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.
- Plain radiographs of primary site.
- MRI of the entire length of the involved long bone
- CT chest
- Bone scan and/or
- PET/CT scan
- 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 (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.
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
- 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.
- 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
- 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.
- 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.
- 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.
- 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
- 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 (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.
- 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.
- 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.
- 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
- 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.
- 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 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.
- 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 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
- Plain radiograph of primary site
- MRI or CT of primary site
- CT chest
- 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.