  • Joint capsule
  • Tendon
  • Tendon sheath
  • Epineurium
  • Vascular sheath
  • Cartilage
  • Pleura
  • Peritoneum

The authors sub-classified the barriers into Thick (ITB, presacral fascia, joint capsule) and Thin (muscle fascia, periosteum, vascular sheath, epineurirum) barriers. They then converted the barriers to thicknesses such that:

  • Thin barrier = 2 cm of normal tissue
  • Thick barrier = 3 cm of normal tissue
  • Cartilage = 5 cm of normal tissue
  • Adherence of tumour to barrier leads to equivalent reduction of barrier by 1 cm

This approach gives both a quantitative and qualitative measure of the extent of surgery where surgeons may chose to determine the extent of the surgery depending on what tissues are included with the surgical specimen. For example, including the vascular sheath gives a 2cm margin which is associated with an 89% local control rate, suggesting that preserving an important vascular structure may have a local control rate very similar to vascular sacrifice, and therefore, surgeons can chose in such a situation to preserve the vascularity to improve the potential for limb sparing surgery.

Kawaguchi et al.[3] also suggested that the response to neoadjuvant therapy, the grade of the lesion and whether the tumour was a primary or a local recurrence should impact the choice of surgical margin. They advocated wider margins when the response to chemotherapy or radiotherapy was less than a complete response, when radiotherapy was not used, when the lesion was high grade or a recurrence.

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Impact of radiotherapy in soft tissue sarcoma on surgical margins

Radiotherapy is an acceptable adjunct to surgery for soft tissue sarcoma whether delivered in pre-operative or post-operative settings.[4][5][6]. Radiotherapy can be delivered via external beam or brachytherapy, or may be given as a continuous course or as a boost after previous radiotherapy. The impact of radiotherapy is on the reduction of local recurrence of disease and in this regard, has been shown to upgrade the quality of surgical margins.[7] Radiotherapy induces a fibrotic rind around the tumour, may reduce the size of the tumour and also reduces the susceptibility of the operative field to seeding if the margins are close.

These effects of radiotherapy can be used to tailor the extent of surgery if limb sparing surgery is contemplated. With the advantages of radiotherapy, the surgical margins may be reduced to leave a more functional limb, or surgery that may avoid the need to resect important neurovascular structures, or musculo-skeletal structures and joints with a similar local control rate of surgery as with wider margins alone.

Low grade tumours are associated with a lower risk of local recurrence. For this reason, some surgeons may choose to operate with closer margins. However, this itself may lead to a higher risk of local recurrence of disease. In a retrospective cohort of cases of low grade soft tissue sarcomas treated by surgery, the addition of radiotherapy was shown to be beneficial when marginal or intralesional margins were employed.[8] Low grade tumours that were smaller than 5cm or excised at a tumour centre with wide margins did not show any additional benefit when radiotherapy was included. The Scandinavian Sarcoma Group also showed that in selected cases of sarcoma a local recurrence rate of 7% was possible with surgery alone.[9]

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Impact of chemotherapy in soft tissue sarcoma on surgical margins

Chemotherapy is used selectively in centre-based care for the management of high risk soft tissue sarcoma. A randomised prospective phase III trial of combined chemotherapy radiotherapy for high risk soft tissue sarcoma demonstrated that administration of pre-operative therapies minimised the local risk of relapse and the prognostic impact of close margins on the local and distant outcome.[10] This result may have relevance for patients with high risk soft tissue sarcoma where problematic margins are anticipated.

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Impact of inadvertent surgery on soft tissue sarcoma

Between 20-30% of soft tissue sarcomas are treated by inadvertent surgery. The majority of surgeries performed outside a tumour centre are associated with inadequate surgical margins. Banghu et al. reported that 2/3 of patients who underwent surgery outside a specialist centre had positive margins.[11] Goodlad et al.[12] reported that almost 60% of patients who had re-excision of the operative field after inadvertent resection of tumours performed outside a tumour centre had residual tumour tissue. This was despite all patients in their retrospective series being declared widely excised prior to referral. Venkatesan reported that almost ¾ of patients who surgery outside a tumour centre had residual tumour in re-excised specimens.[13] The local recurrence rate of patients treated definitively before referral to a tumour centre is higher than patients who are referred prior to excision.[14]

Patients who have been treated with inadvertent surgery and referred for surgical care require a combination of re-excision and radiotherapy. Patients requiring re-excision of previous operative fields will require much wider surgical margins. If they receive this, published data from retrospective cohort studies demonstrate good local control of disease.[15][16] To achieve local control of disease, re-excision often requires margins that are wider than for the primary tumour.[3]

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Impact of response to chemotherapy on osteosarcoma

Chemotherapy induced necrosis is an important factor in determining local recurrence after resection of osteosarcoma.[17] Poor responders were associated with a three times higher risk of local failure. If poor responders also underwent surgery with inadequate margins the risk for local failure rose 50 times. This was in comparison to inadequate surgery in good responders who had a five times higher risk of local failure. These results may be useful for determining the place of amputation in patients known to have sub-optimal response to neo-adjuvant chemotherapy as reflected by restaging studies and in whom the tumour characteristics predicted inadequate margins.

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Histology

In principle local recurrence is related to the quality of the surgical margins. However, in certain histotypes, such as low grade chondrosarcomas and well-differentiated lipoma-like liposarcomas, much closer margins than would otherwise be recommended can be employed because the systemic risks of these tumours are low. For example, in grade I chondrosarcomas, some authors advocate thorough curettage of the tumour in combination with chemical adjuvants such as cementation.[18] In well-differentiated lipoma-like liposarcomas marginal excision is recommended if the functional morbidity is unacceptably high because the risk of metastasis is extremely low and recurrence may be treated with re-excision. However, despite the disease free interval not being influenced by resection margin, patients with well-differentiated lipoma-like liposarcoma have a longer disease free interval with the use of adjuvant radiotherapy.[19]

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Size and volume

Large size (> 8cm or volume (> 150 ml) of the tumour is generally associated with a poorer prognosis.[20][21] The large size and volume may result in tumours extending outside their original compartments and engaging important neurovascular, musculo-skeletal and joint structures. In addition, larger tumours tend to involve more vital structures that may need to be sacrificed requiring a more extensive reconstruction and poorer functional outcome.

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Location

Tumours occurring within the flexor fossae present particular challenges because of the confluence of vital neurovascular structures in these areas and the poor compartmentalization of the tumour which means early and often significant abutment against these important structures. Treatment of tumours in the flexor fossae were traditionally treated with amputation because of the necessity for narrow surgical margins. However with improvements in adjuvant therapy and better medical imaging, these tumours can now be adequately excised with marginal margins and adjuvant radiotherapy or chemotherapy increasing the potential for limb sparing surgery.

In addition, certain tumours such as Ewings,[22] pelvic location greatly influence the overall survival outcome regardless of response to adjuvant therapy and type of surgery. In large pelvic tumours, the role of surgery remains controversial. Reducing tumour burden is thought to be central to effective chemotherapy, however, this must be balanced against the possibility of significant surgical morbidity and functional derangement in the setting of high risk for metastatic disease. Retroperitoneal tumours usually present late and can be quite extensive on presentation. Resectability in these cases depends on response to radiotherapy[23] and the organs involved. Some authors have suggested an aggressive surgical policy. A retrospective case series of 77 patients reported that retroperitoneal sarcoma has a high rate of visceral involvement despite being considered a pushing tumour.[24] This growth pattern may also occur in well-differentiated liposarcoma. That series reported an acceptable five year overall survival of 73%. In palliative situations, incomplete resections may be appropriate to provide symptomatic control and prolong life expectancy.[25]

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Evidence summary and recommendations

Importance of surgical margins


Evidence summary Level References
The risk of local recurrence is related to the surgical margins achieved. II, III-3, IV [3], [26], [27], [28], [29], [4], [17], [19], [20], [22], [30]
Evidence-based recommendationQuestion mark transparent.png Grade
It is important that wide surgical margin is achieved to prevent local recurrence and poor survival outcomes.
B


Unplanned excision

Evidence summary Level References
Unplanned resection of musculoskeletal tumours often result in positive margin surgery. This is associated with higher risk of local recurrence, distant metastasis and poorer survival outcomes. Re-resection often require wider margins and may lead to poorer functional outcome. III-3, IV [31], [13], [12], [32], [14], [16], [33]
Evidence-based recommendationQuestion mark transparent.png Grade
Musculoskeletal tumours are best managed in a specialist sarcoma unit by a multidisciplinary team.
C
Evidence-based recommendationQuestion mark transparent.png Grade
Soft tissue sarcomas initially excised with residual disease and/or positive margins will require re-excision, preferably in a specialist sarcoma unit. These tumours should be re-excised with wide margins and usually require adjuvant radiotherapy.
C

Retroperitoneal sarcoma

Evidence summary Level References
Retroperitoneal sarcomas can be extensive and involve multiple organs. Good results can be achieved, but require an aggressive approach. When carried out in a specialised tumour centre, surgery is safe and is associated with improved local control. III-3, IV [34], [35], [36], [37], [38], [24]
Evidence-based recommendationQuestion mark transparent.png Grade
Retroperitoneal sarcomas are best managed in a specialised tumour centre by a multidisciplinary unit.
C


Limb salvage surgery in Osteosarcoma

Evidence summary Level References
Limb salvage surgery has higher rates of survival and lower secondary amputation. There is no survival advantage from amputation. III-3 [39], [40]
Evidence-based recommendationQuestion mark transparent.png Grade
Limb salvage surgery is an acceptable treatment in the management of osteosarcoma.
C

Effective radiotherapy on limb salvage

Evidence summary Level References
Epineural dissection in conjunction with pre-operative radiotherapy is a safe and effective technique to preserve vital nerves. III-2 [41]
Evidence-based recommendationQuestion mark transparent.png Grade
Pre-operative radiation therapy may allow preservation of vital structures without compromising local control.
C


Evidence summary Level References
Radiotherapy is an important adjunct to the management of soft tissue sarcoma (STS) and reduces the risk of local recurrence. II, III-2, IV [42], [23], [43], [44], [4], [6], [10]
Evidence-based recommendationQuestion mark transparent.png Grade
Pre or post-operative radiation therapy should be considered in the management of soft tissue sarcoma. Decision should be made in the setting of a multidisciplinary team.
A


Isolated limb perfusion

Evidence summary Level References
Isolated limb perfusion can be effective in facilitating limb preservation surgery. III-3, IV [45], [46], [47], [48]
Evidence-based recommendationQuestion mark transparent.png Grade
Isolated limb perfusion should be considered in patients with extensive soft tissue sarcoma where there is doubt whether limb salvage surgery can be achieved. Decision should be made in the setting of a multidisciplinary team.
C


Chondrosarcoma

Evidence summary Level References
Grade 1 chondrosarcoma the distinction of which can be difficult from endchondroma both on imaging and pathology grounds can be safely managed with close follow-up and a multidisciplinary diagnosis. Grade 1 chondrosarcoma can be treated with intralesional excision safely. III-3, IV [49], [18], [50]
Evidence-based recommendationQuestion mark transparent.png Grade
Grade 1 Chondrosarcoma can be safely managed with intralesional excision with cementation. Distinction between this and other grades requires correlation of clinical and radiological features.
C



Practice pointQuestion mark transparent.png

Any lump greater than 5 cm or deep to the deep fascia should be considered a sarcoma until proven otherwise.


Practice pointQuestion mark transparent.png

Persistent and unremitting pain, not responsive to oral analgesics and nocturnal in occurrence should stimulate investigation for a bone tumour.


Practice pointQuestion mark transparent.png

Complete imaging (anatomic and functional including XR, CT, MRI, nuclear scan) should be undertaken of a bone and soft tissue tumour prior to surgical manipulation.


Practice pointQuestion mark transparent.png

Biopsy should be performed under image guidance to determine the track of the biopsy, and the target of the biopsy to confirm representativeness. Computed tomographic guidance is recommended. Biopsy should be performed after all imaging modalities have been completed to minimise the impact of biopsy induced image artifact.


Practice pointQuestion mark transparent.png

Sarcomas are best managed at a specialist sarcoma unit.


Practice pointQuestion mark transparent.png

Local recurrence is related to the adequacy of surgical margins. Wide surgical margins should be employed for bone and soft tissue sarcomas except when close margins are planned and adjuvant radiotherapy/chemotherapy is employed.


Practice pointQuestion mark transparent.png

Tissues of different resistance to tumour invasion that surround a tumour may be used to calculate the quality of surgical margins. In this way, more careful planning of surgical margins may be undertaken when contemplating limb-sparing surgery.


Practice pointQuestion mark transparent.png

Combination therapy is required to adequately manage bone and soft tissue sarcomas. Radiotherapy and wide margin surgery are used for soft tissue sarcomas. Chemotherapy and wide margin surgery are used for bone sarcomas.


Practice pointQuestion mark transparent.png

Radiotherapy is recommended for low grade soft tissue sarcomas particularly if these tumours are large and excised with marginal margins.


Practice pointQuestion mark transparent.png

Adequacy of surgical margins achieved should be assessed by a expert musculoskeletal pathologist. Refer to the Royal College of Pathologists of Australasia Soft Tumour Resection Structured Reporting Protocol 1st Edition 2011

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References

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  2. Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res 1980 Nov;(153):106-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7449206.
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  33. Fiore M, Casali PG, Miceli R, Mariani L, Bertulli R, Lozza L, et al. Prognostic effect of re-excision in adult soft tissue sarcoma of the extremity. Ann Surg Oncol 2006 Jan;13(1):110-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16372156.
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