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Bone Cancer NCCN Clinical Practice Guidelines in Oncology

• NCCN Categories of Evidence and Consensus

Category 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus.

Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus.

Category 2B: The recommendation is based on lower-level evidence and there is nonuniform NCCN consensus (but no major disagreement).

Category 3: The recommendation is based on any level of evidence but reflects major disagreement.

All recommendations are category 2A unless otherwise noted.

Clinical trials: The NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Primary bone cancers are extremely rare neoplasms, likely accounting for fewer than 0.2% of all cancers, although its true incidence is difficult to determine secondary to the rarity of these tumors. 1 , 2 In 2009, an estimated 2570 new cases will be diagnosed in the United States and 1470 people will die of the disease. 3 Primary bone cancers show wide clinical heterogeneity and are often curable with proper treatment. Osteosarcoma (35%), chondrosarcoma (30%), and Ewing's sarcoma (16%) are the 3 most common forms of bone cancer. Malignant fibrous histiocytoma (MFH) and fibrosarcoma of the bone constitute fewer than 1% of all primary bone tumors. Chondrosarcoma is usually found in middle-aged and older adults; osteosarcoma and Ewing's sarcoma develop mainly in children and young adults. Various bone cancers are named based on their histologic origin: chondrosarcomas arise from cartilage, osteosarcomas arise from bone, and fibrogenic tissue is the origin of fibrosarcoma of bone, whereas vascular tissue gives rise to hemangioendothelioma and hemangiopericytoma. Notochordal tissue gives rise to chordoma. Several primary bone cancers, including Ewing's sarcoma family of tumors (ESFT), are of unknown histologic origin.

The pathogenesis and etiology of most bone cancers remain unclear. Gene rearrangements in the EWS and ETS family of genes have been implicated in the pathogenesis of Ewing's sarcoma. 4 – 7 Specific genetic alterations also play a role in osteosarcoma pathogenesis. 8 , 9 Although trauma is frequently implicated in sarcomas, a cause-and-effect relationship between a traumatic event and the development of bone cancer has not been identified. A quantifiable risk exists for developing bone sarcomas after therapeutic radiation. 10 , 11 Osteosarcoma is the most common radiation-induced sarcoma, and is the most common second primary malignancy in patients with a history of retinoblastoma. 12 , 13 Li-Fraumeni syndrome is a hereditary cancer syndrome in which there is a germ-line mutation of the p53 gene resulting in sarcomas such as osteosarcoma, early onset of bilateral breast cancer, and several other neoplasms. 14 – 17

In the past, a diagnosis of osteosarcoma and Ewing's sarcoma was associated with a poor prognosis. A generation ago, Marcove et al. described the survival pattern of newly diagnosed patients with osteosarcoma

Version 3.2010, 03-19-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 6; 10.6004/jnccn.2010.0051

Clinical trials: The NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are category 2A unless otherwise noted.

The NCCN Clinical Practice Guidelines in Oncology: Bone Cancer (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org ) focus on chondrosarcoma, Ewing's sarcoma, and osteosarcoma.

The 2010 American Joint Committee on Cancer (AJCC) staging classification is shown in the staging table (available online, in these guidelines, at www.NCCN.org [ST-1]). This system is based on the assessment of histologic grade (G), tumor size (T), presence of regional (N) and/or distant metastases (M). The Surgical Staging System (SSS) is another staging system for bone and soft tissue sarcomas developed by the Musculoskeletal Tumor Society (available online, in these guidelines, at www.NCCN.org [ST-1]). 21 This system stratifies bone and soft tissue sarcomas according to surgical grade (G), local extent (T), and presence or absence of regional or distant metastases. It may be used in addition to the AJCC staging system.

Principles of Bone Cancer Management

• Multidisciplinary Team Involvement

Primary bone tumors and selected metastatic tumors should be evaluated and treated by a multidisciplinary team with demonstrated expertise in the management of these tumors. Appropriate team members are listed on page 696. Long-term surveillance and follow-up are necessary when considering the risk for recurrence and comorbidities associated with chemotherapy and radiation therapy (RT). Extended therapy and surveillance may be necessary for long-term survivors to address the potential side effects of surgery, RT, and chemotherapy. Patients should be given a survivorship prescription to schedule follow-ups with a multidisciplinary team. Fertility issues should be discussed with appropriate patients before they start treatment. 22

• Diagnostic Workup

Suspicion of a malignant bone tumor often begins when a poorly marginated lesion is seen on a plain radiograph in a patient with a painful lesion. In patients younger than 40 years, an aggressive, painful bone lesion has a significant risk for being a malignant primary bone tumor, and referral to an orthopedic oncologist should be considered before further workup. Patients 40 years and older whose plain films and history do not suggest a specific diagnosis should undergo evaluation for metastatic carcinoma, including chest radiograph; chest, abdominal, and pelvic CT; bone scan; mammogram; and other imaging studies as clinically indicated (see page 690). 23

All patients with suspected bone sarcomas should undergo complete staging before biopsy. Standard staging workup for a suspected primary bone sarcoma should include chest imaging (chest radiograph or CT to detect pulmonary metastases), appropriate imaging of the primary site (plain radiographs, MRI for local staging, and/or CT scan), and bone scan. 24 Imaging of painless bone lesions should be evaluated by a musculoskeletal radiologist followed by appropriate referral to a multidisciplinary treatment team if necessary. Laboratory studies, such as a CBC, lactate dehydrogenase (LDH), or alkaline phosphatase, should be performed before treatment is initiated.

PET is an alternative imaging technique used in the pretreatment staging of soft tissue and bone sarcomas. 25 Recent reports have shown the efficacy of PET scans in evaluating chemotherapy response in osteosarcoma and ESFT. 26 , 27

Biopsy should be performed using either core needle or surgical biopsy techniques. At biopsy, careful consideration should be given to appropriate stabilization of the affected bone and/or measures to protect against impending pathologic fracture. Because location of the biopsy is critical to limb-salvage techniques, it should be performed at the facility that will provide definitive management of the suspected primary malignant bone tumor.

Surgical margins should be negative, wide enough to minimize potential local recurrence, and narrow enough to maximize function. Wide excision implies histologically negative surgical margins and is necessary to optimize local control. Local tumor control may be achieved either through limb-sparing resection or limb amputation, although in selected cases, amputation may be the most appropriate option. However, limb-sparing resection is preferred if reasonable functional outcomes can be achieved. Response to the preoperative regimen should be evaluated with pathologic mapping. Consultation with a physical therapist is recommended to evaluate for mobility training and to determine an appropriate rehabilitation program.

Chondrosarcoma

Chondrosarcomas characteristically produce cartilage matrix from neoplastic tissue devoid of osteoid and may occur at any age, but are more common in older adults. 28 – 30 Conventional chondrosarcomas of the bone constitute approximately 85% of all chondrosarcomas and are divided as either primary or central lesions arising from previously normal-appearing bone preformed from cartilage; secondary or peripheral tumors that arise or develop from preexisting benign cartilage lesions, such as enchondromas; or from the cartilaginous portion of an osteochondroma. 29 , 31 , 32

Malignant transformation has been reported in lesions found in patients with Ollier's disease (enchondromatosis). The anatomic location, histologic grade, and size are essential prognostic features of the lesion, despite whether it is primary or secondary, or central or peripheral. 33 – 36 Peripheral or secondary tumors are usually low grade with infrequent metastasis. 37 Other rare subtypes that constitute approximately 10% to 15% of all chondrosarcomas 29 include clear cell, dedifferentiated, myxoid, and mesenchymal forms.

Symptoms of chondrosarcoma are usually mild and depend on tumor size and location. Patients with pelvic or axial lesions typically present later in the disease course, because the associated pain has a more insidious onset and often occurs when the tumor has reached a significant size. 33 , 38 , 39 Central chondrosarcomas show cortical destruction and loss of medullary bone trabeculations on radiographs, as well as calcification and destruction. 38

MRI will show the intramedullary involvement and extraosseous extension of the tumor. Secondary lesions arise from preexisting lesions. Serial radiographs will show a slow increase in size of the osteochondroma or enchondroma. A cartilage “cap” measuring greater than 2 cm on a preexisting lesion or documented growth after skeletal maturity should suggest sarcomatous transformation. 40

Histologic grade and tumor locations are the most important variables used to determine primary treatment. Resectable low-grade and intracompartmental lesions are treated with intralesional excision with or without adjuvant therapy. 41 – 44 Wide excision with negative margins is the preferred treatment for some low-grade lesions because of their larger size and intraarticular or pelvic localization. High-grade (grade II, III, or clear cell) or extracompartmental lesions are treated with wide excision, if resectable, obtaining negative surgical margins. 34

Unresectable high- and low-grade lesions are treated with RT (see page 691). Proton-beam RT has been associated with excellent local tumor control and long-term survival in patients with low-grade skull base chondrosarcomas. 45 , 46

Chemotherapy is not very effective in chondrosarcomas, especially in conventional and dedifferentiated chondrosarcomas. Although Mitchell et al. 47 reported that adjuvant chemotherapy with cisplatin and doxorubicin was associated with improved survival in patients with dedifferentiated chondrosarcoma, this finding could not be confirmed in other studies. 48 – 50 Recently, Cesari et al. 51 reported that the addition of chemotherapy improved survival rates in patients with mesenchymal chondrosarcoma. Another report from the German study group also confirmed that the outcome was better in younger patients. 52 However, no prospective randomized trials have been performed, and therefore the role of chemotherapy in the treatment of chondrosarcomas remains undefined.

No chemotherapy regimens have been established for conventional chondrosarcoma (grades 1–3). The NCCN Bone Cancer Guidelines suggest that dedifferentiated chondrosarcomas could be treated as osteosarcoma, and mesenchymal chondrosarcomas treated as Ewing's sarcoma, best approached as a function of their grade. Both of these options have a category 2B recommendation.

• Surveillance

Surveillance for low-grade lesions consists of a physical examination, imaging of the lesion, and a chest radiograph every 6 to 12 months for 2 years, then yearly as appropriate. Surveillance for high-grade lesions consists of a physical examination, imaging of the primary site, and/or cross-sectional imaging as indicated. Chest imaging is also indicated every 3 to 6 months for the first 5 years, and yearly thereafter for a minimum of 10 years, because late metastases and recurrences after 5 years are more common with chondrosarcoma than with other sarcomas. 35 Functional assessment should be performed at every visit (see page 691).

Local recurrence or relapse should be treated with wide excision, if the lesions are resectable. RT should be considered after wide excision with positive surgical margins (see page 691). Negative surgical margins should be observed. Unresectable recurrences are treated with RT.

Surgical excision is an option for systemic relapse of a high-grade lesion or patients should be encouraged to participate in a clinical trial.

ESFT are a group of small, round-cell neoplasms that include Ewing's sarcoma, primitive neuroectodermal tumor (PNET), Askin's tumor, PNET of bone, and extraosseous Ewing's sarcoma. Ewing's sarcoma is characterized by the fusion of the EWS gene on chromosome 22q12 with various members of the ETS gene family ( FLI1, ERG, ETV1, ETV4 , and FEV ). 5 , 6 The EWS-FLI1 fusion transcript resulting from the chromosomal translocation t(11;22) (q24;q12) is identified in approximately 85% of Ewing's sarcomas, such as Ewing's sarcoma, PNET, and Askin's tumor.

Ewing's sarcoma is poorly differentiated and is also characterized by the strong expression of cell-surface glycoprotein MIC2 (CD99). 53 , 54 The expression of MIC2 may be useful in the differential diagnosis of Ewing's sarcoma and PNET from other small round-cell neoplasms, although it is not exclusively specific to these tumors. 55

Ewing's sarcoma typically occurs in adolescents and young adults; the most common primary sites are the femur, pelvic bones, and bones of chest wall, although any bone may be affected. When arising in a long bone, the diaphysis is the most frequently affected site and appears mottled on imaging. Periosteal reaction is classic and is referred to as “onion skin” by radiologists.

Patients with Ewing's sarcoma, similar to those with bone sarcomas, present with localized pain or swelling. Unlike with other bone sarcomas, constitutional symptoms, such as fever, weight loss, and fatigue, are occasionally noted at presentation. Abnormal laboratory studies may include elevated serum LDH and leukocytosis.

Important indicators of favorable prognosis include a distal site of primary disease, normal serum LDH level at presentation, and absence of metastatic disease at presentation. 56 – 58 Nearly one quarter will present with metastatic disease, which is the most significant adverse prognostic factor in Ewing's sarcoma as it is for other bone sarcomas. 59 , 60 Lungs, bones, and bone marrow are the most common sites of metastasis. In a retrospective analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) Group, 5-year relapse-free survival was 22% for patients with metastatic disease at diagnosis compared with 55% for those without. 60 The results of the Intergroup Ewing's Sarcoma Study, analyzing the clinicopathologic features of 303 cases of Ewing's sarcoma, showed that patients with primary tumors in pelvic bones have the lowest survival rates compared with those with lesions in distal bones of the extremities. 61

When ESFT is suspected, patients should undergo complete staging before biopsy. This should include CT of the chest, plain radiographs of the primary site, CT or MRI of the entire bone or area involved, PET scan, and/or bone scan. An MRI of the spine and pelvis should also be considered. An ongoing diagnostic study is comparing whole-body MRI and conventional imaging for detecting distant metastases in pediatric patients with ESFT, Hodgkin lymphoma, non-Hodgkin's lymphoma, rhabdomyosarcoma, and neuroblastoma ( www.cancer.gov/clinicaltrials/ACRIN-6660 ).

Cytogenetic analysis of the biopsy specimen should be obtained to evaluate the t(11;22) translocation. Although preliminary reports suggest that EWS-FLI1 translocation is associated with a better prognosis than other variants, 62 – 64 this must be evaluated in large clinical trials. Bone marrow biopsy should be considered to complete the workup. Because serum LDH has been shown to have prognostic value as a tumor marker, the NCCN Bone Cancer Guidelines have included this test as part of the initial evaluation (see page 692). Fertility consultation should be considered for women of child-bearing age and men.

• Primary Treatment

Multiagent chemotherapy regimens, including ifosfamide and/or cyclophosphamide; etoposide; doxorubicin and/or dactinomycin; and vincristine have been shown to be effective in patients with localized Ewing's sarcoma in single- and multi-institutional collaborative trials in the United States and Europe. 65 , 66

The Intergroup Ewing's Sarcoma Studies (IESS-I and IESS-II) showed that the 4-drug regimen VACD (vincristine, dactinomycin, cyclophosphamide, and doxorubicin) was superior to the 3-drug regimen VAC (vincristine, dactinomycin, and cyclophosphamide) in terms of relapse-free (60% vs. 24%) and overall survival. 67 , 68

In the Pediatric Oncology Group-Children's Cancer Group (POG-CCG) study (INT-0091), patients with Ewing's sarcoma or PNET of the bone were randomized to undergo chemotherapy with VACD alone or alternating with ifosfamide and etoposide (VACD-IE) for 17 cycles. 69 In patients with nonmetastatic disease, the 5-year event-free survival rate was 69% in the VACD-IE group compared with 54% in the VACD alone group. Overall survival was also significantly higher among patients in the VACD-IE group (72% vs. 61%). However, the addition of ifosfamide and etoposide to VACD did not improve outcomes of patients with Ewing's sarcoma or PNET of bone with metastases at diagnosis. 70 Kolb et al. 71 from MSKCC also reported similar findings. The 4-year event-free and overall survival rates were 82% and 89%, respectively, for patients with locoregional disease, and 12% and 17.8%, respectively, for those with distant metastases.

The EICESS-92 study investigated whether cyclophosphamide has a similar efficacy to ifosfamide in standard-risk patients and whether the addition of etoposide improves survival in high-risk patients with Ewing's sarcoma. Standard-risk patients (small tumors) were randomly assigned to VAIA (vincristine, dactinomycin, ifosfamide, and doxorubicin) followed by either VAIA or VACA (vincristine, dactinomycin, cyclophosphamide, and doxorubicin). 72 High-risk patients (large tumors or metastatic disease at diagnosis) were randomly assigned to VAIA or VAIA plus etoposide (EVAIA). For the standard-risk patients, 3-year event-free survival rates for VACA and VAIA were 73% and 74%, respectively. In the high-risk patients, the 3-year event-free survival rates for EVAIA and VAIA were 52% and 47%, respectively. The results of this study suggest that cyclophosphamide has the same efficacy as ifosfamide in standard-risk patients. Furthermore, the event-free survival rates in the high-risk group, though not statistically significant, suggest a benefit with the addition of etoposide to ifosfamide.

The European Ewing Tumour Working Initiative of National Groups 1999 (EURO-EWING 99) study is designed to evaluate the efficacy and safety of combination chemotherapy with or without peripheral stem cell transplantation, RT, and/or surgery in patients with Ewing's sarcoma. Six courses of VIDE (vincristine, ifosfamide, doxorubicin, and etoposide) are administered as an intensive induction chemotherapy for patients with ESFT. 73

NCCN Recommendations: All patients with Ewing's sarcoma undergo primary treatment followed by local control therapy and adjuvant treatment (see page 693). Primary treatment consists of multiagent chemotherapy along with appropriate growth factor support for 12 to 24 weeks (see the NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors for growth factor support; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org ). For localized Ewing's sarcoma, VAC alternating with ifosfamide and etoposide (VAC/IE) given on an every-2-week schedule was found to be more effective than on an every-3-week schedule, with median 3-year event-free survival rates of 76% and 65%, respectively. 74

The NCCN guidelines have included the following regimens for first-line therapy (primary/neoadjuvant/adjuvant) for patients with localized disease or metastatic disease at presentation (page 697):

VIA (vincristine, ifosfamide, and doxorubicin) 72

The guidelines recommend VAC (without the alternating cycle of ifosfamide and etoposide) as the preferred option for the treatment for primary metastatic disease at presentation. 70 , 71 VAC/IE, VIDE, and VIA regimens are included as alternative treatment options.

After primary treatment, patients should be restaged with an MRI of the lesion and chest imaging. PET or bone scan can be used for restaging depending on the imaging technique used during initial workup. Patients responding to primary treatment should be treated with local control therapy. Local control options include wide excision with or without preoperative RT, 75 , 76 definitive RT with chemotherapy, or amputation in selected cases (see page 693). Adjuvant chemotherapy with or without RT is recommended (regardless of surgical margins) after local control treatment (surgery or RT). The panel strongly recommends that the duration of chemotherapy be 28 and 49 weeks, depending on the type of regimen and dosing schedule (category 1).

Progressive disease after primary treatment is best managed with RT with or without surgery, followed by chemotherapy or best supportive care.

Surveillance of patients with Ewing's sarcoma consists of a physical examination, and chest and local imaging every 2 to 3 months. 77 , 78 Surveillance intervals should be increased after 2 years, then annually after 5 years.

• Treatment of Relapsed or Refractory Disease

Approximately 30% to 40% of patients with Ewing's sarcoma experience recurrence (local and/or distant) and have a very poor prognosis. The timing and type of recurrence are the important prognostic factors; those with longer time to first recurrence have a better chance of survival. Late relapse (≥ 2 years after diagnosis), lung-only metastases, and local recurrence that can be treated with radical surgery and intensive chemotherapy are the most favorable prognostic factors, whereas early relapses (< 2 years after diagnosis) with metastases in the lungs and/or other sites, recurrence at local and distant sites, elevated LDH at initial diagnosis, and initial recurrence are considered adverse prognostic factors. 79 – 81

Ifosfamide in combination with etoposide with or without carboplatin has been evaluated in clinical trials for the treatment of patients with relapsed or refractory sarcoma. 82 , 83 In a phase II study, the combination of ifosfamide with mesna and etoposide was highly active, with acceptable toxicity in the treatment of recurrent sarcomas in children and young adults. 82 In phase I and II studies conducted by the CCG, the overall response rate in patients with recurrent or refractory sarcoma was 51%; the overall survival rates at 1 and 2 years were 49% and 28%, respectively. Overall survival appeared significantly improved in patients who experienced a complete or partial response. 83

Docetaxel in combination with gemcitabine was found to be well tolerated and showed antitumor activity in the treatment of children and young adults with refractory bone sarcoma. 84 Topoisomerase I inhibitors, topotecan 85 – 88 and irinotecan, 89 – 91 in combination with cyclophosphamide and temozolomide, respectively, have shown promising response rates in patients with relapsed or refractory solid tumors. Cyclophosphamide and irinotecan produced a 44% response rate (35% of patients had a complete and 9% a partial response) in patients with recurrent or refractory Ewing's sarcoma. 86 After a median follow-up of 23.1 months, 25.9% of patients were in continuous remission. In a retrospective analysis of patients with recurrent or progressive Ewing's sarcoma treated with irinotecan and temozolomide at MSKCC, the median time-to-progression (TTP) was 8.3 months. 89 In those with recurrent disease, TTP was 16.2 months. Median TTP was better for patients experiencing a 2-year first remission and those with primary localized disease than for patients who experienced relapse within 2 years from diagnosis and for those with metastatic disease at diagnosis.

Inhibition of insulin-like growth factor-1 receptor (IGF-1R) may be an interesting approach in the treatment of some subtypes of sarcomas. Monoclonal antibodies, such as figitumumab and R1507, have shown safety and suggested possible efficacy in early-phase trials for patients with relapsed or refractory sarcomas, including Ewing's sarcoma.

High-dose chemotherapy with stem cell rescue (HDT/SCR) has been evaluated in patients with relapsed or progressive Ewing's sarcoma in several small studies. 92 – 98 The role of this approach in high-risk patients has yet to be determined in prospective randomized studies.

NCCN Recommendations: Treatment options for patients with relapsed or refractory disease include participation in a clinical trial, or chemotherapy with or without RT (see page 693). If a relapse is delayed, as sometimes occurs with this sarcoma, re-treatment with the previously effective regimen may be useful. The NCCN guidelines have included the following regimens as options for patients with relapsed or refractory disease (see page 697):

Cyclophosphamide and topotecan

Temozolomide and irinotecan

Ifosfamide and etoposide

Ifosfamide, carboplatin, and etoposide

Docetaxel and gemcitabine

All patients with recurrent and metastatic disease should be considered for clinical trials investigating new treatment approaches.

Osteosarcoma

Osteosarcoma is the most common primary malignant bone tumor in children and young adults; 1 the median age at diagnosis is 20 years. Osteosarcoma has 11 known variants with variable natural histories. Classic osteosarcoma constitutes nearly 80% of osteosarcoma and is always a high-grade spindle cell tumor that produces osteoid or immature bone. The most frequent sites for this cancer are the metaphyseal areas of the distal femur or proximal tibia, which are the sites of maximum growth.

Although most osteosarcomas are medullary and high-grade, parosteal lesions are juxtacortical and occur most often in the posterior distal femur. This variant tends to metastasize later than the classic form and has low histologic grade. Another juxtacortical variant is periosteal osteosarcomas, which most often involves the femur followed by the tibia and behaves with a severity that is intermediate between the parosteal and classic lesions. 99 Other variants include osteosarcoma secondary to Paget's disease or prior irradiation. Patients with retinoblastoma are also at an increased risk for developing a very aggressive variant of osteosarcoma.

Pain and swelling are the most frequent early symptoms. Pain in the beginning is often intermittent and a thorough workup sometimes is delayed because symptoms may be confused with growing pains. Osteosarcoma spreads hematogenously, commonly metastasizing to the lung.

Tumor site and size, presence and location of metastases, histologic response to chemotherapy, and complete resection with negative margins are significant prognostic factors for patients with osteosarcoma of the extremities and trunk. 100 , 101 Patients with one or a few resectable pulmonary metastases have a survival rate that approaches that of patients with no metastatic disease.

In an analysis of 1702 patients with osteosarcoma treated with neoadjuvant chemotherapy in cooperative study group protocols, axial tumor site, male gender, and a long history of symptoms were associated with poor response to chemotherapy. Patient age and tumor location at diagnosis had a significant influence on outcome. 100 All factors except age were significant in multivariate testing, with surgical remission and histologic response to chemotherapy emerging as the key prognostic factors. Elevated serum LDH level is also associated with a worse prognosis. Bacci et al. 102 reported on 1421 patients with osteosarcoma of the extremity treated over 30 years. In this cohort, serum level of LDH was significantly higher in patients with metastatic disease at presentation than those with localized disease; 5-year disease-free survival rates were 39.5% and 60%, respectively. The 5-year disease-free survival correlated with serum level of LDH at univariate and multivariate analysis (39.5% for patients with high LDH levels and 60% for those with normal values), although it lost its significance when histologic response to chemotherapy was also considered in the latter.

Osteosarcomas present both a local problem and a concern for distant metastasis. Imaging of the primary lesions is accomplished with plain radiographs, MRI, and/or CT and bone scan. PET scan can also be considered. Plain radiographs of osteosarcomas show cortical destruction and irregular reactive bone formation. Bone scan, although uniformly abnormal at the lesion, may be useful to identify additional synchronous lesions (see page 694). MRI provides excellent soft tissue contrast and may be essential for operative planning. MRI is the best imaging modality to define the extent of the lesion within the bone and soft tissues, detect “skip” metastases, and evaluate anatomic relationships with the surrounding structures. In addition, ALP and LDH are frequently elevated in patients with osteosarcoma.

Although surgery remains an essential part of osteosarcoma management, the addition of adjuvant and neoadjuvant chemotherapy regimens has improved outcomes in patients with localized osteosarcoma. Early trials used multiagent chemotherapy regimens, including at least 3 or more of the following drugs: doxorubicin; cisplatin; bleomycin; cyclophosphamide or ifosfamide; dactinomycin; and high-dose methotrexate. 103 – 110 The updated results of the randomized Multi-Institutional Osteosarcoma Study (MIOS) showed that 6-year event-free survival was significantly higher in patients randomized to adjuvant chemotherapy than in those who underwent observation only after surgery (61% and 11%, respectively). 109

Subsequent clinical trials have shown that short intensive chemotherapy regimens produce excellent long-term results, similar to those achieved with multiagent chemotherapy. 111 – 113 In a randomized trial conducted by the European Osteosarcoma group, combination doxorubicin and cisplatin was better tolerated in patients with operable nonmetastatic osteosarcoma than a multidrug regimen, with no difference in survival between the groups. 113 For both groups, the 3- and 5-year overall survival rates were 65% and 55%, respectively, and progression-free survival at 5 years was 44%. In a phase II/III trial, high-dose ifosfamide in combination with etoposide was effective as induction therapy in patients with newly diagnosed metastatic osteosarcoma despite significant myelosuppression, infection, and renal toxicity. 114 The overall response rate was 59%, and projected 2-year progression-free survival rate for patients with metastases to lung was 39%. The survival rate for patients with bone metastases (with or without pulmonary metastases) was 58%. Combination cisplatin, ifosfamide, and epirubicin was also an active and reasonably well-tolerated regimen in patients with nonmetastatic extremity osteosarcoma, 115 with a phase II study with a median follow-up of 64 months showing 5-year disease-free and overall survival rates of 41.9% and 48.2%, respectively.

Although neoadjuvant chemotherapy is associated with an improved prognosis in patients with high-grade localized osteosarcoma, the results were significantly poorer in those with metastatic disease at presentation. 103 , 116 , 117 Two-year event-free and overall survival rates were 21% and 55%, respectively, versus 75% and 94% in patients with nonmetastatic disease at presentation, treated with the same chemotherapy protocol. 103 Good histopathologic response (> 90% necrosis) to neoadjuvant chemotherapy has been shown to be predictive of survival regardless of the type of chemotherapy administered after surgery. 102 , 118 In an analysis of 881 patients with nonmetastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy and surgery at the Rizzoli Institute, Bacci et al. 119 showed that the 5-year disease-free and overall survival rates correlated significantly with histologic response to chemotherapy and were 67.9% versus 51.3% ( P < .0001) in patients with good response and 78.4% versus 63.7% ( P < .0001) in those with poor response, respectively. A report from the CCG also confirmed these findings; 8-year postoperative event-free and overall survival rates were 81% and 87%, respectively, in good responders to neoadjuvant therapy, 118 and for poor survivors were 46% and 52%, respectively. Attempts to improve the outcome of poor responders through modifying the regimen remain unsuccessful. 105

The safety and efficacy of HDT/SCR in patients with newly diagnosed metastatic osteosarcoma or relapsed osteosarcoma has also been evaluated. 120 , 121 In the Italian sarcoma group study, treatment with carboplatin and etoposide followed by SCR, combined with surgery, induced complete response in chemosensitive patients. 121 Transplant-related mortality was 3.1%. The 3-year overall and disease-free survival rates were 20% and 12%, respectively. The efficacy of this approach in high-risk patients remains to be determined in prospective randomized studies.

NCCN Recommendations: Wide excision is the primary treatment for patients with low-grade (intramedullary and surface) osteosarcomas, whereas preoperative chemotherapy is preferred for those with high-grade osteosarcoma (category 1) and periosteal lesions, before wide excision. Selected elderly patients may benefit from immediate surgery (see page 694).

After wide excision (for resectable lesions), postoperative chemotherapy is recommended for patients with low-grade or periosteal sarcomas with pathologic findings of high-grade disease. For high-grade osteosarcoma after wide excision, patients with a good histologic response should continue to undergo several more cycles of the same chemotherapy, whereas patients with a poor response should be considered for chemotherapy with a different regimen. RT followed by adjuvant chemotherapy is recommended if the sarcoma remains unresectable after preoperative chemotherapy (see page 694).

Chemotherapy can be given intra-arterially or intravenously 122 , 123 and should include appropriate growth factor support (see the NCCN Myeloid Growth Factors Guidelines for growth factor support [to view the most recent version of these guidelines, visit the NCCN Web site at www.nccn.org ]). The NCCN Bone Cancer Guidelines have included the following regimens for first-line therapy (primary/neoadjuvant/adjuvant) in patients with localized disease or primary therapy for metastatic disease (see page 697):

Cisplatin and doxorubicin

MAP (high-dose methotrexate, cisplatin, and doxorubicin)

Doxorubicin, cisplatin, ifosfamide, and high-dose methotrexate

Ifosfamide, cisplatin, and epirubicin

Once treatment is completed, surveillance should occur every 3 months for 2 years, then every 4 months for year 3, and then every 6 months for years 4 and 5, and yearly thereafter. Examination should include a complete physical, chest imaging, and plain film of the extremity. Chest CT should be performed if the plain chest radiograph becomes abnormal. Bone scan (category 2B) may also be considered (see page 695). Functional reassessment should be performed at every visit.

• Treatment for Relapsed or Refractory Disease

Approximately 30% of patients with localized disease and 80% presenting with metastatic disease will experience relapse. The presence of solitary metastases and complete resectability of the disease at first recurrence have been reported to be the most important prognostic indicators for improved survival, whereas patients not amenable to surgery and those with a second or third recurrence have a poor prognosis. 124 , 125

The combination of etoposide with cyclophosphamide or ifosfamide has been evaluated in clinical trials. 126 , 127 In a phase II trial of the French Society of Pediatric Oncology, ifosfamide and etoposide resulted in a response rate of 48% in patients with relapsed or refractory osteosarcoma. 127 In another phase II trial, cyclophosphamide and etoposide resulted in a 19% response rate and stable disease in 35% of patients with relapsed high-risk osteosarcoma. 126 Progression-free survival at 4 months was 42%. Single-agent gemcitabine and combination regimens such as docetaxel and gemcitabine; cyclophosphamide and topotecan; and ifosfamide, carboplatin, and etoposide have been effective in the treatment of patients with relapsed or refractory bone sarcomas. 83 , 84 , 88 , 128

Samarium-153 ethylene diamine tetramethylene phosphonate ( 153 Sm-EDTMP), a bone-seeking radiopharmaceutical, has been evaluated in patients with locally recurrent or metastatic osteosarcoma or skeletal metastases. 129 , 130 Andersen et al. 129 reported that 153 Sm-EDTMP with peripheral blood progenitor cell support had low nonhematologic toxicity and provided pain palliation for patients with osteosarcoma local recurrences or osteoblastic bone metastases. Results of a recent dose-finding study also show that 153 Sm-EDTMP can be effective in the treatment of patients with high-risk osteosarcoma. 130

NCCN Recommendations: The optimal treatment strategy for patients with relapsed or metastatic disease has yet to be defined. If relapse occurs, patients should undergo second-line chemotherapy and/or surgical resection (see page 695). Surveillance is recommended for those who respond to second-line therapy. The NCCN Bone Cancer Guidelines include the following regimens as options for patients with relapsed or refractory disease (see page 697):

Cyclophosphamide and etoposide

Gemcitabine

High-dose methotrexate, etoposide, and ifosfamide

Patients who experience progressive disease after second-line therapy should be treated with resection, RT for palliation, or best supportive care (see page 695). Participation in a clinical trial should be strongly encouraged. The guidelines also include 153 Sm-EDTMP as a treatment option for relapsed disease after second-line therapy.

Primary bone cancers are rare neoplasms, with osteosarcoma, chondrosarcoma, and Ewing's sarcoma the 3 most common forms.

Chondrosarcoma is usually found in middle-aged and older adults. Wide excision is the preferred treatment for resectable low- and high-grade chondrosarcomas. Intralesional excision with or without adjuvant therapy is an alternative option for low-grade lesions. In small series of reports, the addition of chemotherapy improved outcomes in patients with mesenchymal chondrosarcomas. However, the role of chemotherapy in the treatment of chondrosarcomas is not yet defined.

Ewing's sarcoma is characterized by a chromosomal translocation t(11;22), resulting in the fusion of EWS gene with various members of the ETS family of genes, and develops mainly in children and young adults. Multiagent chemotherapy is the primary treatment for patients with Ewing's sarcoma. Patients who experience response to primary treatment are treated with local control therapy (surgery or radiation) followed by adjuvant chemotherapy. Progressive disease is best managed with RT with or without surgery followed by chemotherapy or best supportive care.

Osteosarcoma occurs mainly in children and young adults. Wide excision is the primary treatment for patients with low-grade osteosarcomas, whereas preoperative chemotherapy is preferred before wide excision for high-grade osteosarcoma and periosteal lesions. After wide excision (for resectable lesions), postoperative chemotherapy is recommended for patients with low-grade or periosteal sarcomas with pathologic findings of high-grade disease and those with high-grade sarcoma. RT followed by adjuvant chemotherapy is recommended if the sarcoma remains unresectable after preoperative chemotherapy. Patients with relapsed or refractory disease should be treated with second-line therapy. Participation in a clinical trial should be strongly encouraged for patients experiencing progressive disease after second-line therapy.

The development of multiagent chemotherapy regimens for neoadjuvant and adjuvant treatment has considerably improved the prognosis for patients with osteosarcoma and Ewing's sarcoma. A small subset of patients diagnosed with metastatic disease at presentation can be cured with the proper treatment. Consistent with the NCCN philosophy, the panel encourages patients to participate in well-designed clinical trials to enable further advances.

Individual Disclosure for the NCCN Bone Cancer Panel

Please Note

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representation or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their applications or use in any way.

© National Comprehensive Cancer Network, Inc. 2010, All rights reserved. These guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

Disclosures for the NCCN Bone Cancer Guidelines Panel

At the beginning of each NCCN Guidelines panel meeting, panel members disclosed any financial support they have received from industry. Through 2008, this information was published in an aggregate statement in JNCCN and online. Furthering NCCN's commitment to public transparency, this disclosure process has now been expanded by listing all potential conflicts of interest respective to each individual expert panel member.

Individual disclosures for the NCCN Bone Cancer Guidelines Panel members can be found on page 712. (The most recent version of these guidelines and accompanying disclosures, including levels of compensation, are available on the NCCN Web site at www.NCCN.org .)

These guidelines are also available on the Internet. For the latest update, please visit www.NCCN.org .

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Recent Advancements in Feature Extraction and Classification Based Bone Cancer Detection

19 Pages Posted: 11 Jan 2024

S Kanimozhi

Vellore Institute of Technology (VIT)

Sivakumar R

Ananthakrishna chintanpalli.

Cancer is a deadly disease that occurs due to the over growth of the abnormal cells. Bone cancer is the third most occurring disease; approximately 10,000 patients suffers from bone cancer in India annually. It can lead to death if not diagnosed in the earlier stage. The bone cancer occurs in four stages as follows: in stage 1 cancer does not spread to other bone parts, in stage 2 cancer looks similar to stage 1 but it becomes dangerous, in stage 3 cancer spreads to one or two bone parts and in stage 4 cancer spreads to other body parts. Timely diagnosis of bone cancer is challenging due to the unspecific indications that are similar to common musculoskeletal injuries, late visit of patient to the hospital and low intuition by the physician. The texture of diseased bone differs from the healthy bone. Mostly in dataset, the healthy and cancerous bone image have similar characteristics. Therefore, development of automated system is necessary to classify the normal and abnormal scan images. The objective of this paper is to identify the studies on classification techniques in detecting bone cancer with five criteria: feature extraction methods, machine learning (ML) and deep learning (DL) techniques, advantages, disadvantages and classifier accuracy. The current study performed the systematic literature review of 108 studies selected based on the use of different feature extractions to extract the textural characteristics of the images that are fed into the ML and DL algorithms to classify the normal and subtypes of bone cancer images for better analysis. The result showed that convolutional neural network classifier along with different textural feature extraction techniques like gray level co-occurrence matrix (GLCM) and local binary pattern (LBP) detected the bone cancer with high median accuracy of 94% compared to DL classification without feature extraction techniques in diagnosing the bone cancer using radiopeadia MRI dataset. In this respect, this paper proposes the systematic review on types of bone cancer and recent advancement in feature extraction methods and classification involving deep learning and machine learning models to detect the bone cancer with higher accuracy rate.

Note: Funding Declaration: This work was supported by the third author’s Seed Grant (SG20220094) awarded by the Vellore Institute of Technology. Conflicts of Interest: None.

Keywords: Bone Cancer, Machine learning, Deep Learning, Gra level Co-occurance Matrix, Magnetic Resonance Imaging

Suggested Citation: Suggested Citation

Vellore Institute of Technology (VIT) ( email )

Chennai 600127 Tamil Nadu IN India

Sivakumar R (Contact Author)

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JSmol Viewer

Systematic review of tumor segmentation strategies for bone metastases.

Simple Summary

1. introduction, 2.1. literature search.

• “bone metastasis segmentation”.

2.2. Data Extraction

• Enrollment period of the patients;
• Study type: retrospective cohort study or prospective;
• Study population. Extracted the number of scans or images when patient numbers were not provided;
• Training/Validation/testing cohorts;
• Primary tumor and relevant location;
• Imaging modality;
• Methodology;
• Evaluation Metrics;
• Details of whether the study mentioned the suitability of the approaches for clinical use;
• Country of the Authors.

4. Discussion

4.1. deep learning, 4.2. thresholding, 4.3. clustering/classification, 4.4. statistical methods, 4.5. atlas-based approaches, 4.6. region-based approaches, 5. conclusions, supplementary materials, author contributions, conflicts of interest.

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Share and Cite

Paranavithana, I.R.; Stirling, D.; Ros, M.; Field, M. Systematic Review of Tumor Segmentation Strategies for Bone Metastases. Cancers 2023 , 15 , 1750. https://doi.org/10.3390/cancers15061750

Paranavithana IR, Stirling D, Ros M, Field M. Systematic Review of Tumor Segmentation Strategies for Bone Metastases. Cancers . 2023; 15(6):1750. https://doi.org/10.3390/cancers15061750

Paranavithana, Iromi R., David Stirling, Montserrat Ros, and Matthew Field. 2023. "Systematic Review of Tumor Segmentation Strategies for Bone Metastases" Cancers 15, no. 6: 1750. https://doi.org/10.3390/cancers15061750

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StatPearls [Internet].

Primary bone cancer.

Jack E. Pullan ; Saran Lotfollahzadeh .

Affiliations

Last Update: March 20, 2024 .

• Continuing Education Activity

Primary bone cancer emerges as an uncommon malignant tumor originating from primitive mesenchymal cells within the bone. With distinctive subtypes such as osteosarcoma, chondrosarcoma, and Ewing sarcoma, each presents unique demographics, imaging traits, and biological attributes. Surgical excision, complemented by chemotherapy and radiotherapy, constitutes the primary treatment approach, demanding a nuanced understanding from clinicians for accurate diagnosis and informed treatment strategies.

In this activity, participants explore primary bone cancer assessment and treatment, emphasizing the interprofessional team's indispensable role. Comprising experts from radiology, histopathology, oncology, and orthopedics, this team collaborates to devise a comprehensive care plan. Additionally, the holistic team includes physiotherapists, occupational therapists, prosthetists, dieticians, social workers, and counselors, offering comprehensive support throughout the patient's journey. Through collaborative efforts, clinicians enhance their competence in managing primary bone cancer, ensuring optimal patient outcomes and quality of care.

• Differentiate primary bone cancer from other musculoskeletal conditions and secondary bone cancers.
• Assess the pertinence of laboratory tests and imaging modalities when diagnosing primary bone cancer.
• Determine the appropriate management of primary bone cancer in a stepwise treatment plan.
• Implement care coordination within an interprofessional team to manage patients with primary bone cancer.
• Introduction

Primary bone cancer is a rare malignant tumor of the bone originating from primitive mesenchymal cells. This condition accounts for around 0.2% of all malignancies worldwide and is idiopathic in most cases. Multiple subtypes are prevalent, with osteosarcoma, chondrosarcoma, and Ewing sarcoma being the most common. Each varies in demographics, imaging appearance, and biological behavior. They are frequently aggressive and require early diagnosis, utilizing imaging and tissue biopsy. Surgical excision remains the mainstay of curative treatment, with chemotherapy and radiotherapy used in conjunction. [1]

Though primary bone cancer is most often idiopathic, risk factors also play a role in developing this cancer.

• Genetic factors are linked. Germline abnormalities in hereditary cancer predisposition syndromes have an increased risk of later developing bone cancer through the downregulation of tumor suppressor genes or upregulation of oncogenes. The TP53 tumor suppressor gene is often altered in Li-Fraumeni syndrome, putting patients at an increased risk of developing osteosarcoma. Similarly, a mutation in the Rb1 gene leading to hereditary retinoblastoma is linked to osteosarcoma. Werner and Rothmund-Thomson syndromes are also linked to an increased risk of developing osteosarcoma.
• Previous treatment for cancer with radiotherapy is linked to an increased risk of developing primary bone cancer in later life, particularly when exposed to ionizing radiation in childhood.
• Several benign conditions show the potential to progress to primary bone cancer. Paget disease of the bone is a condition characterized by a disorder of bone metabolism, particularly osteoclastic function. These patients are at an increased risk of developing osteosarcoma; however, it is a rare complication. Enchondromas and osteochondromas are benign cartilaginous neoplasms that can later develop into malignant chondrosarcoma. [2] [3] [4] [5]
• Epidemiology

Primary bone cancer remains uncommon, accounting for 0.2% of all malignancies and 5% of childhood malignancies. In the United States, an estimated 3600 new cases of primary bone cancer were diagnosed in 2020, with 1720 deaths, making up 0.3% of all cancer deaths. The National Cancer Institute data shows that chondrosarcoma (40%) is most prevalent in adults, followed by osteosarcoma (28%). In children and adolescents, osteosarcoma (56%) is the most common, with Ewing sarcoma (34%) second. Chordoma, undifferentiated pleomorphic sarcoma, adamantinoma, fibrosarcoma, and giant cell tumor of the bone are also types of primary bone cancer; however, they are fewer in number. Primary bone cancer has a male predominance, with a worldwide osteosarcoma male-to-female ratio of 1.43 to 1. [6] [7]

• Pathophysiology

Primary bone cancer is a malignant tumor of the connective tissue with mesenchymal origin. The World Health Organisation determined 6 categories: chondrogenic, osteogenic, notochordal, vascular, other malignant mesenchymal, and miscellaneous (including Ewing sarcoma). The pathophysiology varies considerably between groups and, in some cases, is poorly understood. [6]

Osteosarcoma is a highly malignant osteogenic tumor that can develop in any bone. The tumor tends to develop near the metaphysis of long bones in young patients. The most common sites are the distal femur, proximal tibia, and proximal humerus, with high bone turnover. In adults, the axial skeleton is more common, where previous irradiation or metabolic disease of the bone is often associated. Common genetic changes are not present to explain the growth of this tumor type; however, 70% of cases demonstrate some level of chromosomal abnormality. Alterations in p53, Rb1, and deoxyribonucleic acid repair/surveillance genes are present in patients with Li-Fraumeni, Bloom, and Rothmund-Thomson syndrome, all linked to increased rates of osteosarcoma. [8] [9] [10]

Chondrosarcoma is primarily a disease of adults, most frequently diagnosed in patients between 30 and 60. They are generally slow-growing chondrogenic tumors of intermediate malignancy, rarely metastasizing. Chondrosarcoma arising de novo are classified as primary (>85% of cases), with those arising from pre-existing benign osteochondromas or enchondromas as secondary. The most common site for diagnosis is the long bones of the appendicular skeleton. Flat bones, including the pelvis, ribs, and scapula, can also be affected. The exact pathogenesis of chondrosarcoma is unknown, though multiple genes are implicated. Cytogenic studies have identified structural and numerical chromosomal abnormalities. Gene mutations in  EXT1/2,   TP53 ,  Rb1 , and  IDH1/2  have also been linked to malignant transformation in benign lesions. [5] [11]

Ewing sarcoma is an aggressive tumor of childhood and adolescence, most commonly occurring in the bone but also seen in soft tissues. The peak incidence is at 15 years, and the men-to-women ratio is 5:1. The most frequent sites involved are long bones in the lower limb, pelvic bones, and the axial skeleton (ribs and vertebral column). Ewing sarcoma develops characteristically at the diaphysis, in contrast to the pattern seen in osteosarcoma. Ewing sarcoma is genetically well described, with characteristic chromosomal translocations identified. The translocation leads to fusing an FET protein to an ETS transcription factor, most commonly  FLI1  (>85% of cases). The result is the formation of fusion proteins that deregulate downstream genes, altering cell behavior. [12] [13] [14]

• Histopathology

Diagnosis of primary bone cancer requires a tissue biopsy to perform histopathological assessment, with significant heterogeneity seen.

Osteosarcoma

The formation of bone or osteoid characterizes osteosarcoma, and this identification is key to diagnosis. Several histological subtypes have been identified, determined by the tumor's bone location and grade. [15] [8]

Intramedullary:

• Conventional
• Most prevalent subtype, comprising 80% of all osteosarcomas
• Classically high-grade, arising from the intramedullary canal
• Spindle to polyhedral cell shape malignant mesenchymal cells are seen
• Cell nuclei are pleomorphic with occasional mitotic figures
• Extracellular matrix production can be osteoblastic, osteoclastic, or fibroblastic; a combination is common
• Telangiectatic
•   <4% of osteosarcomas
•  Dilated hemorrhagic sinusoids seen with small amounts of osteoid 
• Cavities mimic the appearance of an aneurysmal bone cyst, with the presence of high-grade sarcoma cells distinguishing the tumor
• <2% of osteosarcomas
• Well-differentiated cells embedded in the osseous matrix and fibrous stroma, with small amounts of osteoid
• 1.5% of osteosarcomas
• Numerous small round malignant cells seen within an osteoid matrix. 
• Small cell sarcoma can resemble Ewing sarcoma; production of osteoid and sporadic spindling of cells are distinguishing features  [15] [8]
• Parosteal 
• 1% to 6% of osteosarcomas
• Slow growing, arising from the outer surface of the metaphysis 
• Low-grade, with a well-differentiated, mostly cartilaginous matrix with minimal osteoid
• 1% to 2% of osteosarcomas 
• More aggressive than parosteal osteosarcoma, with intermediate-grade tumors showing increased cell atypia 
• Mostly cartilaginous matrix with minimal osteoid
•   <1% of osteosarcomas 
• Histologically similar to conventional osteosarcoma, showing high-grade spindle-shaped cells with nuclear pleomorphism  [15] [8]

Chondrosarcoma

The production of hyaline cartilage characterizes chondrosarcomas to form a cartilaginous matrix. Lobules of cartilage are seen with significant variation in dimension. Cell nuclei show pleomorphism with chondrocytes varying in size and shape. Conventional chondrosarcoma accounts for over 85% of all chondrosarcomas. Chondrosarcoma can be subcategorized into primary central (developing within the medullary canal) or secondary peripheral (developing from the surface of the bone secondary to pre-existing enchondroma or osteochondroma). Histologically, both primary central and secondary peripheral are alike. Grading is an essential process that allows for the prediction of clinical behavior. [5] [16] [17]

• Grade I:  These are low-grade, lowly cellular lesions with a predominantly cartilaginous matrix and small, dense nuclei. Distinguishing grade I chondrosarcoma and benign enchondroma can be difficult, both radiologically and histologically.
• Grade II:  This shows a reduced cartilaginous matrix and moderately cellular. Nuclei are enlarged and hyperchromatic, with increased atypia. Mitoses may be seen.
• Grade III:  These are high-grade lesions that are highly cellular, with increased cellular atypia showing vesicular and enlarged nuclei. Cartilaginous matrix is rare or absent, with myxoid material evident, and mitoses are more readily identified.

Several rare subtypes of chondrosarcoma are also identified. De-differentiated chondrosarcoma is characterized by low-grade chondrosarcoma next to a de-differentiated high-grade lesion, with a sharp transition between the 2. The tumor is extremely aggressive. Mesenchymal chondrosarcoma is a high-grade tumor occurring in either bone or soft tissue. Undifferentiated small round cells are seen with varying amounts of a cartilaginous matrix. Clear cell chondrosarcoma is a low-grade tumor, with cells showing clear, vacuolated cytoplasm. Areas of hemorrhage and cyst formation are seen. [5]

Ewing Sarcoma

Ewing sarcoma is a high-grade aggressive sarcoma and belongs to the group of small round-cell tumors. Monomorphic small cells are seen in sheets, with round nuclei, finely dispersed chromatin, and nucleoli usually unidentifiable. Frequently, necrosis is seen, with remaining viable cells arranged perivascularly. Cell membranes express the glycoprotein CD99, with immunohistochemistry showing that >95% of Ewing sarcomas have extensive membranous expression. CD99 expression is not specific to Ewing sarcoma; other markers are also used for diagnosis. [18] [14]

Other Types of Primary Bone Cancer

Chordoma, adamantinoma, and giant cell tumors of bone are typically low-grade locally invasive tumors. Undifferentiated pleomorphic sarcoma and fibrosarcoma are aggressive malignant tumors with a generally poor prognosis. [19] [20]

• History and Physical

Primary bone cancer is a rare diagnosis, with primary care clinicians unlikely to encounter a single case. Early diagnosis improves overall survival; however, delays remain common. History and examination form the first steps in diagnosing primary bone cancer, and an urgent referral to a specialist center is needed for all patients with a possible diagnosis. [12] [6]

Pain is the most common symptom, described as deep-seated dull pain progressing over time, refractory to simple analgesia. Pain can be troublesome at night, which is always a red flag. A mass may be palpable with localized tenderness. Patients may exhibit signs of systemic disease, including lethargy, malaise, and fever; however, in high-grade tumors, these are often not present and may suggest metastatic disease. A pathological fracture can be the first sign; any abnormal fracture requires further investigation. History of predisposing genetic conditions (eg, Li-Fraumeni syndrome, hereditary retinoblastoma, Werner syndrome, and Rothmund-Thomson syndrome) or diseases (Paget disease) is crucial. [6]  Physical examination should focus on pain, tenderness, or mass. The site should be inspected and palpated, with size, consistency, mobility, location of the mass, and overlying skin changes noted. Lymph nodes should be palpated. [21]

Diagnostic modalities used in primary bone cancer include imaging, laboratory blood tests, and tissue biopsy.

Plain Film Radiograph

All patients should have orthogonal plain film radiographs when identifying potential bone cancer. Plain x-rays may show the following findings:

• Osteolytic, osteoblastic, or mixed changes
• A moth-eaten appearance (suggests bone destruction secondary to a rapidly expanding tumor within a bone, commonly seen in Ewing sarcoma and telangiectatic osteosarcoma)
• A permeative appearance (suggests the tumor progresses through bone, with an ill-defined zone between the tumor and healthy bone, often seen in small cell tumors, including Ewing sarcoma)
• "Onion skinning," with the tumor lifting partially-formed periosteal bone (classically seen in Ewing sarcoma)
• "Codman triangle," with periosteum lifted off bone and osteoid laid down
• "Sunburst" appearance, with vertical osteoid calcification due to significant periostitis  [22]

Magnetic Resonance Imaging 

A magnetic resonance imaging, MRI, scan remains the gold standard for assessing local tumor extent. The whole anatomical compartment should be imaged, and the MRI should be sensitive for bone and soft tissue lesions. Biopsy planning is crucial, and MRI allows the definition of neurovascular structures. Modern techniques, including dynamic MRI, better characterize high-grade tumor areas and have been used to assess tumor response to chemotherapy. [6] [23]

Computed Tomography 

A computed tomography, CT, scan is used when the diagnosis remains unclear following an MRI or if an MRI is contraindicated. CT remains the modality of choice in pelvic bone cancer and reconstructive surgery. Patients with confirmed primary bone cancer require staging, and although many centers still perform chest radiographs, a chest CT scan is the gold standard for assessing metastatic pulmonary disease. [6]

Whole-Body Bone Scintigraphy 

A whole-body bone scintigraphy bone scan is a nuclear medicine study that utilizes technetium-99m as an active agent, highlighting areas of osteoblastic activity. It allows the detection of malignancy and is useful in diagnosing metastatic disease.

Positron Emission Tomography 

The positron emission tomography, PET, scan is a nuclear medicine study that utilizes the high metabolic rate of tumor cells, measuring the uptake of injected radiolabeled F-18 fluoro-deoxy-glucose. A PET scan is in some centers for the initial staging of primary bone cancer, and studies have suggested it as a modality for follow-up when used in combination with a CT scan. [24]

Laboratory Blood Tests

Specific laboratory blood tests are not used in diagnosing primary bone cancer; however, they form part of the patient workup. In patients treated with chemotherapy, baseline urea, creatinine, and liver function tests allow baseline renal and hepatic function assessment. Biochemical markers alkaline phosphatase and lactate dehydrogenase offer some predictive value, and levels can be monitored in follow-up to assess for disease recurrence. [22]

Tissue Biopsy

A lesion biopsy is needed for definitive diagnosis, allowing for histopathological assessment and tumor grading. Biopsy should be performed with the operating surgical team, ideally in a specialist bone cancer center. The procedure requires meticulous planning, with suboptimal biopsy impacting definitive surgical treatment options. Imaging should be performed before a biopsy, aiding in approach planning and preventing tissue disruption that could make radiological assessment more difficult. Percutaneous, incisional, or excisional techniques are used. Ultrasound, x-ray, and CT scans allow precise guidance. The tract should be well marked, allowing for excision during surgery, and a specialist bone cancer pathologist should assess samples. Specific markers on immunohistochemistry staining would assist in the diagnosis. Greater than 95% of Ewing sarcomas show extensive membranous expression of CD99; this is not specific to Ewing sarcoma, so other markers are also used in the immunohistochemistry panel. [21]

• Treatment / Management

Managing primary bone cancer requires a multidisciplinary approach by a specialist bone cancer center, including staff trained in providing age-appropriate care to children or adolescents. Management depends on several factors, including tumor type, stage and grade, and patient preference. Surgical excision remains the cornerstone of primary bone cancer treatment. Neoadjuvant and adjuvant chemotherapy are also commonplace in the management, with radiotherapy used in specific cases.

Surgical resection aims to remove all tumor tissue with adequate margins while preserving as much limb function as possible. A decision for either limb salvage surgery or amputation is established using imaging, histopathology, response to adjuvant treatment, and patient wishes. Surgery often leads to significant tissue loss, and open discussion with the patient is vital. The surgery's potential risks, benefits, and expected long-term functional impact must be highlighted. Low-grade tumors amenable to surgical excision typically require wide excision (removing the involved part of the bone with a cuff of healthy tissue), with high-grade tumors requiring radical excision (removing the affected bone and associated soft tissues within the anatomical compartment). [6] [25]

Chemotherapy

Multiple chemotherapy agents and regimens are used to manage primary bone cancer. Often, this consists of induction (neoadjuvant) and postoperative combination therapy (adjuvant), with improvements in rates of limb salvage surgery and overall survival since their introduction. Chemotherapy forms part of the standard treatment protocol for osteosarcoma and Ewing sarcoma. Chondrosarcoma is still primarily managed surgically, except in cases of mesenchymal chondrosarcoma, where chemotherapy and radiotherapy are often used. [26] [27]

Neoadjuvant chemotherapy is primarily used to reduce the rate of future metastatic spread; however, study results have suggested it can also contribute to primary tumor control. A good response to neoadjuvant therapy is determined by a histological necrosis rate of less than 90%, with a poor response indicating a change in postoperative adjuvant chemotherapy agents and poorer outcomes. [28] [29] [30]

Radiotherapy

Radiotherapy is often used as adjunctive therapy in primary bone cancer. Ewing sarcoma is a radiosensitive tumor, with radiotherapy commonly used as part of the definitive treatment plan. Preoperative radiotherapy is used if the response to neoadjuvant chemotherapy is poor or the tumor is positioned in a problematic anatomical location, where reduction of tumor volume will aid surgical resection. If sufficient tumor volume cannot be removed surgically or it would be unacceptably disabling, radiotherapy is used for local treatment. Where adequate margins have not been resected, postoperative radiotherapy is utilized. Chondrosarcomas are relatively radioresistant, with radiotherapy only utilized for surgically unresectable or incompletely resected tumors. Radiotherapy has a palliative role in all primary bone cancers and is used to slow tumor growth locally and relieve pain. [6] [31] [32]

• Differential Diagnosis

The differential diagnosis of primary bone cancer includes the following:

Malignant Types of Tumors

• Multiple myeloma

Benign Types of Tumors

• Giant cell tumor
• Osteoblastoma
• Enchondroma
• Chondromyxoid fibroma
• Cortical desmoid
• Osteomyelitis
• Fracture callus
• Aneurysmal bone cyst
• Fibrous dysplasia  [33]

Two staging systems, the TNM and Enneking systems, are used in primary bone cancer.

TNM System, American Joint Committee on Cancer 

This refers to the extent of tumor (T), spread to local lymph nodes (N), metastatic spread (M), and histological grade (G). [34]

Stage IA (T1 N0 M0 G1/GX)

•   ≤8cm in size, with no lymph node or metastatic spread

Stage IB (T2 N0 M0 G1/GX, or T3 N0 M0 G1/GX)

• >8cm in size (T2), with no lymph node or metastatic spread; low grade
• Cancer at more than 1 location in the same bone (T3), with no lymph node or metastatic spread; low grade

Stage IIA (T1 N0 M0 G2/G3)

• ≤8cm in size, with no lymph node or metastatic spread; high grade

Stage IIB (T2 N0 M0 G2/G3)

• >8cm in size, with no lymph node or metastatic spread; high grade

Stage III (T3 N0 M0 G2/G3)

• Cancer at more than 1 location in the same bone, with no lymph node or metastatic spread; high grade

Stage IVA (Any T N0 M1a Any G)

• Any size and maybe in multiple locations in the same bone, with no lymph node involvement. 
• Metastatic spread to the lungs (M1a); any grade

Stage IVB (Any T, N1, Any M, Any G, or Any T, Any N, M1b, Any G)

• Any size; may be in more than 1 location in the same bone 
• Has spread to local lymph nodes (N1)
• May or may not have metastasized to distant organs; any grade
• Any size and maybe in more than 1 location in the same bone. 
• May or may not have spread to local lymph nodes 
• Metastatic spreads to distant sites like other bones, liver, or brain (M1b); any grade

Enneking System

Refers to the histological grade (G), the extent of the tumor to the anatomical compartments of the body (T), and metastatic spread (M). [35]

Stage IA (G1 T1 M0)

• Low grade, intra-compartmental, no metastasis

Stage IB (G1 T2 M0)

• Low grade, extra compartmental, no metastasis

Stage IIA (G2 T1 M0)

• High grade, intra-compartmental, no metastasis

Stage IIB (G2 T2 M0)

• High grade, extra compartmental, no metastasis

Stage III (Any G, Any T, M1)

• Any grade, any location, regional, or distant metastatic spread

The prognosis of primary bone cancer is dependent on multiple factors, and no significant improvement is seen in 5-year survival over the past 25 years. In the United States, the National Cancer Institute shows that the overall 5-year survival rate is 66%, with studies suggesting lower rates in the United Kingdom. [12]

When the disease is localized, osteosarcoma has a 10-year survival of 60% to 78%. This number falls to 20% to 30% in patients with metastatic disease at presentation, with other negative prognostic factors including axial or proximal extremity tumor location, increased tumor size, raised alkaline phosphatase or lactase dehydrogenase, increased age, pathological fracture, and poor response to neoadjuvant chemotherapy. [36] [37] [38]

The most potent prognostic factor in chondrosarcoma is histological grade. Other identified factors are metastatic disease at presentation, increased age, and pelvic tumor location. 5-year survival in grade I chondrosarcoma is 83%, with only 53% of patients surviving to 5 years with grade I and II diseases. [5] [39] [40]  Ewing sarcoma has a 5-year survival of 70% to 80% when the disease is localized. This number falls to 50% in patients with isolated pulmonary metastases and less than 30% in patients with any other metastatic disease at diagnosis. Other negative prognostic factors include pelvic tumor location, increased tumor size, and poor response to neoadjuvant or adjuvant chemotherapy treatment. [14] [41]

• Complications

The complications of primary bone cancer include the following:

Tumor-Related Complications

• Pathological fracture
• Tumor recurrence
• Distant metastasis  [42] [27]

Treatment-Related Complications

• Surgical site or periprosthetic infection
• Implant failure
• Non-union/fracture of the biological implant
• Short-term side effects include malaise, anemia, nausea, vomiting, and alopecia
• Long-term side effects include cardiotoxicity, renal toxicity, hearing loss, and an increased risk of secondary malignancy
• Side effects following radiation therapy are site-dependent, affecting the skin, pelvic organs, gastrointestinal tract, and lungs
• Long-term, a small increased risk of developing a secondary malignancy exists  [43] [44] [45]
• Pearls and Other Issues

The key points are as follows:

• Primary bone cancer is a rare malignancy derived from primitive mesenchymal cells.
• All patients presenting with unresolved bone pain should be assessed, and orthogonal plain film radiographs should be organized.
• MRI is the gold standard for assessing the extent of a local tumor.
• A multidisciplinary team should manage primary bone cancer in a specialized bone cancer center.
• Surgical excision remains the mainstay of treatment for primary bone cancer, with chemotherapy and radiotherapy often used as adjuncts.
• Enhancing Healthcare Team Outcomes

Primary bone cancer should be managed by a multidisciplinary team. The team should include clinicians from radiology, histopathology, oncology, and orthopedics. Radiologists and pathologists interpret initial imaging and tissue samples, indicating a definitive diagnosis and leading to surgical planning.

Oncologists determine the most appropriate neoadjuvant and adjuvant chemotherapy protocols and arrange follow-up and surveillance. Orthopedics plan and perform surgical resection of the tumor, along with any initial or future reconstruction. Other team members include nurses, physiotherapists, occupational therapists, prosthetists, dieticians, social workers, and counselors. [46] [47]

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Disclosure: Jack Pullan declares no relevant financial relationships with ineligible companies.

Disclosure: Saran Lotfollahzadeh declares no relevant financial relationships with ineligible companies.

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Bone Cancer Detection Using Deep Learning

• Conference paper
• First Online: 04 May 2023
• Cite this conference paper

• Mansoor Habib Mazumder 13 &
• Maheshwari Prasad Singh 13  

Part of the book series: Lecture Notes in Networks and Systems ((LNNS,volume 565))

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• International Conference on Innovations in Computer Science and Engineering

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There have been many registered cases of bone cancer or tumor across the world with fatal cases involving in deaths too due to bone cancer. Thus, detecting them at the early stages becomes necessary which can save many lives. In today’s world, tumor is detected using MRI scans, and the process involved is costly and tedious. In the era of machine learning and artificial intelligence, detecting the tumors is still a tedious process, and it is very costly for setting up to train networks. There are various segmentation techniques, and convolutional neural networks can be used using X-ray images to detect the tumors at the early stages. If the tumor is detected and classified at the correct time, then without any hesitance, further complication can be prevented with right medications given at the required time. In this paper, we presented a modified architecture using convolutional neural network and inception modules to classify the stages of the bone cancers. The proposed model is trained on a dataset provided by ‘Stanford ML’ group which is available publicly for research and achieved accuracy of 92.68% on the testing dataset.

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Mazumder, M.H., Singh, M.P. (2023). Bone Cancer Detection Using Deep Learning. In: Saini, H.S., Sayal, R., Govardhan, A., Buyya, R. (eds) Innovations in Computer Science and Engineering. ICICSE 2022. Lecture Notes in Networks and Systems, vol 565. Springer, Singapore. https://doi.org/10.1007/978-981-19-7455-7_21

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Bone Cancer Research

The protein ETV6 appears to promote tumor growth by affecting the behavior of the EWS-FLI1 fusion protein that drives most Ewing sarcomas. The research groups that made the discovery hope it leads to a targeted therapy for the aggressive childhood cancer.

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