Osteosarcoma overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].

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Overview

Bone cancer is a malignant (cancerous) tumor of the bone that destroys normal bone tissue. Osteosarcoma is the most common type of malignant bone cancer, accounting for 35% of primary bone malignancies. It is a malignant tumor that is characterized by the direct formation of bone or osteoid tissue by the tumor cells. Malignant tumors that begin in bone tissue are called primary bone cancer. Osteosarcoma may be classified according to the World Health Organization’s histologic classification of bone tumors into three groups. The osteosarcomas may be localized at the end of the long bones (commonly in the metaphysis). Most often it affects the upper end of the tibia, humerus, or lower end of the femur. On gross pathology, areas of bone formation, hemorrhage, fibrosis, and cystic degeneration on cut surface are characteristic findings of osteosarcoma. On microscopic histopathological analysis, presence of osteoid within the tumor, pleomorphic cells, anaplastic cells, and atypical mitoses are characteristic findings of osteosarcoma. There are no established causes for osteosarcoma. The common risk factors in the development of osteosarcoma are radiation to bones, alkylating antineoplastic agents, Paget disease, multiple hereditary osteochondromas, fibrous dysplasia, Bloom syndrome, Rothmund-Thomson syndrome, and Li-Fraumeni syndrome. Common complications of osteosarcoma include pathologic fracture and metastasis. The most common symptoms of osteosarcoma include bone pain that may be worse at night, swelling, and redness at the site of the tumor. On x-ray, osteosarcoma is characterized by medullary and cortical bone destruction, periosteal reaction, tumor matrix calcification, and soft tissue mass. On MRI, osteosarcoma is characterized by intermediate intensity of soft tissue and low signal intensity of ossified components on T1. High signal intensity of soft tissue and low signal intensity of ossified components on T2. The predominant therapy for osteosarcoma is neoadjuvant chemotherapy (chemotherapy given before surgery) followed by surgical resection. The most common drugs used to treat osteosarcoma are cisplatin, doxorubicin and high-dose methotrexate.

Historical perspective [1][1] [2][3][4][5]

Osteosarcoma is known as the most common bone malignant tumor. Osteosarcoma is an ancient disease and is not completely understood, yet. Nobody knows when and who discovered Osteosarcoma, but recent Paleontology discoveries revealed that Osteosarcoma has a long story in planet earth. Resent discoverers in Germany revealed a 240 million-year-old highly malignant tumor in the fossilized leg bone of a stem turtle[6]. Its been found that osteosarcoma is the earliest case of human cancer which was found on the 1.7 million-year-old fossil of an early ancestor of mankind in Swartkrans cave in South Africa. In 1990, a thousand-year-old mummy of a woman in her mid-30s of age had with a malignant tumor in her upper-left arm which that mass had grown so large that it might burst through her skin while she was still alive.

Classification[7]

Osteosarcoma (OS) is a rare bone cancer which affects both adolescents and young adults. Osteosarcoma was classified as primary and secondary. Later the the World Health Organization sub-typed as intramedullry/central and surface osteosarcoma with a number of sub-types under each group.

Pathophysiology[8][3][9][10][11]

Traditionally, our knowledge about osteosarcoma has been mostly anatomical but it should be noted that it arises most commonly in the metaphyseal region of long bones, within the medullary cavity, then it involves the bone cortex; consequently a pseudocapsule forms around the penetrating tumor. Osteosarcoma is characterised as a highly cellular tumor consisted of: pleomorphic spindle-shaped cells responsible for the producing an osteoid matrix. However, recent developments in the field of medical sciences and the molecular biology have provided huge insights regarding the molecular pathogenesis of osteosarcoma.

Causes[10][12][11]

There are no established causes for osteosarcoma. However, some studies show that an increased level of c-fos proto-oncogene expression can lead to osteosarcoma.

Differential Diagnosis[8][3][9][10][11]

Osteosarcoma must be differentiated from other diseases such as: any type of bone lesions caused by infection and/or tumors. Features such as the eccentric location of the tumor in the metaphyseal portion of the bone and the skeletal location help to distinguish osteosarcoma from Ewing sarcoma. Bone metastases from other primary tumours, less frequent in the young than in adult patients, should also be considered.

Epidemiology and Demographics[13][14][15][3]

Osteosarcoma is the most common nonhematologic primary malignant bone neoplasm causing 35% of primary bone malignancies and occurs at any age, it usually affects patients in the second and third decade of life with a peak incidence between 13 and 16 years of age. It is the 8th leading cancer in children under age 15, comprising 2.4% of all malignancies in pediatric patients and about 20% of all primary bone cancers. The overall incidence of osteosarcoma in U.S. population under 24 years of age are estimated at 0.44 cases for 100,000 individuals. Osteosarcoma is slightly more common in males than in females. Primary osteosarcoma typically occurs in young patients (10-20 years) with 75% occurring before the age of 20. Secondary osteosarcoma occurs in elderly patients.

Risk Factors[16][17][18][19]

Common risk factors in the development of osteosarcoma are radiation to bones, alkylating antineoplastic agents, Paget disease, multiple hereditary osteochondromas, fibrous dysplasia, Bloom syndrome,Rothmund-Thomson syndrome, and Li-Fraumeni syndrome.


Screening[20]

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for osteosarcoma.

Natural History, Complications and Prognosis[21][22][23][24][25][26]

Common complications of osteosarcoma include pathologic fracture and metastasis. Pre-treatment factors that influence outcome of the osteosarcoma are primary tumor site, size of the primary tumor, and site of metastasis. After administration of preoperative chemotherapy, factors that influence outcome of the osteosarcoma are adequacy of tumor resection and necrosis following induction or neoadjuvant chemotherapy. The 5 year survival rate of osteosarcoma after adequate therapy is approximately 60-80%.


Diagnosis

Staging[3][27][28][29][30]

According to the American Joint Committee on Cancer (AJCC), there are four stages of osteosarcoma based on the size of primary tumor, metastasis, involvement of lymph nodes, and grade of the tumor. For the purpose of treatment, there are only two stages of high-grade osteosarcoma: localized osteosarcoma and metastatic osteosarcoma.

History and Symptoms[3][28][31]

The most common symptoms of osteosarcoma include bone pain that may worse at night, swelling, and redness at the site of the tumor. The affected bone is not as strong as normal bones and may fracture with minor trauma (a pathological fracture).


Physical Examination[8][3][9][10][11]

Physical examination findings will depend on the location of the osteosarcoma. Common physical examination findings of osteosarcoma are localized swelling and tenderness at the site of the tumor.

Laboratory Findings[8][3][9][10][11]

Laboratory tests for osteosarcoma include complete blood count (CBC), serum alkaline phosphatase and lactate dehydrogenase.

Biopsy[3][9][10][11]

Biopsy of osteosarcoma is important for confirming the diagnosis and for determining the histologic subtype.[32] Biopsy may be performed percutaneously with either a fine-needle, or a wide-bore needle, or through a formal incision.

X Ray [33][34][35][36]

On x-ray, osteosarcoma is characterized by medullary and cortical bone destruction, periosteal reaction, tumor matrix calcification, and soft tissue mass.

CT [37][38][39][40][41]

CT scan in osteosarcoma may be helpful in biopsy and staging. CT scan adds little to plain radiography and MRI in direct assessment of the tumor.

MRI[42][43][44]

On MRI, osteosarcoma is characterized by intermediate intensity of soft tissue and low signal intensity of ossified components on T1. High signal intensity of soft tissue and low signal intensity of ossified components on T2. Considerable contrast enhancement of solid components on T1 contrast.

Other Imaging Findings[3][45][46][47]

Bone scan in osteosarcoma is used to observe abnormal areas of bone and metastasis.[48]

Other Diagnostic Studies[3][45][46][47]

Bone scan in osteosarcoma is used to observe abnormal areas of bone and metastasis.

Treatment

Medical Therapy[49][50][28][28][51][52][53][54][55]

The predominant therapy for osteosarcoma is neoadjuvant chemotherapy (chemotherapy given before surgery) followed by surgical resection. The most common drugs used to treat osteosarcoma are cisplatin, doxorubicin and high-dose methotrexate. Ifosfamide can be used as an adjuvant treatment if the necrosis rate is low. Samarium is a radioactive drug that targets areas where bone cells are growing, such as tumor cells in the bone. It helps relieve bone pain.

Surgery[56][57][58]

The mainstay of therapy for osteosarcoma is surgical resection. Rather than using the standard staging system, a simpler system is often used when planning treatment for osteosarcoma. This system divides osteosarcomas into 2 groups: localized osteosarcoma and metastatic osteosarcoma.

References

  1. ↑ 1.0 1.1 Bielack SS, Hecker-Nolting S, Blattmann C, Kager L (2016). "Advances in the management of osteosarcoma". F1000Res. 5: 2767. doi:10.12688/f1000research.9465.1. PMC 5130082. PMID 27990273.
  2. ↑ Jaffe N (2009). "Osteosarcoma: review of the past, impact on the future. The American experience". Cancer Treat. Res. 152: 239–62. doi:10.1007/978-1-4419-0284-9_12. PMID 20213394.
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 Moore DD, Luu HH (2014). "Osteosarcoma". Cancer Treat. Res. 162: 65–92. doi:10.1007/978-3-319-07323-1_4. PMID 25070231.
  4. ↑ Jaffe N, Puri A, Gelderblom H (2013). "Osteosarcoma: evolution of treatment paradigms". Sarcoma. 2013: 203531. doi:10.1155/2013/203531. PMC 3678494. PMID 23781130.
  5. ↑ Mirabello L, Troisi RJ, Savage SA (April 2009). "Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program". Cancer. 115 (7): 1531–43. doi:10.1002/cncr.24121. PMC 2813207. PMID 19197972.
  6. ↑ Haridy Y, Witzmann F, Asbach P, Schoch RR, Fröbisch N, Rothschild BM (February 2019). "Triassic Cancer-Osteosarcoma in a 240-Million-Year-Old Stem-Turtle". JAMA Oncol. doi:10.1001/jamaoncol.2018.6766. PMID 30730547.
  7. ↑ Duong LM, Richardson LC (2013). "Descriptive epidemiology of malignant primary osteosarcoma using population-based registries, United States, 1999-2008". J Registry Manag. 40 (2): 59–64. PMC 4476493. PMID 24002129.
  8. ↑ 8.0 8.1 8.2 8.3 Kim HJ, Chalmers PN, Morris CD (February 2010). "Pediatric osteogenic sarcoma". Curr. Opin. Pediatr. 22 (1): 61–6. doi:10.1097/MOP.0b013e328334581f. PMID 19915470.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 Ilaslan H, Schils J, Nageotte W, Lietman SA, Sundaram M (March 2010). "Clinical presentation and imaging of bone and soft-tissue sarcomas". Cleve Clin J Med. 77 Suppl 1: S2–7. doi:10.3949/ccjm.77.s1.01. PMID 20179183.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 Wu PK, Chen WM, Lee OK, Chen CF, Huang CK, Chen TH (November 2010). "The prognosis for patients with osteosarcoma who have received prior manipulative therapy". J Bone Joint Surg Br. 92 (11): 1580–5. doi:10.1302/0301-620X.92B11.24706. PMID 21037356.
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 Obiedat H, Alrabadi N, Sultan E, Al Shatti M, Zihlif M (July 2018). "The effect of ERCC1 and ERCC2 gene polymorphysims on response to cisplatin based therapy in osteosarcoma patients". BMC Med. Genet. 19 (1): 112. doi:10.1186/s12881-018-0627-4. PMC 6035436. PMID 29980176.
  12. ↑ Ma C, Han J, Dong D, Wang N (June 2018). "MicroRNA-152 Suppresses Human Osteosarcoma Cell Proliferation and Invasion by Targeting E2F Transcription Factor 3". Oncol. Res. 26 (5): 765–773. doi:10.3727/096504017X15021536183535. PMID 28810933.
  13. ↑ Foley JM, Scholten DJ, Monks NR, Cherba D, Monsma DJ, Davidson P, Dylewski D, Dykema K, Winn ME, Steensma MR (April 2015). "Anoikis-resistant subpopulations of human osteosarcoma display significant chemoresistance and are sensitive to targeted epigenetic therapies predicted by expression profiling". J Transl Med. 13: 110. doi:10.1186/s12967-015-0466-4. PMC 4419490. PMID 25889105.
  14. ↑ Huang X, Zhao J, Bai J, Shen H, Zhang B, Deng L, Sun C, Liu Y, Zhang J, Zheng J (June 2019). "Risk and clinicopathological features of osteosarcoma metastasis to the lung: A population-based study". J Bone Oncol. 16: 100230. doi:10.1016/j.jbo.2019.100230. PMC 6423404. PMID 30923668.
  15. ↑ Simpson S, Dunning MD, de Brot S, Grau-Roma L, Mongan NP, Rutland CS (October 2017). "Comparative review of human and canine osteosarcoma: morphology, epidemiology, prognosis, treatment and genetics". Acta Vet. Scand. 59 (1): 71. doi:10.1186/s13028-017-0341-9. PMC 5655853. PMID 29065898.
  16. ↑ Stern N, Sakji I, Defachelles AS, Lervat C, Ryckewaert T, Marliot G, Peugniez C, Deplanque D, Penel N (March 2017). "[Incidence and risk factors for ifosfamide-related encephalopathy in sarcoma patients]". Bull Cancer (in French). 104 (3): 208–212. doi:10.1016/j.bulcan.2016.11.007. PMID 27986268.
  17. ↑ Endicott AA, Morimoto LM, Kline CN, Wiemels JL, Metayer C, Walsh KM (June 2017). "Perinatal factors associated with clinical presentation of osteosarcoma in children and adolescents". Pediatr Blood Cancer. 64 (6). doi:10.1002/pbc.26349. PMID 27860191.
  18. ↑ Miller BJ, Cram P, Lynch CF, Buckwalter JA (July 2013). "Risk factors for metastatic disease at presentation with osteosarcoma: an analysis of the SEER database". J Bone Joint Surg Am. 95 (13): e89. doi:10.2106/JBJS.L.01189. PMC 3689260. PMID 23824394.
  19. ↑ Zhang HF, Yan JP, Zhuang YS, Han GQ (September 2015). "Association between angiogenic growth factor genetic polymorphisms and the risk of osteosarcoma". Genet. Mol. Res. 14 (3): 10524–9. doi:10.4238/2015.September.8.14. PMID 26400284.
  20. ↑ Osteosarcoma. U.S. Preventive Services Task Force.http://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=osteosarcoma
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  24. ↑ Parry MC, Laitinen M, Albergo J, Jeys L, Carter S, Gaston CL, Sumathi V, Grimer RJ (April 2016). "Osteosarcoma of the pelvis". Bone Joint J. 98-B (4): 555–63. doi:10.1302/0301-620X.98B4.36583. PMID 27037440.
  25. ↑ Yonemoto T, Hosono A, Iwata S, Kamoda H, Hagiwara Y, Fujiwara T, Kawai A, Ishii T (June 2015). "The prognosis of osteosarcoma occurring as second malignancy of childhood cancers may be favorable: experience of two cancer centers in Japan". Int. J. Clin. Oncol. 20 (3): 613–6. doi:10.1007/s10147-014-0729-8. PMID 25022788.
  26. ↑ Kager L, Tamamyan G, Bielack S (February 2017). "Novel insights and therapeutic interventions for pediatric osteosarcoma". Future Oncol. 13 (4): 357–368. doi:10.2217/fon-2016-0261. PMID 27651036.
  27. ↑ Cates JM (March 2017). "Comparison of the AJCC, MSTS, and Modified Spanier Systems for Clinical and Pathologic Staging of Osteosarcoma". Am. J. Surg. Pathol. 41 (3): 405–413. doi:10.1097/PAS.0000000000000774. PMID 28195881.
  28. ↑ 28.0 28.1 28.2 28.3 Biazzo A, De Paolis M (December 2016). "Multidisciplinary approach to osteosarcoma". Acta Orthop Belg. 82 (4): 690–698. PMID 29182106.
  29. ↑ Cates J (April 2018). "Modeling Continuous Prognostic Factors in Survival Analysis: Implications for Tumor Staging and Assessing Chemotherapy Effect in Osteosarcoma". Am. J. Surg. Pathol. 42 (4): 485–491. doi:10.1097/PAS.0000000000000995. PMID 29200101. Vancouver style error: initials (help)
  30. ↑ Jeys LM, Thorne CJ, Parry M, Gaston CL, Sumathi VP, Grimer JR (March 2017). "A Novel System for the Surgical Staging of Primary High-grade Osteosarcoma: The Birmingham Classification". Clin. Orthop. Relat. Res. 475 (3): 842–850. doi:10.1007/s11999-016-4851-y. PMC 5289182. PMID 27138473.
  31. ↑ Kumar R, Kumar M, Malhotra K, Patel S (February 2018). "Primary Osteosarcoma in the Elderly Revisited: Current Concepts in Diagnosis and Treatment". Curr Oncol Rep. 20 (2): 13. doi:10.1007/s11912-018-0658-1. PMID 29492676.
  32. ↑ Osteosarcoma. surgwiki. http://www.surgwiki.com/wiki/Diseases_of_bone_and_joints#SURGERY_4
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  37. ↑ Isakoff MS, Bielack SS, Meltzer P, Gorlick R (September 2015). "Osteosarcoma: Current Treatment and a Collaborative Pathway to Success". J. Clin. Oncol. 33 (27): 3029–35. doi:10.1200/JCO.2014.59.4895. PMC 4979196. PMID 26304877.
  38. ↑ Sue M, Oda T, Sasaki Y, Kameta A, Okada Y, Ogura I (2017). "Osteosarcoma of the Mandible: a Case Report with CT, MRI and Scintigraphy". Chin J Dent Res. 20 (3): 169–172. doi:10.3290/j.cjdr.a38772. PMID 28808701.
  39. ↑ Heaton TE, Hammond WJ, Farber BA, Pallos V, Meyers PA, Chou AJ, Price AP, LaQuaglia MP (January 2017). "A 20-year retrospective analysis of CT-based pre-operative identification of pulmonary metastases in patients with osteosarcoma: A single-center review". J. Pediatr. Surg. 52 (1): 115–119. doi:10.1016/j.jpedsurg.2016.10.034. PMC 5384104. PMID 27836366.
  40. ↑ Huang L, Xia W, Zhang B, Qiu B, Gao X (May 2017). "MSFCN-multiple supervised fully convolutional networks for the osteosarcoma segmentation of CT images". Comput Methods Programs Biomed. 143: 67–74. doi:10.1016/j.cmpb.2017.02.013. PMID 28391820.
  41. ↑ Xia T, Guan Y, Chen Y, Li J (July 2014). "Askin tumor: CT and FDG-PET/CT imaging findings and follow-up". Medicine (Baltimore). 93 (6): e42. doi:10.1097/MD.0000000000000042. PMC 4602428. PMID 25058144.
  42. ↑ Degnan AJ, Chung CY, Shah AJ (2018). "Quantitative diffusion-weighted magnetic resonance imaging assessment of chemotherapy treatment response of pediatric osteosarcoma and Ewing sarcoma malignant bone tumors". Clin Imaging. 47: 9–13. doi:10.1016/j.clinimag.2017.08.003. PMID 28806574.
  43. ↑ Uchiyama Y, Matsumoto K, Murakami S, Kanesaki T, Matsumoto A, Kishino M, Furukawa S (2014). "MRI in a case of osteosarcoma in the temporomandibular joint". Dentomaxillofac Radiol. 43 (2): 20130280. doi:10.1259/dmfr.20130280. PMC 4064616. PMID 24247589.
  44. ↑ Wakabayashi H, Saito J, Taki J, Hashimoto N, Tsuchiya H, Gabata T, Kinuya S (January 2016). "Triple-phase contrast-enhanced MRI for the prediction of preoperative chemotherapeutic effect in patients with osteosarcoma: comparison with (99m)Tc-MIBI scintigraphy". Skeletal Radiol. 45 (1): 87–95. doi:10.1007/s00256-015-2250-1. PMID 26385785.
  45. ↑ 45.0 45.1 Zhang X, Guan Z (June 2018). "PET/CT in the diagnosis and prognosis of osteosarcoma". Front Biosci (Landmark Ed). 23: 2157–2165. PMID 29772552.
  46. ↑ 46.0 46.1 Costelloe CM, Chuang HH, Daw NC (October 2017). "PET/CT of Osteosarcoma and Ewing Sarcoma". Semin Roentgenol. 52 (4): 255–268. doi:10.1053/j.ro.2017.04.007. PMID 28965545.
  47. ↑ 47.0 47.1 Selmic LE, Griffin LR, Nolan MW, Custis J, Randall E, Withrow SJ (2017). "Use of PET/CT and Stereotactic Radiation Therapy for the Diagnosis and Treatment of Osteosarcoma Metastases". J Am Anim Hosp Assoc. 53 (1): 52–58. doi:10.5326/JAAHA-MS-6359. PMID 27841678.
  48. ↑ Osteosarcoma. Canadian Cancer Society. http://www.cancer.ca/en/cancer-information/cancer-type/bone/diagnosis/?region=bc
  49. ↑ Bishop MW, Janeway KA, Gorlick R (February 2016). "Future directions in the treatment of osteosarcoma". Curr. Opin. Pediatr. 28 (1): 26–33. doi:10.1097/MOP.0000000000000298. PMC 4761449. PMID 26626558.
  50. ↑ Szewczyk M, Lechowski R, Zabielska K (March 2015). "What do we know about canine osteosarcoma treatment? Review". Vet. Res. Commun. 39 (1): 61–7. doi:10.1007/s11259-014-9623-0. PMC 4330401. PMID 25422073.
  51. ↑ Selmic LE, Griffin LR, Rector MH, Lafferty M, Pool R, Ehrhart NP (September 2016). "Treatment of extraskeletal osteosarcoma at a previous injection site resulting in prolonged survival in 1 dog". Can. Vet. J. 57 (9): 950–4. PMC 4982565. PMID 27587886.
  52. ↑ Swift KE, LaRue SM (March 2018). "Outcome of 9 dogs treated with stereotactic radiation therapy for primary or metastatic vertebral osteosarcoma". Vet Comp Oncol. 16 (1): E152–E158. doi:10.1111/vco.12362. PMID 29181871.
  53. ↑ Redondo A, Cruz J, Lopez-Pousa A, Barón F (December 2013). "SEOM clinical guidelines for the treatment of osteosarcoma in adults-2013". Clin Transl Oncol. 15 (12): 1037–43. doi:10.1007/s12094-013-1087-0. PMID 23907290.
  54. ↑ Gill J, Ahluwalia MK, Geller D, Gorlick R (January 2013). "New targets and approaches in osteosarcoma". Pharmacol. Ther. 137 (1): 89–99. doi:10.1016/j.pharmthera.2012.09.003. PMID 22983152.
  55. ↑ Meyers PA (2015). "Systemic therapy for osteosarcoma and Ewing sarcoma". Am Soc Clin Oncol Educ Book: e644–7. doi:10.14694/EdBook_AM.2015.35.e644. PMID 25993235.
  56. ↑ Han G, Bi WZ, Xu M, Jia JP, Wang Y (August 2016). "Amputation Versus Limb-Salvage Surgery in Patients with Osteosarcoma: A Meta-analysis". World J Surg. 40 (8): 2016–27. doi:10.1007/s00268-016-3500-7. PMID 27116252.
  57. ↑ Ma L, Zhou Y, Zhu Y, Lin Z, Wang Y, Zhang Y, Xia H, Mao C (March 2016). "3D-printed guiding templates for improved osteosarcoma resection". Sci Rep. 6: 23335. doi:10.1038/srep23335. PMC 4800413. PMID 26997197.
  58. ↑ Kamal AF, Widyawarman H, Husodo K, Hutagalung EU, Rajabto W (July 2016). "Clinical Outcome and Survival of Osteosarcoma Patients in Cipto Mangunkusumo Hospital: Limb Salvage Surgery versus Amputation". Acta Med Indones. 48 (3): 175–183. PMID 27840351.

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