Home About Journal AHEAD OF PRINT Current Issue Back Issues Instructions Submission Search Subscribe Blog    

Users Online: 722 
Print this page  Email this page Small font sizeDefault font sizeIncrease font size 

 Table of Contents    
Year : 2014  |  Volume : 48  |  Issue : 3  |  Page : 247-254
Osteosarcoma: Diagnostic dilemmas in histopathology and prognostic factors

Department of Pathology, University College of Medical Sciences, University of Delhi, Shahdra, New Delhi, India

Click here for correspondence address and email

Date of Web Publication14-May-2014


Osteosarcoma (OS), the commonest malignancy of osteoarticular origin, is a very aggressive neoplasm. Divergent histologic differentiation is common in OS; hence triple diagnostic approach is essential in all cases. 20% cases are atypical owing to lack of concurrence among clinicoradiologic and pathologic features necessitating resampling. Recognition of specific anatomic and histologic variants is essential in view of better outcome. Traditional prognostic factors of OS do stratify patients for short term outcome, but often fail to predict their long term outcome. Considering the negligible improvement in the patient outcome during the last 20 years, search for novel prognostic factors is in progress like ezrin vascular endothelial growth factor, chemokine receptors, dysregulation of various micro ribonucleic acid are potentially promising. Their utility needs to be validated by long term followup studies before they are incorporated in routine clinical practice.

Keywords: Osteosarcoma, prognostic factors, vascular endothelial growth factor, ezrin

How to cite this article:
Wadhwa N. Osteosarcoma: Diagnostic dilemmas in histopathology and prognostic factors. Indian J Orthop 2014;48:247-54

How to cite this URL:
Wadhwa N. Osteosarcoma: Diagnostic dilemmas in histopathology and prognostic factors. Indian J Orthop [serial online] 2014 [cited 2020 Feb 27];48:247-54. Available from:

   Introduction Top

Osteosarcoma (OS) is the commonest osteoarticular malignancy of nonhematopoetic origin. Conventional OS is a high grade intramedullary neoplasm, often arising in the metaphysis of long tubular bones. [1],[2] The burden of the disease at large is immense considering the young age of patients, residual disability consequent to radical surgeries and long periods of rehabilitation. [3] OS is a great histologic mimicker and poses the diagnostic challenge especially in small tissue biopsies. Triple diagnostic approach, i.e., clinical, radiological and histopathological is essential in all cases. Despite initial significant improvement in patient outcome mainly owing to preoperative systemic chemotherapy (CT) and advancements in surgical techniques, up-to 40% patients still die of the tumor. [4],[5] Patient outcome depends upon a number of variables. The search for novel prognostic markers continues in order to improve prediction of patient outcome and identify potential molecular therapeutic targets.

This review describes the approach toward diagnosis of OS including the dilemmas faced. It also stresses the need for triple diagnosis, especially in atypical cases. The prognostic factors, both traditional and novel, are also listed. PubMed search key words were identified in MeSH database. The key words used were Osteosarcoma, prognosis, diagnosis, differential, immunohistochemistry, biomarker. Articles were shortlisted by systematic search; preference was given to original articles, large series systematic reviews and meta-analyses. The search strategy used various combinations of MeSH terms mentioned above and prognosis with limits of species 'human'. The search was refined by applying limits such as article type in combination or serially. Approximately 100 article abstracts were short-listed after reading. For the purpose of citation, preference was given to full text articles, but not restricted to them alone. Case reports were included when misdiagnosis of certain histologic type was reported to emphasize the point.

Of the 82 references cited in manuscript, full text articles were accessible in 65; 17 abstracts were used.

   Diagnostic Dilemmas of Osteosarcoma Top

Osteosarcoma is a mesenchymal tumor having evidence of osteoid or bone production by malignant stromal cells in some portion of the tumor. Bizarre tumor cell morphology and divergent differentiation are common. [1],[2],[6] The histologic diagnosis of OS rests solely upon demonstration of unequivocal osteoid being laid down by malignant cells. Few specific variants of OS are peculiar in their anatomic location; others may lack obvious atypia and have subtle histologic features. Being a vivid mimicker OS may pose diagnostic challenge especially when coupled with atypical radiologic presentation, which is described in 20% of cases. [7] Peculiar sub-types of OS include surface OS, intracortical, low grade intramedullary, multicentric, secondary (e.g. postirradiation and those arising in Paget's disease). OS arising in the jaw and spine are also considered separately. [1],[2]

Demonstration of osteoid is essential to diagnosis of OS; however, the amount varies widely between tumors. The diagnosis is often straight forward in the presence of abundant osteoid; although in fibroblastic areas, it may be confused with collagen. Minimal/equivocal osteoid requires additional sections, at times resampling and hence increases laboratory turnaround time. Markers of osteoblastic differentiation such as osteocalcin, osteonectin, SATB2 have been proposed to be potentially useful in such cases. Recently, Conner and Hornick have reported their results of SATB2, an osteoblastic differentiation marker, expression in osseous and soft tissue tumors. [8] They found it to be a marker of osteoblastic differentiation in both benign and malignant tumors. They recommended its use as an adjunct in settings to make the distinction between hyalinized collagen and osteoid.

Osteosarcoma is capable of divergent differentiation. It often shows chondroid and fibrous areas besides the pathognomic osteoid deposition by malignant tumor cells. [1],[2],[6] A tumor is designated as specific subtype only when the given differentiation exceeds 50% of tumor area. [1],[2] Extensive chondroid differentiation might be confused with chondrosarcoma (CS). CS does not show osteoid deposition. They typically arise from flat bones of the trunk and proximal appendicular skeleton and present almost two decades later than OS. OS arising in the axial skeleton is uncommon and likely to be secondary. [1],[2] In a retrospective comparative analysis of 10 cases, each of histologically confirmed CS and chondroblastic OS, Yen et al. compared number of features on radiology and magnetic resonance imaging (MRI). They found chondroblastic OS to have metaphyseal tumor location (P = 0.039) and aggressive periosteal reaction (P = 0.008) and presentation at significantly younger age (mean age: 24.7 years vs. 56.7 years, P < 0.001). Some of their chondroblastic OS did have radiologic and MRI findings typical of CS and posed diagnostic challenge. [9] Cases are also on record wherein initial diagnosis of CS rendered on cytology or biopsy have been revised to OS on resection specimens. [10] Unni suggests that in an adolescent patient, chondroid tumors should be considered as chondroblastic OS unless proven otherwise. [11] As management of CS and OS are very different, there is a need of markers to distinguish them on limited tissue specimens. Immunohistochemistry (IHC) for galectin-1 has been reported to be discriminatory. Gomez-Brouchet et al. performed galectin-1 staining on 165 bone tumors and demonstrated significantly higher intensity and proportion of positivity than in OS including chondroblastic OS in comparison to CS. [12] High grade fibrous areas of OS may be mistaken for fibrosarcoma, malignant fibrous histiocytoma and sometimes fibro-osseous lesions. The diagnosis of OS hinges on demonstration of osteoid, which may require diligent search. [2] According to Dahlin differentiation between fibroblastic OS, fibrosarcoma and malignant fibrous histicytoma is arbitrary. [13] Low grade fibroblastic areas of OS may look deceptively akin to fibrous dysplasia. Periosteal reaction and destructive lesional margins are alerting radiologic features in such situations. [1]

A typical OS may be accompanied by areas rich in giant cells (giant cell rich OS), large blood filled spaces (telangiectatic OS) or small cells with minimal osteoid production (small cell OS). [1],[2],[6] These tumors are likely to be misdiagnosed as giant cell tumor (GCT) of bone, aneurysmal bone cyst and Ewing's sarcoma (EWS) respectively. Numerous giant cells obscuring malignant OS cells are a rare event. Such cases may be mistaken as GCT of bone. Demonstration of atypical tumor cells is the key to correct diagnosis. [14] Careful viewing of X-ray for location, periosteal reaction and physis plate is beneficial. OS is metaphyseal centered tumor of immature skeleton often with raised periosteum. GCT arises in the epiphysis of mature skeleton; periosteal reaction occurs in the setting of complication (biopsy/fracture). [2],[6] Telangiectatic OS has overall low cellularity and sparse osteoid production. Interrupted periosteal reaction and detection of bone matrix are helpful in establishing the correct diagnosis of telangiectatic OS. [2],[6],[15] Minimal osteoid in small cell OS makes its radiology atypical. Distinction from EWS, mesenchymal CS and lymphoma is essential. OS do not respond much to radiotherapy which is the standard treatment modality in EWS. [6] Diagnosis of OS would require demonstration of osteoid, however minimal. Positive immunostaining for galectin-1 is expected in small cell OS. [16] EWS would be decorated by CD99 and harbor translocation of EWS gene on chromosome 22. Immunostaining for leukocyte common antigen and S-100 would exclude lymphoma and mesenchymal CS respectively. [2],[6],[17]

Low grade central OS is a rare type of locally aggressive OS with limited potential for metastases. [2],[18] It shows fibrous areas with minimal atypia, small bony trabeculae with or without chondroid areas. Radiologically, it may resemble fibrous dysplasia by virtue of deceptive circumscription and lack typical features of OS. Low grade central OS with predominant bony element and minimal fibrous element may be mistaken either for osteoblastoma or peri-lesional bony trabeculae. Careful search for minimal atypia, abnormal mitoses, attention to lesional radiologic borders and periosteal reaction are helpful in preventing mis-diagnosis. [2],[6] The distinction has clinical relevance. Unless the tumor is de-differentiated, its outcome is distinctly better; 5 years survival being more than 80%. [6],[19] Unlike conventional high grade OS which have complex cytogenetic aberrations, low grade OS (both central and parosteal) specifically harbor amplification of chromosome 12q13-15 region including murine double minute type 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) leading to respective protein over-expression. Staining for MDM2 and CDK4 is hence useful in difficult cases. Positive results are seen in low grade central OS, fibrous dysplasia is typically negative. [19]

Osteosarcoma with epicenter outside bone cortex are termed surface OS. [2],[6] Different types of surface OS are parosteal OS, periosteal OS and high grade surface OS. This definition precludes medullary involvement, which is typically primary tumor site in conventional OS. These tumors arise a decade later and barring high grade surface OS have a better prognosis than conventional OS. Parosteal OS, the commonest surface OS are sclerotic lesions attached to the underlying bone. They are histologically similar to low grade central OS and share the same genetic alteration, i.e., amplification of MDM2 and CDK4 genes. [20] Sometimes they may be mistaken to be osteochondroma; lack of marrow fat, subtle anaplasia and radiologic correlation allow correct diagnosis. [21] Parosteal OS do not require CT and have distinctly better 5 year survival (>90%) with surgery alone. De-differentiation worsens prognosis and is known to occur in almost 25% cases. [6] Periosteal OS are located more toward diaphysis with fusiform periosteal involvement unlike parosteal OS which outgrow their attachment in metaphyseal region. [6],[22] Periosteal OS shows grade 2 cartilaginous matrix with small areas of osteoid deposition. It is less aggressive than conventional OS, but worse in comparison to parosteal OS. The largest series until date has reported 84% survival at 10 years. [22] Wide excision is sufficient, preoperative CT does not improve survival. High grade surface OS may arise de novo or else be de-differentiated parosteal OS. Their outcome is no better than conventional high grade OS arising from medulla. [2],[6]

   Practical Considerations Top

Tumor samples for tissue diagnosis of OS may be obtained by any one of the following ways - fine-needle aspiration (FNA), needle biopsy or open surgical biopsy. FNA is minimally invasive and cost-effective; however it is also likely to be least sensitive. Dodd et al. reviewed FNA results of 40 patients of OS accumulated over 8 years in their institution. They found the technique to have high accuracy (95%) with moderate sensitivity (65%). Inconclusive diagnoses were more likely in cases of OS variants. [23] Koscick et al. compared diagnostic performance of FNA and needle biopsy in a series of 144 cases of which 17 were primary bone tumors (excluding EWS). The diagnostic concurrence rate for osseous tumors was 59% only when compared to 73% for the entire series. [24] Other authors have reported diagnostic accuracy of needle biopsies with failure rates as low as 9.3%. [25] Obtaining needle biopsies under radiologic guidance has advantage of avoiding cystic and necrotic areas. [26] The diagnostic yield of open biopsies may be as high as 98%. [27] Hence, an open biopsy should be performed in case of conflict between radiologic and preliminary pathologic diagnoses.

   Prognostic Factors of Conventional High Grade Osteosarcoma Top

The outcome of OS patients excluding the specific histologic/anatomic types mentioned above depends upon a number of variables. These prognostic factors may be classified as traditional and novel. The need for novel prognostic factors stems from a better understanding of molecular pathways of carcinogenesis in recent times and potential therapeutic targeting.

   Traditional Prognostic Factors Top

Age at presentation

Young adults between 25 and 30 years of age fare best. [7] Patients older than 40 years have significantly poorer survival statistics than young adults even when secondary OS are excluded. [28],[29],[30],[31] In a multiinstitutional study of 86 patients of OS older than 40 years of age, Iwata et al. found that these patients were more likely to have truncal location and metastatic disease at initial presentation, factors associated with worse outcome. [28] Elderly patients, >60 years fare worst. [32],[33] Shaylor et al. followed 26 patients of OS secondary to Paget's diseases of bone. They noted rapid decline in survival from 53% at the end of 1 st year to 25% by 2 years' time; significantly no patient survived until 5 years. [33] The negative influence of increasing age on final outcome has been attributed to reduced ability to tolerate CT and often refusal for radical surgery. [29] Survival statistics in children were earlier inferior to young adults with increased risk of recurrence. [4],[7],[34] This is no longer the case.


The prognostic impact of gender on final outcome is not fully established. Male gender has been reported to be associated with poor response to CT, more likelihood of local recurrence and death (up to 4 times) and higher case fatality ratio. [30],[35],[36],[37],[38] Others have failed to document favorable prognostic association of female gender. [4],[7],[34],[39]

Serum alkaline phosphatase (AP) enzyme level

Serum AP values should be interpreted in context of age; higher values are physiologic in children and adolescents. Bacci et al. found elevated serum levels to correlate with significantly shorter event free survival (EFS). [4] It is noteworthy, that serum AP level may not be elevated at presentation in up to 50% patients. This is likely to happen in anaplastic tumors with little osteoid deposit. [2] Rise in serum AP value in postoperative period may precede clinical local recurrence and/or metastasis by months. [1],[4],[35]

Radiologic findings

Up to 20% of OS present with atypical radiologic features. Although, it may contribute to delay in diagnosis, it has not been found to have any influence on final patient outcome. [7],[39] Fracture secondary to typical OS is an uncommon event, described in <5% cases. [6],[7] Telangiectatic OS may have fracture in up to 25% cases. [2] By increasing unexpected chance of micro-metastasis, fracture is theoretically an adverse event. However, it has not been found to be an indicator of either recurrence or overall survival. [4],[40],[41]

Tumor site

Tumors arising in truncal location fare worse in comparison to those located in limbs. [7],[30],[31],[37],[40] Bielack et al. have reported significant difference in 10 years actuarial survival between groups (axial 29.2% vs. limb 61.7%, P < 0.0001). [30] OS of femur fare significantly worse when compared to those located distally in tibia. [7],[30],[42] Spinal location accounts for <5% of all OS. Sacrum followed by lumbar and thoracic segments is commonest sites of affliction. [43] Almost 2/3 rd patients of spinal tumors die within 2 years of diagnosis. [44],[45]

Gnathic OS constitute <10% OS. [1],[2] These tumors present later in life, 4-5 th decade. [46],[47] Maxilla is more likely to be involved than the mandible. They are usually considered a separate category in view of their low histologic grade, less frequent metastases and better prognosis. Female gender and chondroblastic predominance may be associated with worse prognosis. [46] Nongnathic craniofacial OS often arise in the background of head and neck irradiation or Paget's disease in elderly individuals. [6]

Tumor burden

Bulky tumors have worse outcomes than smaller ones. [4],[30],[36],[37],[48],[49] Primary tumor burden may be expressed either as tumor size or volume as determined on preoperative radiologic investigation. [50],[51] Petrilli et al. found the risk of death to be 3.4 times higher when tumor diameter exceeds 15 cm. [36] Gobel's criteria are followed widely to calculate tumor volume. [51] However, collapse and/or displacement in the setting of pathologic fracture may lead to inaccurate tumor measurements. Tumors with volume exceeding 150-200 mL have significantly less likelihood of limb salvage, poor response to CT and increased risk of recurrence. [4],[30],[37] Up to 20% OS patients have evidence of metastases at their initial presentation. The risk of mortality is significantly more in those with metastases at initial presentation. [30],[31],[38],[41],[52],[53] They are also likely to have shorter EFS than their counterparts with limited disease. [28],[41] Some authors do not consider stage at presentation as a prognostic factor, rather a consequence of other poor prognostic factors. [7]


The impact of histology on patient outcome is modest. [48] Fibroblastic differentiation has been considered better prognostic histology. It has been reported to be a significant predictor of CT related necrosis and associated with lower risk of death (bordering statistical significance) than other histologic sub-types. [4],[7] Worse outcome in chondroid predominant tumors has been noted by some authors. [29],[38] Telangiectatic OS no longer denotes inferior prognosis. It is especially sensitive to CT given its high cell turn over and increased vascularity. [15]

Response to preoperative chemotherapy

Systemic CT is warranted in almost all cases of OS. It is an important therapeutic strategy to reduce tumor bulk, make surgical procedure easier, better the chance of limb salvage, improve opportunity to obtain tumor free margin, increase the number eligible patients for conservative treatment and targeting of micrometastases. [4],[5],[30],[37],[42],[48] It is a consistently strong prognostic factor besides stage at presentation. The response may be assessed either radiologically immediately preceding surgery and/or by histologic examination of the resected specimen. Radiologic methods have the advantage of being noninvasive, guiding the type of surgery, modification and/or addition of postoperative CT. However hematomas, fibrosis could be mistaken for residual tumor itself. [42]

Histologic assessment is the most accurate method to determine response to preoperative CT. Tumor mapping is performed to assess percentage area occupied by necrosis and viable malignant cells. Huvos criteria (>90% necrosis-good response) is most commonly followed. [54],[55],[56],[57] Poor response is a strong predictor of local recurrence, metastases and overall survival. [28],[30],[31],[37],[41],[50],[55] The preferential sites where viable malignant cells are most likely to persist include soft tissues, cortex, sub-cortex, ligaments and areas in contact with cartilage. [57] Response to preoperative CT correlates significantly with tumor volume, probably with histologic type but not with anatomic location. [4],[6]

Combinational prognostic indices

In view of rather limited predictive power of individual prognostic factors, many authors have attempted to improve prognostication by constructing combinational prognostic model. Using combination of age, anatomic location, symptom duration and histology, Bentzen et al. were able to stratify their patients (n = 184) into three different survival groups. [7] The group with best outcome (estimated 10 years survival 79%) had all favorable factors (age 25-35 years, distal extremity, symptoms >6 months and fibroblastic histology). Poor outcome (estimated 10 years survival 8%) was predicted when all adverse factors (elderly age, trunk/proximal appendicular location, short symptom interval and nonfibroblastic histology) occurred together. Typical cases (having admixed prognostic factors) had intermediate outcome (estimated 10 years survival 29%). Petrilli et al. stratified Brazilian patients of OS into different death risk categories based upon multivariate analysis of various prognostic factors. The relative risk of death of a male patient with >15 cm OS was more than 2.0 times when compared to a female patient with smaller tumour. [36]

Outcome after development of relapse

Introduction of preoperative CT in OS has resulted in strikingly fewer metastases and longer EFS. Despite preoperative CT, more than one third of conventional OS eventually relapse. Lungs, often with bilateral involvement are the commonest site of metastases followed by bones. The reported median time of relapse and number of metastatic lesions are 13-15 months and three respectively. [58],[59] The final outcome after development of metastases depends upon number of lesions, time interval, success of metastatectomy surgery and adequacy of salvage CT. The chances of achieving complete second remission are higher with solitary metastatic lesion, disease free interval more than 24 months and accomplishment of complete metastatectomy. [58],[59] Patients with local recurrence with/without metastasis tend to fare worse than those with metastasis alone. [4],[50]

Incorporation of preoperative CT in management of OS (in 1980s) was a landmark event. It dramatically improved 5 years survival figures from 15% to 20% to above 60%. However, further advances in treatment of OS have been modest at best. [5],[49] Pulmonary metastases remain the most common cause of death. Better understanding of tumor biology and metastasis is essential to improve both EFS and overall survival. [3],[49],[60],[61] Experimental models allow valuable insight into carcinogenesis and identify novel prognostic and therapeutic targets.

Emerging prognostic factors (novel)


Ezrin is a cytoskeleton linker protein with diverse functions. It is involved in cell to cell interaction, cell to matrix adhesion and signal transduction. [62] Dysregulation of ezrin has been implicated in metastasis of various cancers including OS. Salas et al. compared ezrin expression by IHC in primary tumors (37) to metastases (13). They found the protein expression to be higher in metastases than the corresponding primary tumours. [63] Two meta-analyses on prognostic significance of ezrin expression in OS were published recently. [62],[64] Li et al. and Wang et al. found only 5 and 7 original studies to be eligible for evaluation from 54 to 23 published works respectively. Majority of analyzed studies had used 1% cut-off criteria on IHC. Both meta-analyses concluded ezrin expression in OS tumor cells to be an independent factor predictive of death at 2 years, but not of EFS. Its association with AP levels and histologic response to CT were found to be insignificant. In an animal model, Pignochino et al. studied effect of Sorafenib, a multikinase inhibitor drug on OS cell proliferation and potential for lung metastases. They found the treatment to dramatically reduce tumor volume and its ability for lung metastases. [65]


P53 is a protein product of a tumor suppressor gene. Patients carrying germline mutations of p53 are at significantly higher risk of developing OS than general population. [66] Fu et al. analyzed results of 609 sporadic cases of OS pooled from 15 studies in relation to p53 protein expression. They found significantly reduced overall survival (odds ratio = 0.29, P < 0.001) and disease free survival (odds ratio = 0.06, P < 0.001) of patients with up-regulated p53 expression in comparison to those with low or undetectable expression. They concluded that p53 was an effective biomarker of survival in patients of OS and suggested more studies with large sample size to identify the effect of p53 expression in OS. [67]

Vascular endothelial growth factor

Vascular endothelial growth factor is a key regulator of angiogenesis, an event essential to all cancers and metastases. Kaya et al. investigated the impact of VEGF expression as determined by IHC on patient outcome. Of the 27 cases, 15 developed pulmonary metastases. The distribution of cases was 14/17 and 1/10 of VEGF positive and negative cases respectively. [68] Recent meta-analyses on prognostic significance of VEGF expression in OS have also shown VEGF expression to have adverse prognostic impact on both disease free and overall survival at 5 years. [69],[70] Clinical trials exploring endostatin as a candidate for anti angiogenic therapy have yielded encouraging results. Xu et al. compared outcome of 54 OS patients receiving intravenous endostatain in combination with four cycles of CT to 62 cases who received CT alone. The treated group had increased EFS and decreased occurrence of metastases; however overall survival was not affected. They concluded that anti angiogenic therapy using endostatin had potential to prevent progression of metastases. [71]

Chemokines and chemokine receptors

Chemokines are small peptides, initially identified as molecules mediating communication between various types of leukocytes through G-protein coupled receptors. Chemokine receptor, CXCR4 has been implicated in determining metastatic destination of tumor cells. [72] Laverdiere et al. estimated messenger ribonucleic acid (RNA) expression levels of CXCR4 and CCR7 in 47 OS patients and sake its correlation with patient outcome. CXCR4 and CCR7 were expressed in 63% and 43% cases respectively. Levels of both showed correlated inversely with overall survival (P < 0.0001 and P < 0.03 respectively) and metastasis free survival (P = 0.002 and P = 0.007 respectively). In addition, CXCR4 expression correlated with advanced stage at presentation and poor EFS (P < 0.001). [73] Kim et al. tested CTCE-9908, a small CXCR4 antagonist in two murine OS metastases models. The test group had 50% reduction in number of gross metastatic nodules and a marked reduction in micro-metastatic disease compared to controls. [74]

Micro ribonucleic acid (miRNA)

These are small fragments of noncoding RNA, which act at posttranscriptional level and hence regulate numerous important cell functions. [75] Depending upon their function, their effects may be classified as either oncogenic or tumor suppressive (increased or decreased respectively in malignancy). [76] Up-to 22 miRNAs have been found to be up-regulated in OS cell lines and human tissues and almost equal number have been found to down-regulated. Some miRNAs have also been implicated in drug resistance. The testimony to their involvement in OS lies in development of several experimental therapeutic strategies aimed to block oncogenic miRNA or use mimics of tumor suppressive miRNA. [77]

Other emerging novel prognostic markers in osteosarcoma

Genome wide expression studies and proteomics have identified differential expression of several genes and proteins in OS. Up-regulated proteins include growth factors, their receptors, enzymes and others involved in various cellular functions. [3],[60],[61] Few examples of such identified markers are up-regulation of enzyme matrix metalloproteinase 2, cycloxygenase 2 enzyme expression, insulin like growth factor receptor type 1 and RANK-L expression, all associated with inferior outcome. [3],[60],[61],[78],[79],[80] Research is also ongoing to determine markers of poor response to CT, an indirect measure of outcome. Polymorphism of endothelin-1 and peroxiredoxin2 expression has been found to be associated with increased risk of chemo-resistance to OS. [81],[82]

To conclude, OS is a great mimicker capable of posing diagnostic challenge to all, i.e., surgeons, radiologists and pathologists alike. Any case which fails to show concurrence between triple diagnostic approaches should be viewed with suspicion. Prognosis of conventional high grade OS remains grim, especially in those who present with metastases. Molecular techniques permit detailed analysis of cellular pathways at play in OS carcinogenesis and offer scope of identifying novel prognostic markers and therapeutic targets. Of the many new markers currently under investigation, few have shown promising results and likely to be clinically useful in future.

   References Top

1.Mirra JM, Gold RH, Picci P. Osseous tumors of intranedullary origin. In: Mirra JM, Picci P, Gold RH, editors. Bone Tumors. Clinical, Radiologic and Pathologic Correlations. Philadelphia: Lea and Febiger Publishers; 1989. p. 143-438.  Back to cited text no. 1
2.Fechner RE, Mills SE. Atlas of Tumor Pathology. Tumors of the Bones and Joints. Washington DC: Armed Forces Institute of Pathology; 1992.  Back to cited text no. 2
3.Broadhead ML, Clark JC, Myers DE, Dass CR, Choong PF. The molecular pathogenesis of osteosarcoma: A review. Sarcoma 2011;2011:959248.  Back to cited text no. 3
4.Bacci G, Longhi A, Versari M, Mercuri M, Briccoli A, Picci P. Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer 2006;106:1154-61.  Back to cited text no. 4
5.Allison DC, Carney SC, Ahlmann ER, Hendifar A, Chawla S, Fedenko A, et al. A meta-analysis of osteosarcoma outcomes in the modern medical era. Sarcoma 2012;2012:704872.  Back to cited text no. 5
6.Klein MJ, Siegal GP. Osteosarcoma: Anatomic and histologic variants. Am J Clin Pathol 2006;125:555-81.  Back to cited text no. 6
7.Bentzen SM, Poulsen HS, Kaae S, Jensen OM, Johansen H, Mouridsen HT, et al. Prognostic factors in osteosarcomas. A regression analysis. Cancer 1988;62:194-202.  Back to cited text no. 7
8.Conner JR, Hornick JL. SATB2 is a novel marker of osteoblastic differentiation in bone and soft tissue tumours. Histopathology 2013;63:36-49.  Back to cited text no. 8
9.Yen CH, Chang CY, Teng MM, Wu HT, Chen PC, Chiou HJ, et al. Different and identical features of chondroblastic osteosarcoma and chondrosarcoma: Highlights on radiography and magnetic resonance imaging. J Chin Med Assoc 2009;72:76-82.  Back to cited text no. 9
10.Akpolat N, Yildirim H, Poyraz K. Sacral chondroblastic osteosarcoma misdiagnosed as chondrosarcoma and chordoma. Turk J Med Sci 2007;37:243-9.  Back to cited text no. 10
11.Unni KK. Cartilaginous lesions of bone. J Orthop Sci 2001;6:457-72.  Back to cited text no. 11
12.Gomez-Brouchet A, Mourcin F, Gourraud PA, Bouvier C, De Pinieux G, Le Guelec S, et al. Galectin-1 is a powerful marker to distinguish chondroblastic osteosarcoma and conventional chondrosarcoma. Hum Pathol 2010;41:1220-30.  Back to cited text no. 12
13.Unni KK, Inwards CY. Fibrosarcoma and desmoplastic fibroma. In: Dahlin′s Bone Tumors: General Aspects and Data on 10,165 Cases. 6 th ed. Republic of China: Lippincott Williams and Wilkins; 2010. p. 169-78.  Back to cited text no. 13
14.Wang CS, Yin QH, Liao JS, Lou JH, Ding XY, Zhu YB. Giant cell-rich osteosarcoma in long bones: Clinical, radiological and pathological features. Radiol Med 2013;118:1324-34.  Back to cited text no. 14
15.Liu JJ, Liu S, Wang JG, Zhu W, Hua YQ, Sun W, et al. Telangiectatic osteosarcoma: A review of literature. Onco Targets Ther 2013;6:593-602.  Back to cited text no. 15
16.Machado I, López Guerrero JA, Navarro S, Mayordomo E, Scotlandi K, Picci P, et al. Galectin-1 (GAL-1) expression is a useful tool to differentiate between small cell osteosarcoma and Ewing sarcoma. Virchows Arch 2013;462:665-71.  Back to cited text no. 16
17.D′cruze L, Dutta R, Rao S, Anuradha R, Varadarajan S, Kuruvilla S. The role of immunohistochemistry in the analysis of the spectrum of small round cell tumours at a tertiary care centre. J Clin Diagn Res 2013;7:1377-82.  Back to cited text no. 17
18.Puri A, Jaffe N, Gelderblom H. Osteosarcoma: Lessons learned and future avenues. Sarcoma 2013;2013:641687.  Back to cited text no. 18
19.Dujardin F, Binh MB, Bouvier C, Gomez-Brouchet A, Larousserie F, Muret Ad, et al. MDM2 and CDK4 immunohistochemistry is a valuable tool in the differential diagnosis of low-grade osteosarcomas and other primary fibro-osseous lesions of the bone. Mod Pathol 2011;24:624-37.  Back to cited text no. 19
20.Yoshida A, Ushiku T, Motoi T, Shibata T, Beppu Y, Fukayama M, et al. Immunohistochemical analysis of MDM2 and CDK4 distinguishes low-grade osteosarcoma from benign mimics. Mod Pathol 2010;23:1279-88.  Back to cited text no. 20
21.Papathanassiou ZG, Alberghini M, Thiesse P, Gambarotti M, Bianchi G, Tranfaglia C, et al. Parosteal osteosarcoma mimicking osteochondroma: A radio-histologic approach on two cases. Clin Sarcoma Res 2011;1:2.  Back to cited text no. 21
22.Cesari M, Alberghini M, Vanel D, Palmerini E, Staals EL, Longhi A, et al. Periosteal osteosarcoma: A single-institution experience. Cancer 2011;117:1731-5.  Back to cited text no. 22
23.Dodd LG, Scully SP, Cothran RL, Harrelson JM. Utility of fine-needle aspiration in the diagnosis of primary osteosarcoma. Diagn Cytopathol 2002;27:350-3.  Back to cited text no. 23
24.Koscick RL, Petersilge CA, Makley JT, Abdul-Karim FW. CT-guided fine needle aspiration and needle core biopsy of skeletal lesions. Complementary diagnostic techniques. Acta Cytol 1998;42:697-702.  Back to cited text no. 24
25.van der Bijl AE, Taminiau AH, Hermans J, Beerman H, Hogendoorn PC. Accuracy of the Jamshidi trocar biopsy in the diagnosis of bone tumors. Clin Orthop Relat Res 1997;334:233-43.  Back to cited text no. 25
26.Tsukushi S, Nishida Y, Yamada Y, Yoshida M, Ishiguro N. CT-guided needle biopsy for musculoskeletal lesions. Arch Orthop Trauma Surg 2010;130:699-703.  Back to cited text no. 26
27.den Heeten GJ, Oldhoff J, Oosterhuis JW, Schraffordt Koops H. Biopsy of bone tumours. J Surg Oncol 1985;28:247-51.  Back to cited text no. 27
28.Iwata S, Ishii T, Kawai A, Hiruma T, Yonemoto T, Kamoda H, et al. Prognostic factors in elderly osteosarcoma patients: A multiinstitutional retrospective study of 86 cases. Ann Surg Oncol 2014;21:263-8.  Back to cited text no. 28
29.Grimer RJ, Cannon SR, Taminiau AM, Bielack S, Kempf-Bielack B, Windhager R, et al. Osteosarcoma over the age of forty. Eur J Cancer 2003;39:157-63.  Back to cited text no. 29
30.Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: An analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 2002;20:776-90.  Back to cited text no. 30
31.Pakos EE, Nearchou AD, Grimer RJ, Koumoullis HD, Abudu A, Bramer JA, et al. Prognostic factors and outcomes for osteosarcoma: An international collaboration. Eur J Cancer 2009;45:2367-75.  Back to cited text no. 31
32.Hansen MF, Seton M, Merchant A. Osteosarcoma in Paget′s disease of bone. J Bone Miner Res 2006;21 Suppl 2:P58-63.  Back to cited text no. 32
33.Shaylor PJ, Peake D, Grimer RJ, Carter SR, Tillman RM, Spooner D. Paget′s Osteosarcoma-no Cure in Sight. Sarcoma 1999;3:191-2.  Back to cited text no. 33
34.Ferrari S, Bertoni F, Mercuri M, Picci P, Giacomini S, Longhi A, et al. Predictive factors of disease-free survival for nonmetastatic osteosarcoma of the extremity: An analysis of 300 patients treated at the Rizzoli Institute. Ann Oncol 2001;12:1145-50.  Back to cited text no. 34
35.Scranton PE Jr, DeCicco FA, Totten RS, Yunis EJ. Prognostic factors in osteosarcoma. A review of 20 year′s experience at the University of Pittsburgh Health Center Hospitals. Cancer 1975;36:2179-91.  Back to cited text no. 35
36.Petrilli AS, Gentil FC, Epelman S, Lopes LF, Bianchi A, Lopes A, et al. Increased survival, limb preservation, and prognostic factors for osteosarcoma. Cancer 1991;68:733-7.  Back to cited text no. 36
37.Smeland S, Müller C, Alvegard TA, Wiklund T, Wiebe T, Björk O, et al. Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: Prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders. Eur J Cancer 2003;39:488-94.  Back to cited text no. 37
38.Szendroi M, Pápai Z, Koós R, Illés T. Limb-saving surgery, survival, and prognostic factors for osteosarcoma: The Hungarian experience. J Surg Oncol 2000;73:87-94.  Back to cited text no. 38
39.Petrilli AS, de Camargo B, Filho VO, Bruniera P, Brunetto AL, Jesus-Garcia R, et al. Results of the Brazilian Osteosarcoma Treatment Group Studies III and IV: Prognostic factors and impact on survival. J Clin Oncol 2006;24:1161-8.  Back to cited text no. 39
40.Zuo D, Zheng L, Sun W, Hua Y, Cai Z. Pathologic fracture does not influence prognosis in stage IIB osteosarcoma: A case-control study. World J Surg Oncol 2013;11:148.  Back to cited text no. 40
41.Colomina J, Peiro A, Trullols L, Garcia I. Telangiectatic osteosarcoma. J Orthop Surg (Hong Kong) 2013;21:96-9.  Back to cited text no. 41
42.Miwa S, Takeuchi A, Shirai T, Taki J, Yamamoto N, Nishida H, et al. Prognostic value of radiological response to chemotherapy in patients with osteosarcoma. PLoS One 2013;8:e70015.  Back to cited text no. 42
43.Katonis P, Datsis G, Karantanas A, Kampouroglou A, Lianoudakis S, Licoudis S, et al. Spinal osteosarcoma. Clin Med Insights Oncol 2013;7:199-208.  Back to cited text no. 43
44.Feng D, Yang X, Liu T, Xiao J, Wu Z, Huang Q, et al. Osteosarcoma of the spine: Surgical treatment and outcomes. World J Surg Oncol 2013;11:89.  Back to cited text no. 44
45.Mukherjee D, Chaichana KL, Gokaslan ZL, Aaronson O, Cheng JS, McGirt MJ. Survival of patients with malignant primary osseous spinal neoplasms: Results from the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2003. J Neurosurg Spine 2011;14:143-50.  Back to cited text no. 45
46.Paparella ML, Olvi LG, Brandizzi D, Keszler A, Santini-Araujo E, Cabrini RL. Osteosarcoma of the jaw: An analysis of a series of 74 cases. Histopathology 2013;63:551-7.  Back to cited text no. 46
47.van den Berg H, Schreuder WH, de Lange J. Osteosarcoma: A comparison of jaw versus nonjaw localizations and review of the literature. Sarcoma 2013;2013:316123.  Back to cited text no. 47
48.Dai X, Ma W, He X, Jha RK. Review of therapeutic strategies for osteosarcoma, chondrosarcoma, and Ewing′s sarcoma. Med Sci Monit 2011;17:RA177-190.  Back to cited text no. 48
49.Osborne TS, Khanna C. A review of the association between osteosarcoma metastasis and protein translation. J Comp Pathol 2012;146:132-42.  Back to cited text no. 49
50.Jeon DG, Song WS, Kong CB, Cho WH, Cho SH, Lee JD, et al. Role of surgical margin on local recurrence in high risk extremity osteosarcoma: A case-controlled study. Clin Orthop Surg 2013;5:216-24.  Back to cited text no. 50
51.Göbel V, Jürgens H, Etspüler G, Kemperdick H, Jungblut RM, Stienen U, et al. Prognostic significance of tumor volume in localized Ewing′s sarcoma of bone in children and adolescents. J Cancer Res Clin Oncol 1987;113:187-91.  Back to cited text no. 51
52.Durnali A, Alkis N, Cangur S, Yukruk FA, Inal A, Tokluoglu S, et al. Prognostic factors for teenage and adult patients with high-grade osteosarcoma: An analysis of 240 patients. Med Oncol 2013;30:624.  Back to cited text no. 52
53.Miwa S, Takeuchi A, Ikeda H, Shirai T, Yamamoto N, Nishida H, et al. Prognostic value of histological response to chemotherapy in osteosarcoma patients receiving tumor-bearing frozen autograft. PLoS One 2013;8:e71362.  Back to cited text no. 53
54.Huvos AG, Rosen G, Marcove RC. Primary osteogenic sarcoma: Pathologic aspects in 20 patients after treatment with chemotherapy en bloc resection, and prosthetic bone replacement. Arch Pathol Lab Med 1977;101:14-8.  Back to cited text no. 54
55.Rosen G, Marcove RC, Caparros B, Nirenberg A, Kosloff C, Huvos AG. Primary osteogenic sarcoma: The rationale for preoperative chemotherapy and delayed surgery. Cancer 1979;43:2163-77.  Back to cited text no. 55
56.Bacci G, Mercuri M, Longhi A, Ferrari S, Bertoni F, Versari M, et al. Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with nonmetastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution. Eur J Cancer 2005;41:2079-85.  Back to cited text no. 56
57.Picci P, Bacci G, Campanacci M, Gasparini M, Pilotti S, Cerasoli S, et al. Histologic evaluation of necrosis in osteosarcoma induced by chemotherapy. Regional mapping of viable and nonviable tumor. Cancer 1985;56:1515-21.  Back to cited text no. 57
58.Saeter G, Høie J, Stenwig AE, Johansson AK, Hannisdal E, Solheim OP. Systemic relapse of patients with osteogenic sarcoma. Prognostic factors for long term survival. Cancer 1995;75:1084-93.  Back to cited text no. 58
59.Hawkins DS, Arndt CA. Pattern of disease recurrence and prognostic factors in patients with osteosarcoma treated with contemporary chemotherapy. Cancer 2003;98:2447-56.  Back to cited text no. 59
60.PosthumaDeBoer J, Witlox MA, Kaspers GJ, van Royen BJ. Molecular alterations as target for therapy in metastatic osteosarcoma: A review of literature. Clin Exp Metastasis 2011;28:493-503.  Back to cited text no. 60
61.Yang J, Zhang W. New molecular insights into osteosarcoma targeted therapy. Curr Opin Oncol 2013;25:398-406.  Back to cited text no. 61
62.Li H, Min D, Zhao H, Wang Z, Qi W, Zheng S, et al. The prognostic role of ezrin immunoexpression in osteosarcoma: A meta-analysis of published data. PLoS One 2013;8:e64513.  Back to cited text no. 62
63.Salas S, Bartoli C, Deville JL, Gaudart J, Fina F, Calisti A, et al. Ezrin and alpha-smooth muscle actin are immunohistochemical prognostic markers in conventional osteosarcomas. Virchows Arch 2007;451:999-1007.  Back to cited text no. 63
64.Wang Z, He ML, Zhao JM, Qing HH, Wu Y. Meta-analysis of associations of the ezrin gene with human osteosarcoma response to chemotherapy and prognosis. Asian Pac J Cancer Prev 2013;14:2753-8.  Back to cited text no. 64
65.Pignochino Y, Grignani G, Cavalloni G, Motta M, Tapparo M, Bruno S, et al. Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways. Mol Cancer 2009;8:118.  Back to cited text no. 65
66.Ognjanovic S, Olivier M, Bergemann TL, Hainaut P. Sarcomas in TP53 germline mutation carriers: A review of the IARC TP53 database. Cancer 2012;118:1387-96.  Back to cited text no. 66
67.Fu HL, Shao L, Wang Q, Jia T, Li M, Yang DP. A systematic review of p53 as a biomarker of survival in patients with osteosarcoma. Tumour Biol 2013;34:3817-21.  Back to cited text no. 67
68.Kaya M, Wada T, Akatsuka T, Kawaguchi S, Nagoya S, Shindoh M, et al. Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis. Clin Cancer Res 2000;6:572-7.  Back to cited text no. 68
69.Chen D, Zhang YJ, Zhu KW, Wang WC. A systematic review of vascular endothelial growth factor expression as a biomarker of prognosis in patients with osteosarcoma. Tumour Biol 2013;34:1895-9.  Back to cited text no. 69
70.Qu JT, Wang M, He HL, Tang Y, Ye XJ. The prognostic value of elevated vascular endothelial growth factor in patients with osteosarcoma: A meta-analysis and systemic review. J Cancer Res Clin Oncol 2012;138:819-25.  Back to cited text no. 70
71.Xu M, Xu CX, Bi WZ, Song ZG, Jia JP, Chai W, et al. Effects of endostar combined multidrug chemotherapy in osteosarcoma. Bone 2013;57:111-5.  Back to cited text no. 71
72.Liao YX, Zhou CH, Zeng H, Zuo DQ, Wang ZY, Yin F, et al. The role of the CXCL12-CXCR4/CXCR7 axis in the progression and metastasis of bone sarcomas (Review). Int J Mol Med 2013;32:1239-46.  Back to cited text no. 72
73.Laverdiere C, Hoang BH, Yang R, Sowers R, Qin J, Meyers PA, et al. Messenger RNA expression levels of CXCR4 correlate with metastatic behavior and outcome in patients with osteosarcoma. Clin Cancer Res 2005;11:2561-7.  Back to cited text no. 73
74.Kim SY, Lee CH, Midura BV, Yeung C, Mendoza A, Hong SH, et al. Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases. Clin Exp Metastasis 2008;25:201-11.  Back to cited text no. 74
75.Poos K, Smida J, Nathrath M, Maugg D, Baumhoer D, Korsching E. How microRNA and transcription factor co-regulatory networks affect osteosarcoma cell proliferation. PLoS Comput Biol 2013;9:e1003210.  Back to cited text no. 75
76.Zhou G, Shi X, Zhang J, Wu S, Zhao J. MicroRNAs in osteosarcoma: From biological players to clinical contributors, a review. J Int Med Res 2013;41:1-12.  Back to cited text no. 76
77.Miao J, Wu S, Peng Z, Tania M, Zhang C. MicroRNAs in osteosarcoma: Diagnostic and therapeutic aspects. Tumour Biol 2013;34:2093-8.  Back to cited text no. 77
78.Salinas-Souza C, De Oliveira R, Alves MT, Garcia Filho RJ, Petrilli AS, Toledo SR. The metastatic behavior of osteosarcoma by gene expression and cytogenetic analyses. Hum Pathol 2013;44:2188-98.  Back to cited text no. 78
79.Wen X, Liu H, Yu K, Liu Y. Matrix metalloproteinase 2 expression and survival of patients with osteosarcoma: A meta-analysis. Tumour Biol 2014;35:845-8.  Back to cited text no. 79
80.Jiao G, Ren T, Lu Q, Sun Y, Lou Z, Peng X, et al. Prognostic significance of cyclooxygenase-2 in osteosarcoma: A meta-analysis. Tumour Biol 2013;34:2489-95.  Back to cited text no. 80
81.Zhou Y, Liu B, Wang M, Ni J. Endothelin-1 gene polymorphisms and risk of chemoresistant pediatric osteosarcoma. Pediatr Blood Cancer 2014;61:612-7.  Back to cited text no. 81
82.Kubota D, Mukaihara K, Yoshida A, Tsuda H, Kawai A, Kondo T. Proteomics study of open biopsy samples identifies peroxiredoxin 2 as a predictive biomarker of response to induction chemotherapy in osteosarcoma. J Proteomics 2013;91:393-404.  Back to cited text no. 82

Correspondence Address:
Neelam Wadhwa
Department of Pathology, University College of Medical Sciences, University of Delhi, Shahdra, New Delhi - 110 095
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-5413.132497

Rights and Permissions


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  

    Diagnostic Dilem...
    Practical Consid...
    Prognostic Facto...
    Traditional Prog...

 Article Access Statistics
    PDF Downloaded266    
    Comments [Add]    

Recommend this journal